Document 6Bzan9xZn1QmrGD5jy8Jgo4nd

II MI TECHNICAL REVIEW OF THE HEALTH EFFECTS OF PC* &T Robart C. Jam. Ph.D. Morrti F. Cranmar, Ph.D. Raymond D. Hartaion. Ph.D, August 17,1981 ecology and environment, inc. 19S SUGG NOAO. A 0 .80X0 BUFFALO NSW YONK1432S. TIL 71M33-4M1 Smcimii hi ih* Environsmil Semes* rtercMdpipfi HONS 213150 CONTENTS Executive Sueeary ................................................................................................... I 1. Phytic* 1 ChaeicalProperties ........................................................................ 6 2. Production tad Uses ........................................................................................ 7 3. Occurrence ............................................................................................................. 3.1. Air................................................................................................................. 3.2. Water.............................................................................................................. 9 3.3. Soil*.............................................................................................................. 10 3.A. Marine Organises........................................................................................ 10 3.3. Pith tad Other Aquatic Organises. ................................................ 10 3.A. Birds............................................................................................................. 10 3.7. Man................................................................................................................. 11 3.8. Food............................................................................................................... U 3.9. Sueenry of Occurrence............................................................................... 11 A. Anieal Studies . ....................................................................................... 12 4.1. PhaxMcokinetica aad Metabolise............................................................ 12 4.2. Acute A Subchronic Toxicity.................................................................... IS 4.3. PCS Coatsaiaeats........................ ................................................................ 17 3. ttutagaaielty . .......................................................................... IS t: taproduction ......................................................................................................... 19 7. Birth Defects ...."......................... 20 S. Carcinogenicity ......................................................................................... 21 8.1. Whet Mechanises Provide forthe Expression of Carcinogenicityor Oncogenicity? ...................................................... 22 Contents HONS 213151 1.2. Coaparisoa of the Characteristics of Oncogens ird Effects ef pci* .............................................................................................................. :s 4.3. Casparison of the Charsetoris tics of Carcinogens sad the Effects of PCS* ..................... 29 1.4. tfhst Has Boon Characterised ss Csacor In TheHoaaeay Literature? ...................................................................................................... 20 0.5. Cholaagsofibrosia CAdsaofibrosis)....................................................... jj. 0.4, Foci or Area* of Cellular Alteration................................................... ji 4.7. Neoplaisle Nodules..................................................................................... 32 0.4. Hepatocellular Caresnons. ............................................. 3s 4.9. What Lovol of CoBfidonc* Can b* Placed on Liver Tuaors? .... 35 4.10. PCI Oncogenicity sad Related Studio*................................................. 57 0.11. Tuaor Initiation Modification..................................................................44 4.12. tnmaosuppeeasive Effects onTuaor Celle...............................................50 0.15. Are Chlorinated Hydrocarbon*Different? .................................... 51 4.14, Carcinogenicity Suanary- ................................................................ 53 0.LS. CoacluaioB............................................................................................................ 53 9. Efface* of PCI* ia Kuaaaa ................................................................................. 54 9.1. Suiseary of Kumb Health Effects............................................................. 59 10. Suaaary tad Cone In* ion ..................................................................................... 40 11. List of Table* 61 Table 1 - laoaara of PCS* a Table 2 * Physical Propertie* of Cooaercial PCS* Table 3 * Cad Use* of Aroclor* by Type Table 4 PCS* ia Food Table 5 * Toxicity Rating Chart Table 6 * Actual Toxicity and th* Toxicity Rating Chart of Sosa Selected Contents HONS 213152 ChmaicAls Tablm 7 Conor*! Symptom* of "Tuaho" Patiant* TibU 8 tuaorigooie Effet* of PCI* 12. List of Flguraa Figaro 1 Chomical Structur* of PCI Roforoncoo Glossary Biographical Information on the Author* Contanta HONS 2U1S3 EXECUTIVE SUMMARY Th* Fd eniasl toxicity literature documents chat acute Mpeturai to Fda pro duce relatively uaraaerkable acuta eexic reeponsea. OtiUtacioe af stan dardised critaria results in PCBe acuta toxicity being classified u only slightly toxic eo aou-taxie (Table 3). This ranking ii baa ad in part on tba fact that doses required to product abort term banful affecta la aout eaae apaclaa art ao high that a doaa predicted to product aiailar affacca La a uaa would axetad 1 quart. Bovavar, aa ii often th* caaa with many otbmr balegaoatad organic chamieala, additional concern ia'justifiable beccuaa of ubiquitoua diatribution (Table 4) and potential to eeuee long-term affecta vitb freedona of the individual deaea necessary to produce acute exposure. The dieproportinnate concern vitb long-tare lev-level exposures ia primarily due to biolngicel and ecological, per listener mi aectaulatieo in tba body fat. Tba primary bunas health and environmental concerns relate to long-term, low leveL exposures- Tba total apactrun of asimal cadi bumca toxic r aspens as auat be consideaad and related- to anticipated human exposure before tba extant of haaerda eaeoeiatad vitb any given expoeura to pcia can be estlaeted or documented, dll available date on the toxielty of PCI* to aninala have bean raviovad tad compered vitb carefully documented cases ef human expoeura. k pattern of com* potable, cooperative toxicity merges. Mutual expression of most human end animal reapontes enhance* the relevance ef comparative toxicological eonciuticna and generalizations which are necessary before extrapolating from poet experi ence to possible hazards or margin* of safety associated with future exposure to HONS 213ISA 1 PCS*. The following paragraphs briefly suaosrixe the date reviewed end taoee component! of the dec* eophatited in the even cue! eetieaciou of the hazard posed by exposure to PCS*. The effect* of PCI* can include acne form lesions, heir Iom, e levered imune response, liver daasga and death (Table 7). The severity of the observed re sponse* is not unusual or inconsistent with toxic dose* of most chemical* and unremarkable when compered to many useful chemicals or drugs. PCI* yield negative eutagenic results is tbs See* Teat (eeasure of eueageaic po tential at the geo* level) and tbe doeiaaat lethal teat (ceet far heritable danege leading to anbryotoxieiey and birch defects), and ere not elaatogeaie (groaa, sorphologlcal danage to chrovosoees) to blood or span cells of ret* or cultured huean blood eella. PC8t mutt ba returned to bo nonmutagenlc. PCla have produced eobryoroxicity and tpoetaaeoua abortions only at dots* dear ly producing asternal toxicity and are no aore toxic to tbe fecus then ecst chealcala when given at toxic doeea to the asternal aninal. PCla can induce fe tal liver sicroeoael annyaea. PCBs produce minimal change* in newborns and *r* much isss toxic than soma common vitamins and hormones. The carcinogenic potential of PCBa is dtbatsbl* because one test rssult is inconslatent end contradictory with sil others (Table 8). aeeulte in the feeal* rats ' in one of the neny studies reported was interpreted aa associating an increase in liver cancer with PCI trsatsent. Two other chronic tests in the sane epeciea, the ret, ae well as teata in the aouae, did not reveal a statistical, significant increase in liver cancer with PCS treatment. The seat recent test. HONS 213155 2 ptifsrsk by tha Nation*! Caaeor loatituto, did not daoonatracs that PC3* pro* due* eoneor is tut tat, Th* rasults ot all chrome taat* ar* coupatibl* oni/ if tho assumption l> aad* that tha fasala* of th* Sharaan rat strain ar* unusual ly suacaptibl* to a slagla PCI (Aroelor 1260}, A sax-spacifie aasitivity it docusaatad, tine* only th* faaalas and not th* talas *' th* Shaman rat strain dvolopod livar eancsr; tharaforo, th* faaaloa of thia strain of rat oust b* aoc* tuseaptibl* than th* oala*. In addition, a strain diffaroae* *xssts baeaus*, in addition to th* sal* Sharaana, both ax*a of two othor strains of rat did not d*vlop liv*r caaeor *a a raault of axposur* to PCI*, A ap*ci*a diff*r*ac* is docuautod, tine.* a*ith*r tan of aavarol strains of oica produca pesitiva rosulcaA compound'spacifie saajitiviey oay also exist in rata, alnea only th* neat coo* plataly chlorinated PCI (Aroelor 12*0) tastad produced livar caneer, whila th* laaa ehlorlnatod PCS (Aroelor 125) did not in aithor son. It should bo no cad that tha PCSs that war* iattrprottd to indue* livar cancar la tha Shortan strain rat war* likaly contamlnatad with unknown amounts of th* highly toxic chloruur*4. dibannofusses. Th* poaaibility that polychLorinata>d dibonrofurana mfluencod tha only poaitiv* taat cannot bo ignored. Finally, it oust ho emphasised that th* critorla utilized in diagnosing th* cantor in th* faoal* Sbanaa rat* is centrovsrsial. Human data rovoai that PC8s produca unremarkable toxic offsets. A oats poi soning apiaoda in Tusho, Japan producad chloraeaa, axcaaalv* diacharga froa tha ayes, irregular oanatruatioa, and high blood triglycarid* lavala but no evidane* of substantial livar danaga (Tabl* 7). Th* PCS at Fuaho contained exceptions!'.y high lavala of polychlerinaead dibonrofurana. Studio* ovar tha last dacada of workors occupotionally axpoaad to PCI* provido avidane* of oininal toxicity, primarily akin probi**a, and occasional minimal changoa in livar function. i [ f 1 HONS 213156 3 There are no data substantiating an uetaa cancer risk after SO years af PCI use. However, the question of PCBa' carcinogenic potential in huaass will re* Min a theoretical possibility for aoaa time bacauaa the latency period at low levels could approach aan'a normal lifaapan. Tha largest study co data, with 2,500 employees from two capacitor factoriaa, <1*d not damonstrate any cauaal relatlouhlp batvaan axpoaura to PCls and any axcaaa cancar. A thoughtful evaluation of cha hazard pocantlal of PCla must review, analyze, and ralata all tha ralavant evidence available, Almost all raaldanta of induetrlallzad countrlaa contain datactabla lavala of PCla in their bodies and la* veral ppm have bean cons latently measured In tha body fat of "norMl" people. Measurements of blood PCI levels in "norMl" workers in PCI manufacturing plants reveal that blood levels My be hundreds to thousands of times higher than tha average population. Thus, it appears that small doses of PCBs obtained from our environment and food supply sre ganaraily toiarstsd. Tha toxicological da* ta indicate that concern for hazard at high lavala of axposuraa to PCla should be no grantor and oftnn less than for many other comoon lnduatrisl chemicals. PCls ware once a uaeful chemical ia out society. Uncontrolled waste disposal practices rssultad In hunsn exposures and environmental contamination. Since PCls wars widely dispersed and are persistent, they became ubiquitous 1a our an* vlroameat. Concern over adverse health effects ere largely due to the poasil hllllty of long'tarm exposure ta PCls. Drastic regulatory oeasures were 1 considered necessary ia 1977 due to the then existing enormous scientific uncer tainty surrounding health sffacts. Compounding this uncertainty is the effect thst ail PCBs do not presont tho some hazard because they sre different com pounds (Table I). The toxicity of PCls varies greatly with the degree of chlo- MOWS 213157 4 riaation end extent of contamination with polyehloro dibenzofursns, Analym of th toxicological literature load* to conclusions that support cha view mat PCla ha*a not baas demonstrated to ba hazardous undat most conditions of exposura to tha public and that intermittent, ainiscula exposures are not likely to lead to disasterous consequences. HONS 2L3LS8 i TECHNICAL REPORT HONS 213159 1. PHYSICAL - CHEMICAL PROPERTIES Polychlorinated biphonyli CPC3t) ro formed by chlorinating any ono of '.on avail*blo carbon atoms of the baphony 1 molecule (aaa figure 1). In the commereial synthesis of PCIa, the biphenyl molecule la chlotinated with anyhydrous chlorine uuf either (*::. chloride or iron fillings aa a catalyst (Kutlinger at si. 1974). The chlorination of the biphenyl structure cannot be controlled strictly enough to generete only two pure, atereoeheoically homologous products. Thus, the commercial preparations of PCts are actually mixtures of chlorinated biphenyls with varying chlorine content and chlorine position. Sines chars ara 10 availabla carbons to ehlorintto on cho biphanyl molecule, tbara ara a post ibis 209 diffarant PCS isooars that can be generated, as seen in Table L, An aatineted 40*70 different chlorinated biphenyl compounds can be present in each of tha higher chlorinated eooaercial slxturee. For example, *roclor 1254 contains 69 diffarant molecule* chat differ in the number and peti tion of chlotine atoms. A scheme wee developed to identify specific PCS isooers from the many possible choices. The lowest possible numbers are always assigned and the prime cumbers ere always given to the chlorines on tha phanyl ring con taining tha fewast chlorine atoms {aaa Figure 1). About half of tha 209 possi ble chlorobiphenyls do net occur in any commercial preparation*, and tha majority of those compounds are chose in which only one ring is completely or predominantly chlotinated (Hutsinger ot si. 1974, NICSH 1977). For example, there arm am pants*, hexa-, or haptaehlorobiphanyl Isomers in which one ring is " fully chlorinated, nos ara there pants or haxachloro derivatives containing four chlorine stems on one ring. PCts have unique physical and chemical properties chat have made them useful and HONS 213160 6 applicable to. stay connerciai needs, These properties nckd* tharaal stability; resistance to oxidation by acida, baaaa, and othar chtmcal agents, excellent alactrieal insulation; fir* resistance; and low volatility, A partial list of soae partinant chaeicel propartlaa hat baan provided for a few PCS iuc turns in labia 2. 2. PRODUCTION AND USES Tha synthasis of PCBa has baan known for ovar 100 yaara. It waa first praparad lb 1887 by Griefs, who haatad biphanylbls (diasoniun) platinum ehlorlda with to* dium carbonata (IARC 1978), PCBs wart first producad la 1929 by tha Swann Chemleal Company, which was than purchased in 1935 by tha Monsanto Company (Monsanto 1979). ly 1991, thara wars at laast tlx U.S. companies with registered trada* aarfcs for commercial brands of PCls (IARC 1978). Commercial PCS products hava alao baan producad by Great Britain, Japan, Germany, Franca, Italy, Spain, Creehoslovakia, Poland, tha USSR, India, Sraril and Argentina (KIOSK 1977, IARC 1978). It has baan as tinstad that ovar 1 billion pounds of PCBs warn sold in North Aaariea alone (IARC 1978, Monsanto 1979) and thay hava baan in usa la si* oat avsry induatrialixad nation of tha world. Tha physical propartlaa of PCBs (as nentlonod above) ware applicable to a any in* da ustrial situations and prompted chair use in nany commercial areas (too Table 3). Because of tbolr resistance to fire and breakdown by heat contained with their electrical insulating capabilities, they found numerous usee in tha aloe* trical industry prinarlly in capacitors and transformers. Thay wars also found to be useful as lubricants, hast transfer liquids, and hydraulic fluids, i'nfor* tunatsly. they ware alao utilised for many "open'* applications whara their aeis- HONS 213161 7 loss Into the anvlronaant could not be controlled. Such uses included combina tion* with plasticisers. ink*, surface coatings for wood and cement surf ices, adhesives, pesticide (omul sc ions 4J aa extender, carbonless duplicating paper and loaetsion oils for Microscopes (IARC 1979, Monsanto 1979). Dacaehlorobishsnyl was also imported fro* Italy into the United States for use as a filler for invescaenc casting waxes. Because of concern generated In the late 1960's concerning the environmentJl persistence of PCIe, production of PCBs began to be pbaaed out in the U.S, in the early 1970's. In 1971, the sale of PCBs was voluntarily limited to cloaed systea usea by the aole Manufacturer at that time, and production was later com pletely discontinued in 1977. It is important to nets that, oven with the cessation of PCS production par so, other eaviroaaental sources of PCS any exist. For example, it has been reporrad that soae PCS* are producta of DOT photolysis (Plimr and Kligaball 19*3) tnd Uyeta at al. (1?*6) reported the photoforastion of PCBa froa the sunlight irra diation of aoso-, di-, tri-, tstra-, and hexachlorobaoxinea. Besides these sources of PCBs, Gaffney (1977) reported cho formation of various aono-, il-, and trichloro-bipbonyls resulting froa the final chlorination of Municipal wastes containing bipbanyl. Laboratory chlorination of influent and affluent froa a Municipal waste treatment facility alio resulted in the fornetion of these end other chloroorganic substances sueb as di* and trichlorobanzanas. c HONS 213162 I 3. OCCURRENCE PCBs were first recognized to ba an environmental continuant m 1966. I.i :ha next few years, PCBa vara idsntified la tbs environment worldwide ud found to hava become s traea contaminant avao in thosa paopla not occupational1/ exposed to then. Sinea tba environmental occurranca of PCBa baa beta discussed exten sively in aavaral articles (Paakall 1973, NI05X 1977, IARC 1978, tfassaraan at al., 1979, EPA 1980) eba following suamsry paragraphs will only include a faw examples that illuatrata tba ubiquitous natura of tba PCI contamination problao. For axsmple, PCBa hava boon found in: 3.1. Air. A Japanese survey reported the the concentration of PCBa in urban air rang* from 0.002 - 0.02 ug/m*. A 1975 report on tbraa American cities (Fort Col* 11ns, Colorado; Jackson, Mississippi; sad Miami, Florida) revealed that the Iv orage concentration of PCIs in air was 0.1 ug/a1. To put tbaae data into perspective, tba currant government standard for workroom air is only 0.1 ug/m1. It was eatiaated in 1975 that approximately 2 million pounds of PCBs are depos ited and redistributed in tbe U.5. yearly as rain and particulate matter. 3.2. Water. It has been estimated that tba waters of Lake Michigan contain 10 ng/1 of PCBs, while the average concentration oeasured in seswatar from the Med iterranean was 13 ng/1. PCBs in the Hudson River have been measured as high as 2.8 mg/1 in the water and 6700 mg/kg in the sediments. Municipal water supplies have been contaminated with up to 20 ug/1 of PCBt from paint contaminated with in excess of 1". C . HONS 213163 s 3.3. Soilt, A survey la 1972 revealed that whil* only 0,1" of the staples taken froo agricultural areas contained detectable anounts of PCBa, 63% of siailar staples froo netropolitan araaa had aaasurable lava la. 3.4. Marins Organisms. PCBa hava baas idantified la alaoat all plants aad utiala la cha Atlantic Ocaan. Raaiduaa in plankton hava baan found aa hi|h aa 1.5 ppa, in aussela of 1.70 ppa, in shriap of 7.0 ppo, in gray aaala of 14,3 ppo, aad in whales aad dolphiaa, lava la up to 147.0 pp* hava boon rocorltd, 3.3. Fiat) and Othar Aquatic Organiama. Flab can bloaecuoulate PCBa in tha range of tana of theuaanda to several hundred chouaaada of tlna greater chan tbo concentration of PCBa in water. Thus, it la not surprising to find roporta where flab froa ear tern rivere of the United Statea have had PCBa aa high as lto ppo in their fleah or fiab froa the Great bakes have at one tine contained levels ranging froo 2.7 - 26,0 ppo. Sardines taken froa the Mediterranean have had 0.7 4.7 ppo, while sardines froo other areas such as the Atlantic coaat, Adriatic Sea, France and Tokyo Bap had 0.3 - 0.4, 0.3 1,06, 0.7 - 3.1 and 1.0 - 11.0 ppo, reapeetivslp, 3.4. Urds. Tin highest concentrations of PCBa for any species are probably tboae found in birds. Birds are often at the top of food chains and therefore tip aost often affected by chenlcala that can be bioeoncentrated. Raaiduaa ra* ported in carnivorous, bunting species art aa follows: 14,000 ppo in white tsllad eagles, 2,000 ppo in paregrln falcons, and 900 ppo in barons. Liver eoncentrat Iona in gansets of England ranged froo 4,720 9,590 ppo. Reduction of evlan populations by PCBa has been feared because of the excessively high real* dues oeasured and the fact that they oay affect reproduction by altering the HONS 213164 10 aggn thaaialval^ causing neurological ehangaa raducing ficaaas and dafansa, and daersssing tha immunologic dafansa against infactiaus disaaaas. PCBa Hava baan found in bird aggs ac coneanerteions a* high aa aavartl thou*and ppa, although thay art nora of tan rap ortad in the 10-100 ppa ranga. 3.7. Man. Studies hava ahown that iu ia exposed to PCBa through tho environ* aant because they hava baan found in tha fat or blood of persons not occupa tionally axpoaad- Jaliaek and Coraaliuaaan (1976) ealeulatad tba daily uttko of PCBa in tha diat of a taanaga aala at g-15 yg/day for 1971-19*3. Fat eoncantratlotu of tba "normal" population can ba several ppa with blood lovals la tha pph ranga. PCB laval* ara usually highar ia tha aala populatioa. and aaasursbla levels of PCSa hava baan raportad in paopla froa tha U.S., Ingland, Noway, Fin land, Hatbarlaad, France, Germany and Japan, Thu*, it can ba concluded that hu man PCS contamination from our environment is a worldwide phanoaanon. 3.8. Food. Possibly tba aajor sourea of human axposuro to PCBa has baan our food. Food aay boeoaa eontaainatad ia aaay ways including rasidua* of pasticida formations containing PCBa, migration froa packaging sado froa racyclad papar, rainfall and particulata fallout onto crops, and, of courts, froa fish and aaat grown in eontaainatad trass, tha arrant of PCB contamination of food hat baan aottitortd by tba FDA and USCA tinea 1949, Tha ratults of aoaa of tho aonitoring ia praaantad in Tabla 4. Currant FDA tolaranca lava la ara raportad in Tabla S. Tha praaoaca of PCBa in food doellnad ovar tha yaara and this dacraaaa cortelataa with tha daelina in ita industrial uaa for this parlod, 3.9. Summary of Oecurranea, Thara hat baan a sharp curctilsont of PCB pro duction and disparaiva uaa applications froa a record high of TO ail lion lba in HONS 213165 11 1969. It la believed that it will taka oaay years for ecosysteas such a* Lax* Michigan to ba cleaned of the PCBa even if no naw input is aada. Dua to high ad sorption eoaffieiant and resistance to dagradation, tha PCla hava eceuouleced ls quantity in bottoo sediment*. Tba final environmental sink for PCBa is predictad to ba dagradation in tha atoosphara and aequaatrnciea by lrravarsibla binding to oetebolically stagnant sediments of lakaa (Naelay 1977). 4. ANIMAL STUOIES 4.1.Pharmacokinetic* and Metabolism. it ia generally acknowledged that tha toxicological aaaaasnant of eoaoereially available PCBa has beta, coop lieatad by tha hatarogaaait7 of tha chlorobiphanyl aixturas. Marked differences anise in tha physical and chaoical prepareias of aach spacific chlorobiphanyl that My influence tha rasas of absorption, distribution, hlotrasaformation and excre tion . According to the schaaa of Matthews and Kato (1979), PCI* are a Type III class, of baloganatad arooatic hydrocarbons. Aa aanbara of this class, one correctly predicts that PCBa would bo quits noo-polsr, roadily absorbed orally, and slowly astabo lined. PCla are a loos t coop lately absorbed by the gut, having a 91 94.9% efficiency of oral absorption in tha rat which is largely independent of tba dsgree of chlorination for tha doaaga range of 3 - 100 og/kg (Albro and FishbolA 1972). In ametbar study in rsts by Matthews and Andersen (1973), it wts found Cbtt PCBs are taken up froo the blood initially by the liver (high perfu sion and affinity) and ousels (large percent of the total body nass). PCBs then rodiatribute to tha skin and adipose tissue (highest affinity, low perfusion) such that tha tissue concentrations ultimately equilibrate ia the following or* HONS 213166 12 <j*t: adipose tissue > skin > liver > ousel* (Matthews and Anderson 1975, Lucs et si. 1977). The absorption and eh* distribution patterns of the various chlorinated biphe nyls are slallar, but aetabolisa is not. Studies have shown that the aonochloro and dichloro biphenyl coapounds sr* extensively eetabolixed, but that increas ing the chlorinaeion decreases th* extene of aeeabolisa (Matthews and Anderson 1975)- For exaaple, in the rat th* aonochlorobiphenyl is aetabollxad 5 tiaes faster than the dichlorobiphenyl, 25 tines faster than pentachlorobiphenyl, and 200 tiaes faster than hexachlorobiphenyl (Lutz et si. 1977). Thus, vhil* the aono and dlchloroblpheayls are extensively aetabollxed and excreted vichin days, it was calculated that less than 20H of a single 0.6 ag/kg dose of 2, 2', A, A', 3, S' hexachlorobiphenyl would be eliainated during th* lifatla* of the aniaal (Matthews and Anderson 1973). The extent of chlorination and th* posi tion of the chlorine atoas on tbs biphenyl ring both significantly alter rha rate of aetabolisa. Studies in aic* and rata indicate that the hydroxylation rat* increases with the relative availability of adjacent unaubstleuted carbon atoas (Tuhey sad Matthews 1977, Mitzutani et si. 1977), For exaaple, in aice the tetrachlorobiphenyls are aetabollxed at rat*a auch chat the accuaulation of PCI is 2, 2', 3, 3'a3, 3', A, A'<2, 2' , 5, S'<2, 2', A, A'<3, 3', 5. S' . Vhen a*tablisa of the aice was increased by induction with phenobarbltal. th* order {or accuaulation was eseentially th* saue with 2, 2', 5, 5'<2, 2', 4, 4*0, 3`, 5, 5' leaving the authors to conclude that this reflected th* recalcicrancy of th* particular chlorinated biphenyl to b* eetabolized (Mitzutani et si. 1977). Siailar evidence has been provided in rat studies where adding chlorines at the A and A' positions, thereby eliniaating eh* unsubstituted vicinal carbons of 2, HONS 2131*? 2', 3, 3* tetrachlorobiphanyl, dramatically lowered the rate of xetaboliia (`.'at* thews and Anderson 1975, Tuhey and Matthews 1977). Tba ability of PCla to induce hepatic enrywe* aad thereby lacrosse aetaboliis baa been wall documented (Litcerst aad Vaa Loon 1972, -Litcerst at al. 1972, Teata aad Janaar 1971, Ecobichen and Coaaau 1975, Johnstons at al. 1974 aad Cold* ataia at al. 1977). PCSa ara vary affective inducing agents wboaa potancy on a aolar baaia far exceeds that of phaaobarbieal or DOT aad ara capabla of causing a ion increase ia cytoebroaa P-430 at cha ralativaly low doaa of 5 ag/kg (Lit* carat aad Vaa Loon 1972). Howavar, tha poaitioa aad dagraa of chlorination on tha biphanyl nuclaua atill playa an iaportaat rola in tha affaeta alicitad. Ecobichon aad Coaaau (1975) found that to aahaaca oxidative aataboliaa, chlori nation at tha 4 or 4` poaitioa vaa required. They aad othera have alao reported that iacreaaod chlorination iacreaaea the aaount of induction aeea (Licterac et al. 1972, Johaatone et al. 1974 aad Co Idatain et al. 1974). Goldateia aad eo* workers (1974) demonstrated that while PCI oixturea can induce both cytochroae P*450 aad cyeochrooe P-4Ag, cytochroae P-450 ia alwayn induced by iaoaera ia which chloriaea art praaaat at tha ortho aad para positions rogardlaas of tha exteat of chlorination, whilt ayaaetncally chlorinated biphenyl iaoaera with chloriaea in tha aata aad para poalcioaa only iaduca cyctochrooe P*44g. Tha aataboliaa of PCla ia alao of intoroat becauae of ica poaalbla rolatlonahip to tha ceapeuad'a toxicity. Tha foraatloa of aa araaa oxide during tha hydroxy* 1st ion of PCla baa boaa auggeated froa aeudlaa deaonatratiag dihydrodiol aecabolitaa and MXH ahifta ia dautariua aad chlorine atoaa placed et the pert poaitioa (Matthews et el., 197g, Dely et al., 1972). Arana exidea of certain polyaroaatic hydrocarbon* (PAH) ara known to bind to nucleic acide aad it haa HONS 213140 14 been postulated that the interaction of these reactive aeieculea with nucleo philic aicaa of DMA and other aacroaolaeulaa laada to tha induction of tuners Thus, It hat been hypothesized that arana oxide formation of PCBs nay also la4 to alkylation of critical callulax aitas thereby inducing cancer (LUtC 1978, i?A 19*0, Allan aad Norbeek 1973), However, thara are aavaral differences betvaan PCBs aad PAHs that should also ha conaidarad when suggesting auch a aachaaisa for exaaple, while thara la a food corralation between tha mutagenicity of PAHs in tha tee* assay and thair carcinogenicity in rodanta, auch la not tha cast for PCls. Only nanochlorobiphenyl is positive in tha teas assay, whila tha poly chlorinatad biphanyla wars not (Vyndhan at al. 1971). Kara it appaara that tha daeraasad aatabolisa with incraaaad chlorination would reduce tha likelihood of fomation of a raactiva nataholita nacaasary for interacting with tha DMA. Thara/ora, tha raduction of metabolias aad lack of mutagenicity associated with lnctaaaad chlorination of tha biphenyl ring la in dlreet opposition to tha pro* position that an arana oxids intermediate, capable of gaaotoxicity, la responsi ble for tha tumorogaaic affects of highly cblormated biphanyla. It should ba notad that phanathzasa, which la probably tha PAH aoat closeLy related to biphe nyl by structure, is not autagenic in tha Anas assay (McCann at a). 1975) and does not indues tuaors in newborn nice, nor doss the epoxide of phenenthrane (Grover at al. 1973). On tha basis of structure activity, relationships of PAKs, it would soon aors prudent to predict that PCla would ba acre likely to act like tha noneareinogaa phananthrana than tha carcinogen banaanchracana. Mora recently, it has also bean suggested that tha actual ultimate carcinogen among tha PAHs is a dihydrodiol-apoxida aacabolita which ia auch acre autagenic and carcinogenic than tha parent compound (Xapitulnik at al. 1977). Since apoxida formation beeoaaa lass likely with incraaaad chlorination of the biphenyl nucle us, It would saaa that formation of dihydrodiol apoxida intermediates ara un* HONS 213169 15 likely to correlate with either obaarvad tuaoroteaieity. Aaochar feature of ?CB netebolisn that should ba considered whan postulating potential nechsmsea for eaacar induction ia tha spaeias differences in tha rata of eetebollae. Based upon tha fornatlon of raaetiva aatabolitaa leading to tuaor Induction, it nay ba poaalbla to induca cancar in rodanca but auch lasa likely to do ao ia priaatas or aaa. This staaa froa tha finding that rata metabolise and olialaata 76* of a doaa of PCBa in 3 daya whila priaatas aliainata only 2% of tha saaa dosaga for tha saaa interval (Van Millar at at. 1973). Thus, not only would autational events leading to cancar ba laaa likely to occur in priaatas, but DNA repair oe* chanisas would also ba auch acre likely to prevent tha peraanence of any nuts* tioaal event. 4.2.Acuta 4 Subchronic Toxicity. Several reviews of the aaaaelian toxicity of PCli have appeared in tha last decade (Fishbein 1976, Kiotorough 1976, Peekall 1975, NIOSH 1977, IMtC 1975, SPA I960). Therafora, an exhaustive review of the literature will not be offered here. A suaaary of the pertinent ecute aide effacts of PCIs in enlaals follows. Ujq's era large for aoat speciee teatod. Ia rata, the acuta lethal dnaa ranges froa 6,000 ag/kg 16,000 ag/kg and incraaaaa with tha chlorine content of the nixtura tatted (Fishbein 1976). The scute toxicity of PCBa nay ba claasified as sli^tly toxic to non-toxic as described in Tables 3 and A (Doull at al. 1980). Skin disorders aiailar to chose seen in huaans heve been observed in nonkeys, where feciel edemas, hair lota and acne occur at oral doses of 230-600 og (Allan et al. 1974). PCIs spplied directly to tha akin of rabbits indues hyperkerato sis, erechyna, blister* and desquamation (IARC 1978). HONS 213170 16 Endocrine effect! era another chans* elicited oy PCS*. Eatrogemc activity, which is possibly related to offsets on staroid metabolise, has ban rsported in rats (Hlguchi 1976). In primates, PCS exposure results in prolonged menstrual cycles sad increased bleedins (Sarsotti *t ai., 1976). Other symptoms reported in various species include: gastric hyperplasia, thymic atrophy, decreases in red blood cells and lymphocytes, splenic atrophy, and an increase in the sarusi level of triglycerides, cholesterol and phospholipids (for review sae HIOSH 1977, lAJtC 1978, Higuchi 1976 and EPA 1980). 4.3. PCS Contaminants. No discusaion of the toxicity of the polychlorinated biphenyls can be complete without stressing the possible role of trece contan* inants of PC8s, e.g., the polychlorinated dlbenxofurens. For example, embryotoxicity of the PCIa has baen attributed to chlorinated dibeosofurana present as trace contaminants in the commercial preparations. Subsequently, tetra-, pants-, and hexechlorodlbenzofurans ware detected in a number of American prepa rations of PCls (e.g., Aroclor 124g, 1254, 1260). Concentrations of the indi vidual polytblorodibeasofurans were in the osder of 0.1 mg/kg of the PCS. Chlorinated dlbenxofurens have been considered as possible causes of eobryonic mortality and birth defects observed in PCI-faedlag experiments in birds. The polychlorinated dlbenxofurens are structurally related to the chlorinated dibenxo-p-dioxin, some of which are highly toxic, teratogenic and carcinogenic. a A number of possibilities exist to account for the presence of polychlorodlbenxofurans in coMareial PCI mixtures. One explanation considers the presence of the parent compound (dibenxofuran) in the technical grade biphenyl subjected HONS 213171 17 a to til* chlorination precast. It La also conceivable that polychlorinated dioengofurana nay be produced froo ?C3* ui the a&vironaant. It ahotiid be atreaaed that the t rant format ion of only 0.002% of a aajor constit uent of an Aroelor nurture to the corresponding chlorinated dibauofuran* would produce concentration* in the nurture corresponding to the values reported ay Vos at al. (1970) as toxicologically significant. 3. MUTAGENICITY The Aaes assay utilizes Salmonella typhimunum to detect reverse point autation at ths histidine locus. Only aonochlorobiphenyls have deaonstrated any activity in the Aaes 1333 tester strain. In this aaae study, the polychlorinated biphe nyl* such as 2, 2*, 5, 5' tetrsehlorabiphenyl, 1234 and 1230 were negative (Vyndhaa ft al, 1973; Safe, EPA 1980). Sreen at al. (1975a) have deaonstrated that KBs do not causa significant elastogeaic effects in bon* narrow or span cells sf the rst even at high doses. Aroclor 1242 was given ac a single doe* of 1230 - 5000 ag/kg and at 500 eg/kg for four days (a refines causing the condition of the an tael* to deteriorate), while Aroclox 1234 was given at doses of 75 300 ag/kg for five days. These findings are consistent with the lack of chroaosoaal aberration* observed in huaan lym phocyte culture* with doses of 100 ag/kg Aroclor 1254 (Hoopingsrner et si. 1972), The possible autagenicity of PCSs has been studied by Green at al. (1975b), us ing the doalnant lethal test. Thera was no statistically sigaifleant increase HONS 213172 is lA the nuaber of dead iaplants, again 4t high dosages of Aroclor 1242 nd i;jiKaplingar at >1. C1971) (lie eoployed the dominant lethal assay and reported no evidence of mutagenic effects far tha Aroelors. Polychlorinated biphenyl* do not have significant mutagenic potential. * t. REPRODUCTION Studios in various spocias indicate that PCBs do not affect conceptual rstas >n animals. Calandra (1979) studied the effaces of Aroclor 1254 nd 12(0 in ret* through three generatloos. Is the first generation of offspring, he found no changes related to treatment in. the meting index, in the second generation he found reduction, and in the third generation he found results aInline to those of the first generation. Calandra concluded that there van no suggestion of any alteration in response in succeeding generations. Siailsrly, Linder at at. (1974) found no effect on reproduction in Sherman strain rsts exposed through two generations at dietary lavela of 5 ppe. Exposure of rsts to 50 eg/kg/day of Aroclor 1254 jr 100 ag/kg/day of Aroclor 12S0 also did not affect reproduction (Linder 1974). In the rabbit, Vllleneuve at al. (1971) found no decrease in the nunber of pregnancies in aaiaals fed 0.1 or 1.0 ag/kg body weight of either Ar oclor 1221 or 1254. Finally, feaale rhesus aonkeys given Aroclor 124g st 2.5 or 5.0 ppa In their diet and bred to untreated sales had normal conception rates (Barsotti at al. 1979). Other Indices of reproductive toxicity ware aieilary unchanged by PCS*. Clan* dre (1979) noted that neither of the reproductive tracts of male nor feeele rsts were effected following exposure to PCBs. Dikshith at al. (1975) reported that Aroclor 1254 produced no histopathological changes in the testes or epididymis. HONS 213173 19 nor did this Aroclor 123* eauaa significant chrooosooal damage or arrest i parrottogeaeais ia the male rat, Animal studies indicate that thara ia littla rap rod uctive rlak associated with exposure to PCBs, a finding which agraea with the lack of reported fertility problem ia human* after exposure or consuaptlon of PCSs. 7. BIRTH DEFECTS Aroclor 1242, 1234, or 1240, at doaaa up to 30 ag/kg adaialatered to rata during the organogenic period of geatatioa, did not produce exceaa eabryotoxicity or aorphological dafacta CCalandra 1976), Other experimental evidence documents the lack of adverae effacta of PCBs on either eahryo or fetal development. Lin der at at,. (1974) reported that adaiaiatration of Aroclor 1234 to pregnant rata at 100 ag/kg/day on geatational daya 7-15 did not produce any groealy abnormal offapring. Although only 30% of the offapring of aothere exposed to 100 ag/kg/day aurvived until weaning, greater than 20% of the treated aothera died prior to delivery. The 20% aatamal aortality produced by the treatment suggeata overt maternal toxicity contributea to neonatal aortality. The increaaa in liver welghta noted aaong theae offapring vaa aporadie and not doae related, which alniaiaea the, likelihood that the increaaed liver weight reported waa a apecific PCI-induced effect. In other atudiea, Aroclor 1234 adalniatered during geatatioa again reeulted in no fetal aorphological abaonalitiea or reduction in viability (Villeneuve at al. 1975), PCIa alao did not induce cerate in pupa bon of daaa fed the equivalent of 12 ppa ia the diet or ia pigleta of aowa fed the equivalent of SO ppa ia the diet. However, increasing theae eonauaptioca by 4 to 30 tinea apparently reeulta in aoae fora of terata (NI0SH 1977). Theae data cannot be properly evaluated since they have not been published. Doses of PCBs up to 300 ag/kg were not teratogenic in aice when given on geatational daya 1 MOWS 213174 20 through 6 or otv gestational days 7 through 11 (Toeruek 1973). Similarly, feed ing pregnant aonkays Aroclor 1245 at lavels of 2.5, 5 or 25 ppm did nor produce malformations (Allan at al. 1974, Saraotti 19*6 and Allan and Sartotci 197a) However, baeauaa of overt aatamal toxicity raaulting (:oa exposure to tha Mjn* ar lava la, abortions vara coaion, aa vail aa radnet ions in fatal body waignts PC8s have not significantly sltarad ambryo or fatal development m either rodanta or subhuman pnmataa and thara appaara to ba little teratogenic risk assoclstad with axpoaura to PCBs. S. CARCINOGENICITY Tha polychorlnatad bipbanyla (PCSa) praaant distinct problems wbau attaapta sra aada to estimate a potential cancar risk to aaa froa data davalopad in rodent studies- The crux of tha dilaaaa la tha need for a relevant interpretation of an excess incidence of liver tumors in rodents fad certain PCSa. Similar problems in interpreting haxard, baaed upon an exceaa of rodent liver tumors, have bean experienced for a number of other structurallyralated persistant, halogenuted organic compounds. Included among these related compounds are DDT, dialdrin, mirex, Keponet, hoxachlorobanxena, polybrominatad biphenyls, 2,3,7,S tetrac.Uorodlbenro*p-dioxin (TCDD) and haxachlorodibenxodioxln. The polyhalogenated dibenxofurans, naphthalenes, and terphenyls which are related structurally, hava not been tested for a carcinogenic affect, Mott of tha chemicals mentioned are a of special concern, since they are persistant in mentis ones they have been ab sorbed and poorly dagreded in the environment. While most of the chmmietla re presenting theae classes sra commercial products, tha polyhalogenstad dibanrodioxins and dibeaxofurans occur only aa contaminants of ocher products. Tha following expanded discussion of oncoganatit sod carcinogenesis emphasises the MONS 213175 21 comparative pathology of lHaas produced in the livsr of rodents by chronic PC3 adats1stration. 9.1, What Mechanisms Provide for the Expression of Carcinogenicity or Onco genicity? For the purpose of our discussion sad, as oppoaad to NCI suggestions for classification (which arc discussed lstar), caacar will ba defined tradi tionally- Cancer is the production of life threatening eallgnant tumors of po tentially unlimited growth that expand locally by invasion and lysteaically by aetaataaia- A chemical is by definition only a carcinogen under those condi tions which irreversibly initiate sonatic nutations, promote uncontrolled neo plastic transformation and ultimately produce cancer. A chemical will be defined as a carcinogen only under United circumstances. Several horaonea and elements are essential at physiological levels snd carcinogenic at toxic levels. A chemical is only a earcinogan undar conditions which irreversibly initiate and ultimately produce cancer. Initiation is defined as the production of damege to SNA which is of a magnitude sufficient to be sustained but of a nature whieh permits cell aurvivel and pre disposes the capacity of uncontrolled growth. Cells containing damaged DNA can, under certain circumstances, act as the stem cells for the formation of clones of cells containing heritable mutations. Mutagenicity is defined as the pro duction of permanent alterations in the genome. The related processes of somat ic mutagenesis and initiation have the potential to alter the genome of any cell. An altered genome inevitably increases the probability of dysfuactlooCaneer is cellular regulatory dysfunction expressed as irreversible and uncon trolled growth. Heritable somatic mutations which result in the initiation of genes responsible for cellular regulation increase the probability of producing 213176 22 cancer. Meat aaonalian genet exist in allelic pair*. Evidence froa soaatic call hybri disation studies indicates chat the salignent phenotype appaara to ba recessiv* for non-virsl iaduead eaaeara. Consequently, a raeaaaiva toastie autation in on* of tha alia la* would not noraally b* axpacttd to eanifest ltaalf as cancer until a aaeond autatioa oecurrad ia tha rtaaining normal allala earriad m th* seat call. Tha probability of two iadapandant autatioa* occurring ia cb* a an* allalie pair of genes ia tha aaaa call is extreaoly rar*. Howavar, given enough autatioa* ia enough calls tad a prior iabaritaaea of suscaptabla genes through tha gara lima, tha ehanca of having a call with both allala* of a critical g*n* being autaead and eharaby producing callular dysfunction become* not Just probe* bla but vary likely. In tha case where there is a history of a spontaneous inci dence of cancer in tha test animal, dysfunction is inevitable and the question changes from whether or not cancer will develop to how much and how soon can cer will develop. Liver cancer, which is vary eeaoa in the rat and eousa, has bean shown to he an exsap1* of this process. Cancer riak incraaaaa with tie*, primarily haeauea tha eagnitud* of initiation is s cuaulativ* probability, Rodent liver tunor causation ia oftan referred to as eultifactorisl. This ia just another way of saying eany indirect factors can altar tha incidence of tuworn. Total calories, fat content, vitamin E, strati, crowding, and a*x of the host can all Influence tuoor incidence. Thara fora, in order to ba specifically defined a carcinogen, rather then a factor of unknown necheniae, a coapound oust be an initiator. Initiation, the suetaimed oodification of genes via specific alteration of aoaatic call to SNA, is dose dependant. Thus, whether and when a chemical ia or is not defined as a carcinogen ia dependent on dose. How then do MONS 213177 23 wa categorize compounds which increase the observed incidence of tumors when the data available describing the tumors are noe sufficient to strictly or unambig uously classify the tumor as cancer? Promoters have bees postulated to act not as initiators but through aodulatioa of gene expression and cellular communication. The molecular mechanisms of pro moters are tore varied than those of initiators which suit alter DNA. Included among the known aechanisns of proaotion is the ability to control various cones which provide a selective growth advantage. Vo will define proaotion as the ability to enhance the selective proliferation of previously initiated cells. By definition proaotion cannot occur until a critical gene is initiated. The DNA of dividing cells replicates proportionately to the rate of cell division. DNA is aore susceptible to nutation by cheaicals during replication. Silent nu tations of dormant cells are acre likely to be expressed during replication. Wounding, growth stimuli, necrosis, inflammation, or certain chemicals can se lectively and rapidly allow cells containing ths mutated gene to form a done of semi-imtiated cells. A rapidly dividing clone of initiated cells containing one nutation of a critical gens obviously enhances the probability per unit tine of initiating a ascend nutation of the remaining normal allele "Foci" or "Arena" discussed in detail later are likely clones of cells rapidly developing in re sponse to chronic injury inflicted by PCB treateent. How can we account for progreaaion as well as regreaaion of tuaora? The biolog ical environment controls normal growth, development, end maturation. These controls constrain the growth of cryptic in situ cancer. Vhes these controls deteriorate, ea in old ege, or are overwhelmed by external influences, cancer develops. The growth of moat cells with malignant phenotype in hetlthy animals HONS 213178 24 U repressed by.contact with norsal clli through process celled contact inhi bition. Saill oolecules and aecrooolecules responsible for contact inhibition, including aeabrane antigens, are readily transferred between cells therefore, even if e outat ion, reducing cncicsl gene products controlling differentiation end growth, occurred in one gene of 4 cell, the close physical presence (contact inhibition) of nemal cells would contribute to aaintaming the required level of gene producte. The net effect is that healthy tissue can usually repress the tendency of initiated ceils to proliferate. When initiated cells do proliferate, cells in the center of the for*LAg clone will be subjected to lest and less con tact with normal cells. Less control increases the opportunity for the clone to further undergo differentiation or incorporate s second autetioa during the pe riod of proliferative activity, after e boaosygoua eutsnt is focsed, the like lihood of either s normal hoensygous or heterozygous call being able to trsnsfar enough of the needed gene products oven by direct contact is greatly reduced. Escape fro* the eati-prolifocative influence of normal calls is also enhanced by the ostebliahaent of e critical ess of autttod colls; such a critical aaas also aide the clone in evading twine surveillance. Our hypothesis is based on the basic assumptions that each soaatic cell of the differentiated aeaMlisa orgeats* (rat, aouea or nan) contains the sane genes; eaeh cell type has only a few specific genes In tha active state; eech differen tiated efll type has specific gene products; and the various differentiated cells of the organise contain receptors which differentially respond to spaelflc sets of snrlrrufsnfil signals. If we assu*e that *olocular signals detected by the aembrase can all he trensferred to the nucleus and then to specific genes, a aechaniaa by which a suiti-diffcrenelated organise can specifically respond and adapt to the environment hes been constructed. Receptors of various cell types MONS 213179 2S are no* likely to ba equally influenced by toy chtaical sine* they are eodad by different genes- Tharafora, it is only reasonable chit there ra tissues where tho production of mutation* may or may not ba expressed ** dysfunction. Gene dosage is * ralatad phanoaanoa whereby tha affective level of gene products is dateruined by pbanotypa. Tha quality as veil as tha quantity of salaetad gana products influence tho aaintenanca of tha aon-prelifarativo stats via aas~ saagars tor tha rocoptors producing call-division rsprossion. Call proliferation will occur if calls producing call-division raprassor massangors art das troy ad, modified or disruptad by chemicals, surgary or wounding; if tha ability of rt* prassors to act is inhibited; or if tha receptor type or numbers hsve bean si terad by mutational or epigenetic repression. If the danaga is xevsrsibla, calls nay retain tha ability to raatora tha original nunber. lava Is, and ttats of gana products. Under such conditions, tha call ia capable of raestablishing feedback control over prolifarstion/diffarantistion, Say avant facilitating a sacond nutation of a gana resulting in a call type honosygous for tha neoplastic pbanotypa will facilitate eventual prograaaion of tha resulting call line into a ditaana state expressed as utlignant, true bread ing, natastasiging tunors- Agents that only pronota tha ability of preexisting phenotypes to ba expressed would ba expected to accelerate tha rata of develop- ant but not necessarily create a new disease type. Tharafora, appropriate di agnosis of cancer would ba accoaplisbad by asking cosparlsona of nallgaancy only at point# in tine whan spontaneous lesions in tha controls and induced lesions ia the treat ad occur at tha sane incidence- Processes only promoting cancer m situ would ba expected to regress upon removal of the promoter and not change tho ratio of metsstssiaing to nonmstsstasmng tumors. It is noteworthy that r HONS 213180 26 ucb often appears to be the east with liver canesr in rodents produced by cy clic chlorinated eoapouad*. A compound can Increase eaneer either by initiation or selective proliferation of cloae(s) of naturally occurring neoplastic calls or by a coatInst ion of both proc-assas. Tissue eoepouad interaction characteristic* aadleta the expression of these basic proeeaeee and ultimately tbe presence or absence of tuaor davelopaent. A compound is so incomplete carcinogen when it only initiates or only promotes. Tor exanple, when the level of adainittration of an initlatior is not sufficient to hill any or aaay colls and a hyperplastic response is not produced, other sources of proaotioa ars Deeded to aaplify tbe growth characteriacies of initiated cells. If, on the otber hand, the exposure to an initiator kills or injures asay of the target cells, the rapid growth of progeny of che surviving initiated cells will be triggered by tbe process of repopulating the organ. In this case the initiator, through its cytotoxic action, 1* both direct initiator and ptoaoter and, therefore, a coaplete carcinogen. If a compound is present at t level which proaotea selective growth of cells with neoplastic phe- notypeo but doea not sustain eoapouad Induced nutations, the coapound would be functioning only as a pronotar. Since both promotion and initiation are inde pendently dosa- and time-dependent and tissue, sex, and species sensitivities very, the definition of a compound as an initiator or promotor is dose, durstion, end route, a* well as tissue, sex, species, and time-dependent. It will be documented later that PCI* do not Increase tbe incidence of tuaors at any sita excapt tha rodaat livar. Livar call death, trauma snd hyperplasia art at) produced by PCBs snd can be expected to yield conditions favoring prefer ential growth of cells with dormant neoplastic phenotypes. Liver tuaors are a i HONS 213161 27 CMBon pert of the natural disease process of rodents On* can safely general ize that eh* tuaorigsme properties of PCS* to :h* rodent Uvar rtzult at leas; la (futtit pare froa alteration of th* hoeeoscaais of control aacbaiuiss. Thu*, ch*nt* 1a rodent* with * natural history of high incidence of Uver tuaer* oust b* iat*rpr*t*d carefully. Toxic rtspoos* tad promotion oust not b* is taken for initiation. 8.2. Comparison of tha Characteristics of Oncogens and Effect* of PCS* 1. OacoftB* product iscrtasas of spontaaaou* tuaor at s*l*ct*d tie**. PCBs product livar tuaer*. 2. Tuaor* produced by oncotaas usually do not increase tha aatastatic eharte* taris tic* of spontaneous tuaors of th* saaa sit*. PCI increased liver tu* ora do not tatastesis*. 3. Oncogens do not produce transplantable tuaors unless tha naturally occur* ring tuaor la capable of transplantation. PCS tuaors do not transplant. Tuaors Influenced by oncogens are often affected by factors such as autrl* tion, stress, chronic injury, and sax of the anina1. Livar tuaors *r* ef* feetad by thase factors. 3. Oncogens naad nee ha putaganic. PCBs era not utaganic. 6. Neoplastic lesions increased by oncogens aey be reversible PCI increased ' livar tuaors regress. 7. Progression of different1stion of neoplastic lesions increased by oncogens often ceases whan sciaulu* is raaoved. Continued presence of PCBa is re* quixed to suatsin liver neoplasia. B. Neoplastic effects of oncogons are usually associated with th* chronic dys function of ths affected sit*. PCBs produce chronic hapatotoxie rasponsts. c HONS 213182 II 9. Oncogens da not necessarily mereaae tha effect of carcinogens acting at :ha target alt*. PCBa reduce the response of aavaral other liver carcinogen* 10. Oncogen* affecting the Uvar oftan increase Icroaoaal enzyae activity and eventually produce, avldanca of natabolie dyafunction. PCBa stimulate VX tad product catabolic dya function. 11. Oncogens rtraly if avar increase tuaor incidence at exposure lava la produc ing no toxic affacta. PCBa ara cuaorogeas only at toxic doaaa. 12. Oncogenic affacta oftan raquira contiauad praaaaca of tha atiaulua. Conttnuad praaaaca of PCB la required to auataia neoplastic alterations of the liver. 8.3. Comparison of the Characteristics of Carcinogen a and the Effects of PCBa 1. Carcinogens usually produce neoplastic Lea ion* at aultlpla sltas. PCBa only ineraasa letiona of tie liver. 2. Carcinogens often Increase tha aalignsney of apontineous tuaora at tha aaaa alto. PCB increased liver cuaors ara of low oslicnancy. 3. Carcinoma* irraversably progress once a critical tiaaua naas la astsbliabod. PCB increased tuaora can tastaaa. 4. Carcinogens produce tuaora which aataataaixe. PCB ineraaaad liver tuaora do not etastaaiaa. 5. Carcinogens produce lethal tuaora. PCB ineraaaad liver tuaera ara not le thal. *. Carcinogens produce transplantable tuaora. PCB ineraaaad liver tuaora do not transplant. 7. Carcinogens ara oftan affective at single exposures. PCBa Increase liver tuaora only after prolonged continuous axpoauras. MOMS 213183 29 8. Carcinogens ara often active it nentoxie doaaa. PCS* only mciiut Uvr tuaors at hapatotoxic doaaa. 9. Carcinogens art Initiator* PCS* are not initiator* and therefor* aot car cinogens . 10. Initiator* ara eutagans. PCI* ara not nutagau and therefor* not initiator*. It i* apparent that the naoplaatic affects o PCS* natch tha definitions of an oncogen and do not natch tha dafinition* of carcinogens. 8.4. What Haa Bnnn Characterized at Cancor In Thn Bioaaaay Literature? Thar* haa haan great controvarap ovar tha ralavanc* and noaanclatur* of rodant hapatic laaions. Host of tha controvarap surrounds tha uncertainty aaaociatad with tha diagnosis of cancar histologically prior to progression to tha classical nallgnant state. Tha National Cancar Iontitut* aponaorad a workshop on tha classification of ha* patoeallular cusor* and ralatad laaions of rats. Thar* war* 20 participants. A rtcomndtd class iflest ion and nonane latura of tha livar laaions resulted (Squire and Lnvit 1973). Than* raconandations war* not unaninoua and hav* not baan uaivaraallp accepted, hut ara utilised in aanp of tha govarnnnnt supported retports of PCS carcinogenesis. The following definitions reflect tha NCI posi* tins. Consents haw* baan added whan relevant to eaphssisa the ganaral affect of tha NCI raeoanandations that can ha characterized as enforcing an expansive phi* loaophp in defining ch* neoplastic potential of livar laaions. HONS 213164 8.3. Cholsnplofibroais (Adenofibrosis) This lsion is characterirad by foci or araas of hyperbasophlUc, atypical ducts In a fibrous stroaa. In most cisas, thara Utar develops an excessive formation of collagen or of cystic gltnduler apacaa. These laslons could ba tha "clones" rafarrad to aarllar. Tbs aatura of tha lasloa la coatrovarslal but was aot conaldarad precarcinogenic by Stawart and Snail (1937). Adaaoflbroaia rafarrad to by Kimbrough la Idantlfiad as tha cholanglofibro*is rafarrad to by Ito. Kimbrough and Ito have obsarvad adaaoflbrosls la rats sad lea that wara fad PCJs. Tha PCJs tastad by Kimbrough, producing adaaoflbrosls, vara eontanlnatad with traca aaouats of chlorinated dlbanxofurana. Sdanofibro sis can but doaa aot always occur concomitantly with hapatocallular carcinoma In redacts, although lncraasad incidaaca of hapatocallular tumors hsva also baan raportad In rodaata aftar exposure to DDT, Disldrin, hirax, and Kepoae, thaaa compounds do not producs adaaoflbrosls llvar pathology. Kimbrough spaculatad that it is posslbla tha PCla causa adaaofibrosis through lipid paroxldatioa, vhila Nlrax, Kapona, DDT, and Disldrin do not. 8.1. Foci or Armas of Callular Altmrstion. Tha choice of the term "foei" versus "arts" has traditionally dspaadad upon tha judgamant of tha pathologist Tha tars "foci" la usad for small laslons lass than 1 llvar lobula in alas. Tha tarm "aran" vaa racommandad by NCI for daslgaatlng laslons approximately as Urge as or larger than a lobule. Tha primary alterations involve the tinctorial quali ties and taaxursl appearance of tha eytopUsm of hapatocytas, and tha recom mended terms are purely descriptive. Thara is no obvious disruption of the llvar architecture, and tha plates of affected calls marge without demarcation with surrounding llvar tissue. Affected liver calls nay ba larger or mailer MONS 213185 31 then normal hepatocytes, and son* nuclai nay be enlarged, vaaicular, or hyperch* remade and have large nucleoli The calls in ground glass or eosinophilic foci are usually nlarged due co an increase in cytoplasm. The cells in basophilic foci have a diffuse cytoplasmic basophilia and may be larger or smaller tnss normal liver cells. Clear ceils are usually normal in size or somewhat larger- The nature of these lesions is controversial. Some feel that the basophilic "foci" or "areas'' have greater significance with respect to tumor development then do the other cellular aitarations. Moat agree that "foci" or "areas" sre eytologically similar to the cellular elemaata of neoplastic nodules end some feel that "foci" or "areas" may possibly be pert of tho spectrum capable of pro gressing to the formation of nodules. These lesions muse be considered to be functionally equivalent to elonos. 8.7. Neoplastic Nod ulna. This term was suggested by NCI to replace "hyperplas tic nodules." The term describes spherical lesions that uaually occupy an arse equivalent In size to that of several liver lobules in which the normal liver architecture Is absent within the nodules. Hepatocytes within the nodules ere similar to those in foci or areas end may show mixtures of the cytoplasmic al terations. Nitoses and varying degrees of nuclear etypia Including enlargement, hyperchroaesle, doubling in number, end enlarged nucleoli ere sometimes present. The cells may be arranged in solid or Jumbled sheets or in irregular e plates, one or more cells thick. Sinusoids osy be compressed by enlarged hepstocytee or show varying degrees of dilation or ectasig. Portal areas are usual ly not prosent, although in rare cases they may be localized inside the nodules. An important feature is the architectural distortion sad sharp demarcation of the nodule from the surrounding liver around at least e portion of its HONS 213186 32 periphery, The pitta* of nodules' etllt ere usually not continuous with cheat of uatffocttd llvor; rathtr they taping* perpendicularly or obliquely upon :h tangentially arranged normal plataa. Tht lattar art often narrowed dua to eopraaaioa by tha expanding aodult. The NCI daciaiona to recomead tha tan aaoplaatic aodula waa hat ad upon tha SCI conclusion, aot universally shared, that tha experimental and biological evidaaca aval lab la juatiflad it. Tha NCI evidence ia interpreted u suggesting that auch aodulaa art proliferative laaioaa, tad faw would argue this point, however, NCI goea one a tap farther tad atataa that aodulaa are known to be ia* duead by carciaogeas tad, at tha laaat, aodulaa indicate an iaeraaaad probebili* ty for tha development of hepatocellular carclnoaa, Moat worker* would agree that chronic Injury will reault ia prolifarativa laaioaa but aoat workara would alao agraa that, at laaat initially, theaa laaioaa have tha capacity to ragraaa upon removal of tha agent cauaing Injury, Chlorinated compounds precant unique problem becauaa their paraiataaea complicates experiments atudying raaoval of tha agent. It should b* pointed out, however, chat theaa leaiena are typica. of other compounds auch as phanobarbital. The diffaraace is that phanobarbital ia rapidly excreted. Tha induction of prolifarativa lesions due to chronic cellu* lar injury la part of a predictable biological response and should not be con* fusad with similar lesions that are associated with tha irreversible procaaa of care Inoganaais. Neoplaatle aodulaa are considered by NCI and other* to represent part of tha epeetrua of response elicited by hapatocarcinogens ia rodents. However, this view la aot shared by all scientists ia the field. Persona subscribing to this thesis suggest that areas of alteration will develop, that some of these will HONS 213i7 33 bacons nodules Ud chat sooa of cha nodules will in tiaa transfora into hepato cellular carcinoses. A nuabar of carcinogens hsva produced this ipactrua of rs* apoaaa. It la cautloaad chat chara aaad ba no difference In tha obaarvad raapoasa spectrua even vhaa cha chaaicel producing cha aodula 1a an unaabiguoua gaaotoxlc carcinogen or oaa of tha polyhelogenated cyclic hydrocarbon*. 8.8. Hepatocellular Carcinoma. The diagnoala of hepatocellular carcinoaa by NCI is based upon charactarlstic histological and cytological features whose cores* let ion with cancer NCI claiaa is wall docuaenced in the pathology Utarstura. This definition aiiminatad tha necessity of observing several classic endpoints including invasion, metastasis and lethality. Hepatocellular carcinomas, by NCI definition, are usually considerably larger and aore irregular than naoplascic nodules, and they aay involve major portions of liver lobes At tha periphery, they coapreas or axtend into tha surrounding paranchyaa. Trabecular carcinomas aay ba classified as wall to poorly differen* tlaced, depending upon their rasaablanca to normal liver. Tuaor calls are in broad sheets or in plates one to several calls in thickness. .Tha lattar are ha* phuardly arranged in linear, papillary or peeudoaclnar patterns. Tuaor calls may also ba individualized or in isolated neats and corda enveloped by lining calls. A histological variant of hepatocellular carcinoaa is tha carcinoaa with a predominantly glandular, papillary pattern, resaabliag adanoesreinoaa. ` According to NCI, much variability in lesion architecture is permissible. For exaaple, the tumor calls aay res amble norasl hepatocytes, or they aay ba an* larged or anaplaatic in leas well differentiated tumors. The cytoplasm aay ba clear, eosinophilic or hyperbeaophilic, and nuclai art frequently enlarged and MONS 213188 34 hypsrehrooatic. Multiple ouelei and eitotic figures say be present. This x> ceseive inciuaiveneaa and lack of aeriet einioal eritaria war* necessary if laaiona produced bp polyhalogsnatad eye lie hydroearbont tmra to ba consis tently diagnosed aa earcinooa. It waa concluded by NCI that banign hepatic call tuaors, i.e., without potential for oalignant behavior, could not ba consistently diagnoaad. Tharafora, tana auch as "adenose" ware not reeoonended. It was alao agreed that the tan "heps* tons" was inprecise in ita usage and was not reco--ended for any of the laaiona under discussion at the workshop. The raeomandationa developed by NCI allow for the inclusion of proliferative lesions that are clearly capable of regressing when the stimulus is raaoved. Detection of vascular invasion or oetastasts in contrast to tradition waa not considarad by NCI to be eaaentlal for the diagnosis of hapstocellular carcinosa. The utilisation of Inclusive cytological criteria to define what sight have the potential to becoae tha disease process we call cancer waa eeeonplished at the expense of including nany responses which will never progress, invade, metasta size or kill. 8.9. What Lsvel of Confidents Can bo Pieced on Liver Tumoral Over the past saveral years, 3* er 23X of the 230 chesicals teated by tha National Cancer In* atitnte (NCI) have been found to Induce hepatocellular neoplaaus in rata and/or ice. Vhat predictive power do these results hold for aetlaating risk eo ehe huaan diseasa CANCES? If we are to sake rational decisions, we aust appreciate the cooperative patho- MONS 213169 35 genesis of rodent liver neoplasia. The hepatocellular neopleeas of nice have variously been referred to ae livor tuaor*, hyperplastic nodulas, typs A or 3 codulas, and hepatocellular adeooaa* tad earelnoaas (Ward and Vlahakis 19*9, Frith and Ward 1979, Butlar and Nawhama 1975). Tha biologies! bahavior of that a nodulaa has baaa and continual to bo a subject of hsatad dabata. It has boon demonstrated, at loaat In soae systeas, that sone of tha poorly difforantiatad snail nodulaa can grow progressively to larger nodulaa that ara transplantsbla and nataataalza to othar tlaauaa (Vard and Vlahakis 1979, kil lians at si. 1979). Tha snail and/or battsr differentiated nodulaa (sonatinas eallad hyperplastic nodulaa, adanonas, or typo A. nodulaa) ara usually not transplantsbla and do not natastasizs (lutlar and Newborns 1975). Tha norphelogy and biologic behavior of these nodulaa are slnilar to these of adanonas in other aurine tissues (Vard and Vlahakis 1979). However, foci of trabecular carciooots often appear in these adanonas (Frith and Vard 1979, Vard and Vlahakis 1979). The larger and/or lass differentiated nodulas (tamed hepatocellular earelnoaas or type I nodules) usually appear norphologically different fron snail nodulas (Frith and Vard 1979). A fair earelnogans indues hepatocellular naoplasss that appear the sane fron the tine they are snail tuners (early stages) until ehey bacons netastatie minors (Butler and Nevbeme 1975, Vard et si. 1979). Sons le sions have been classified by eerttln authors as hyperplastic nodules without evidence that they were not neoplastic or did not represent the early stages of careinone. There ere reports (Ito at el. 1976, Periano et at. 1973) that indicate that he- HONS 213190 36 patocellular nodules is nous* liver nay regress if exposure to ch alleged car cinogen la discontinued at a specified tin*. Studies with other carcinogen* de monstrate this does not always occur (Frith and Ward 1979, Butler and Newberna 1973). An extreme view suggests that all hepatocellular neoplasms originate as carcino- an (Stewart 1975); therefore, cheaicals indue in* these tumors are carcinogens, even if the carcinomas do not Invade or aetastasLze. A aore aoderate view la that soae, hut not all, liver tuaors teraed edenoaaa, hyperplastic nodule* or type A nodules aay represent as early stage of earcinoaa formation (Vard and Vlahakis 1978). Whan evaluating the following oncogenicity studies, the reader is cautioned that the aeaning given certain tarainology is that of the original author's and no atteapt has been nade to provide translations. 8.10. PCB Oncogenicity and Related Studio*. The polychorlasted biphenyls (PCI*) present distinct probleats when stteopts are aade to estimate a potential cancer risk to saa. The crux of the dileans is the need to develop a relevant Interpretation of cancer risk froa reports of an excess incidence of rodent liv er tuaors of unknown etiology. The effects covered in the following expanded discussion of liver toxicity enphsalse lesions produced by PCI* in the liver of rodents. 8.10,1. Oenersl Hepatotoxic Effects. Polychlorinated biphenyls in* dace aicroeooal mixed-function oxidases and cause hepatomegaly in ro dents and ether navels. Hepatomegaly has been interpreted by Kimbrough to be the result of the hypertrophy of individual bepatocytes. Hyperplasia also coononly occurs and increased mitotic activ- HOMS 213191 37 icy caa occasionally be notad. Kapacoeytas enlarge and nay accumulate lipid in chair cytoplasa. it tha ultrastructural laval, enlarged hepacocytaa show an increase in sisooth andoplasnie reticulum and inclti' a ions within tha cytoplasa, which appaar lika concentric whorls, surrounding lipid vacuo las. Morphologic changas in tha a^tochondria hava also baan dascrihad (Kimbrough at al. 1972). In addition to thasa altarations, PCBs induca experimental hapacic porphyria (Gold' stain at al. 1974). In tha rat, axparinantal hapacic porphyria only occurs in tha Shaman strain famela. This ebsarvation indieatas a unique aansitivity for the Shaman feaale rat. On aicroseopic^exam ination, an incraasa in aacrophagaa and pronlnant Kupffer calls con taining brown ceroid pignant and necrobiosis of liver calls is proalnent. Lipid accumulates in tha cytoplasna of hapatocytss, re sulting at tines in hapatocytss with foany cytoplasa. cute as wall as chronic toxicity of PCBs has bean studied in rats, aonkeya, aica and cows (SHEW 1976, Kimbrough, at al. 1972, Allan, at al. 1976) and tha organ consistently affected was tha liver. For ex* sap la, whan asla Sprague-Sawlay rats ware fad a diet containing eixturas of PCS isornrs (Aroclor 1248, 1254 and 1262) at a concentration of 100 ppa in tha diet for 32 weeks, chare was an incraasa is chair Sa na lipids and cholesterol and a transient increase in triglycerides accompanied by distinct aorphological changes In tha liver (Allan at at. 1976). Generalised liver hypertrophy and focal areas of hepato cellular degeneration were followed by a wide spectrum of repair proc esses. The tissue levels of PCI were greater in the aniaal receiving e MONS 213192 38 the high chlorine mixtures and high lava la persisted after the PCI treatment had bean discontinued. 8.TO.2. Neoplastic Effects. Nlshisual, (1970) acudlad tha effects on mouse and monkey livar of long-term oral administration of polychlo- robiphenyli (PCB), 1.) mg/dey or more, at aalactad Intervals 67 light and alactron microscopy. Kepatocytee of craatad alca eontalnad larga amounts of acidophilic aatarlala la tha crtoplasa, and fatty vacuoles vara obaarvad latar, Structural ehangaa la tha hapacocytaa coualatad of a marked lacraaaa of aaooth aadoplaaalc ratlculua, a raductloo of rough aadoplaaalc ratlculua, "ayalla figure" formation la tha cyto- plaaa, and an lacraaaa of aicrobodlaa aad lyaoaoaaa. A marked la* craaaa la lipid droplata van obaarvad latar. Results of alactron alcroacopy avaluation of aookay livar showed as lacraaaa of aaooth aa* doplaamie ratlculua la tha hapatocytaa aad awalllag in tha Kupffar calla, with as lncraaaad nuabar of lyaoaoaaa aad vacuolaa. Judging froa tha findings by alactron microscopy, characteristic las Iona of . livar calls warn produced by PCI administration. Kiaura and Baba. (1973) obaarvad similar changes la the livar of rats. Crossly, all the rata logaetiag more than 700 mg of PCB showed hypertrophy of tha . liver. Pinhead- to pear-aired (sic.) round and pale brown flacks or nodular were acattarad on the surface and on tha cut-aurfaca of tha liver of all the faaala rata In tha experimental group ingaatlag more than 1,200 ng of Kanechlor-iOO. Mona of the mala rata showed such vi sible nodular ehangaa in tha liver in spite of having ingaatad a cor responding or even higher amount of PCB than females. Again a female rat aalactiva sensitivity la observed. c HONS 213193 39 MicroscopicalLy, changes in the liver of experimental rota showed fatty degeneration and multiple adenomatous nodules. Th* former waa aaan, irrespective of sax, in all the animals of the experimental group, hut only In 2 faaalet in tha control group. Tha lattar, which appaarad to ha a benign naoplaatic laaiou, was aaan 1a all tha faaala rata lngaating more than 1,200 mg of Kanechlor*400 aa pradictad by tha groaa axaainatlon. In sharp contrast, howavar, tha liver specimens of tha aala rats ravaalad no such nodular changas, avan in tha anintis who had ingastsd a eooparabla or highar amount of Kanech lor*4.00 chan fasulas. Lung abacaasas, pnauaoaia, aplaan atrophy, and intracranial abscaaaaa wara found frequently in tha axpariaantal group, and this auggostad that tha rasistanca of tha rata traatad with Kanechlor*400 to in* faction waa lowarad- Oapilatioa also appaarad frequently in tha u* pariaantal group, especially in tha faaalas whan tha PCI intake amounted ^o about 600 ag. PCBa induced banign adenomatous nodulas axclusivaly in fomalo rats. Nagasaki at al., (1972) studied tha bapatocarcinoganic affacta of po lychlorinated biphenyls in dd nice. Strain dd nice with an average weight of 19.Og ware used. A total of 114 nice ware divided into the following 10 groups and tha aninala wara fad on a basal diet (Oriental NHF) supplemented with various kinds of polychlorinated biphenyls, Kanecrol'SOO, Kanacrol-400, and Kanecrol-300, which are classified by tha nuaber of chlorines, purchased froa Kanegafuchi Chaa- Co., Osaka. The groups wore as follows: Group 1, 500 ppa Kanecrol-iOO; Group 2, MONS 213194 40 f 1 30 ppa Kanecrol-SOO; Group 3, 100 ppa Kanecrol-SOQ; Group 4, 500 ppa Xaaacrol-400; Group 5, 250 ppa Kanecrol-400; Group 6, 100 ppa XBerol*400; Group 7, 500 ppa Kaaecrol-300; Croup 0, zjO ppa Xa&ecrolOOO; Gzoup 9, 100 ppa Kanecrol-300; Group 10, basal diet alone. Etch group contained 6 to 12 aie. The aninels vara given vc tor and the experimental diat freely. After 32 vka, ale* vara sac rificed with ether and examined his to logically. Grossly, 7 of the 12 aica (5S.3*) in Group 1 had aany tuaors la tha liver. Tha livar inetaaaad in weight, and had a rough surfaca with oultiplo tuaors up to 0,2 to 1.0 ea in diaattar. In othar groups, axcape in Groups 1 to 3, no rtaarkablo changas wars obsarvad in tha liv ar of aica. Microscopically, hepatooea vara obsarvad in tha livar of aica in Group 1. Soaa araa of nodulas shovad an adanoaatoua pattern. tlany nacrotlc foci vara aaan in Group 1 animals. Nualear irragulari- / tias and oitotic figuraa vara frequently saan in noatuaoroua araas of tha livar la Group 1. Kovever, aicreacopical chaagaa in tha livar vara not obaarvad in Groups 4 to 9. Tho hepatomas induced In mica by tha Kanacroi-SOO of potyehlorinatad biphenyls appaarod similar to thosa inducad by tha -iaomar of banzona hexeehloride. Kanacrol-400 and Ktnecrol-300 had no carcinogentc activity In tha livar of mica. Uabrough, at al. (1972) fad aala and faaala Sharoan (train rats poly chlorinated biphenyls Aroclor 1260 and Aroclor 1234 at 0, 20, 100, 500 tad 1,000 ppa in chair disc. Rats rseaivad the dietary levsla for MONS 2131*5 eight neatht- Light eicroacopie changes consisted of hypertrophy of the liver cells, inclusions ia the cytoplasm, brown pigment in Kupffar cells, lipid aeeuBulstion, sad, at the higher dietary levels, adeaofibrnsis. Ultrestructural changes ia the livers of exposed aaiaals consisted of an lacrosse la saeoth eadoplesaic reticulum sad atypical ltochoadria. Lipid vacuoles were oceassionally surrounded by con centric membranes - The epithelial component of edenofibroiis consisted of goblet cells and eells that resembled the epithelium that lines the bile duets. In gen eral, the effect of Aroclor 1254 on the liver was more pronounced then that of Aroclor 1260. Allen end Abrahaasoa (1973) fed rats diets containing 0.1% of throe polychlorinated biphenyls (?Cls) (Aroclor 1248, Aroclor 1234, Aroelor 1262) for six weeks; those rats showed a progressive enlargement of the liver. This liver hypertrophy is attributed to proliferation of the smooth endoplasmic reticulum, development of large eenbraaous concentric arrays, and increase in lipid droplets within ehe cyto plasm of the affected liver cells. Liver homogenates had increased levels of protein end WfA and reduced concentrations of DNA, while the mierosomel fraction had increased levels of protein end phosholiplda, mad reduced levels of cholesterol. Alto, there were modifications ia the activity of certain hepatic microsomal enzymes, By the sixth weak, the animals progressed from a stimulatory effect on the liver by PCBa to a stage where regressive hepatic changes ware occurring, such as a decreased activity of microsomal enzymes, dissolution of concern- HQ NS 213196 trie aeabrana arrays, vasiculation of tha endoplasaic rsticulua, and accuaulstion of lipid droplots within tha cytopltsa of tha affactad calls. Ito at al. (1973) studied tha affacta of technical grade polychlorinatad biphenyls (PCIa) on aousa livar histologically and ultrastrue* rurally. Pathologic studies ware also aada on tha affacta of PCIa on tuaorlganesis induead by bannaaa haxachlorida (BHC) in aousa livar. Naoplaatic changaa wara obaarvad in livara of alea fad a basal diae containing 300 ppa of tha PCI, Kanachlor 300, for 32 waaks. dayloid daganaratioa in tha livar of aica was obaarvad in (roups fad a diat containing lowar coacantrations of PCIs. Histologically and ultra* structurally, tha neoplastic areas of aousa liver Induced by PCIs ap* ' peered to bo typical of nodular hyperplasias and vol^differentiated hepatocellular carcinoaas induced by 8HC. The affects of PCBs on neo plastic changes induced by isoaors of BKC in the livar of aiee fad a diet containing BKC with or without PCBs was dotaralnad. Only those receiving 100 or SO ppa of tha a-isoaar developed nodular hyperplasia and hepatocellular carclnoaa. However, aaong the groups fed 3HC plus PCBs, only those receiving 100 or 30 ppa of a*3HC or 230 or 100 ppa of B-BHC developed nodular hyperplasia and hepatocellular carclnoaa. Groups fad T*1HC with or without PCBs did not show naoplaatic changes of tha liver- PCBs themselves me res sod hepatic neoplssms in mica and also sddad to tha inerossa in tumors inducad by a*BHC and B-SHC. Bursa, at si. (1974) fsd rats 100 ppa of Aroclor 1242 (B.g to 3.B9 MONS 213197 43 eg/kg/day) or 100 ppa Aroelor 1016 (6.9 to J.5 ag/kg/day). Plasma, kidneys, urine, brain, liver, and adlpoaa tissue war* analyzed for po* lychlorlaaead biphenyl (PCS) residue* at 0.5, 1, 2, 4, 6, 8, and 10 oaths of exposure. Ib additional groups fed the experimental diet for 6 ngnth*, PCS tissue levels were determined 2, 4, 5, and 6 aont&s after ths exposure to PCBs was discontinued. PCS* were highest In adipose tlssua whera a steady state was approached la 2 and reached in 4 Months. Little ?CS*darivad eatsrial was excreted in urine. After discontinuing PCI exposure, Aroelor 1016 was eliminated aor* rapidly fro* the organ than Aroelor 1242. Measurable residue levels war* still present after 3 (Aroelor 1016) and 6 (Aroelor 1242) sooths of recovery. Microscopic examination of the liver showed ehlgrgtd livor cells with vacuolated cytoplssm snd inclusions. Kimbrough and Linder (1974) fad two groupt of 30 BAU/cJ inbred sale alee 300 ppm of a polychlorinated biphenyl, Aroelor 1254, in the diet for 11 dad 6 Montha, raapactivsly. The 6 aontha' feeding was follewsd by 5 abntfth' recovery. Two additional groups of 50 oice each ware fad plain shoe. All 22 surviving ales fsd Aroelor 1254 for 11 oonths had grsatly In* larged livers representing 25* of their body weight, whereas thoiA fid the experimental diet for 6 oonths only had slightly, but significant1 ly, enlarged livers. Adanofibrosis was observed in all 22 livers of lem fad Aroelor 1254 for 11 aontha hut not in the other groups. Of the 22 mica fad 300 ppm Aroelor 1234 for 11 months, 10 hsd hepaiomBs measuring 0.1*1.5 cm in diameter. On# of 24 surviving mica fad Aroc* lor 1254 for only 6 montha, followed by a control diet for 5 month I, had a hepatoma 0.3 cm in diameter. No controls had hepatomss. MOMS 213198 u I to, at *1., (1974) observed Uvir weigh: increases in groups on discs suppleeented with Kaaachlor-500. -400, or -300, ths incrssss being greatest la ths group that received 1,000 ppa of Kaneehlor-500. In ssvsrsl groups, irregular-shaped yellowish oodulss of up to 1.0 ca in diaastsr wars sssa oa ths liver, but oo cirrhotic changes wars do* tsctod. ' No hepatocsilular carcinoma was sssn in any of ths rats, but arsas of eholangiofibrosis wars found in ths liver of rats given 1,000 ppm of Kanechlor-500, -400, or -300- Nodular hyperplasia was found la 34 12.OX of ths aalaals given Kenechlor*i00, 30 - 12-5X la those treated with Kanechlor-400, and 6 4,J% of those which received Kaaechlor-300. The Incidence of aoduler hyperplasia of the liver was highest la the groups given Kaaechlor-500 sad lowest la those given Kaaechlor-300. Oval call proliferation and bile duct proliferation were seea ia all- groups of aalaals treated with Kanachlor. Hyper trophic changes of liver psrsachyaal cells la caatrllobular areas wars clear la groups that received 1,000 ppa of Kaaeehlor-500 or -400. Aaylold degeaeratioa of the liver was seea oaly ia the group given 100 ppa of Xaaeehlor*400. No raaarkable changes were seea 1a other organs of either experlaeatal or eoatrol rats. Kakiura, at si., (1974) Studied the affects of polychlorinated biphe nyls (KBs) oa liver carcinogenesis in rsts treated with the hepatic carcinogens 3'aethyl*4*dlsethylaalaoazobearane (3'-tie*0AB), N-2fluoraaylaeetaaide (2-FAA), and/or diechylaitrosaaine (DEN). Aalaals were exaainad histopathologically after they had received the exp- MONS 213199 exlaeneal diet lor 20 weeks tad then eh* stock di*t for 4 week*. Liv er erasers developed in 63.2, 33.8, end 92.3% of rtts in groups treated with 0.03% 3'M**DAB, 0.013". 2-FAA, ud 0.0025% DEN, respectively. kata that received 0.03% PCI only did not develop liver tutors, and thoee treated with PCB sad eh* carcinogen* developed only a few tutors. Multiple liver aimers developed altar treatment with 0.03% 3-Me-DAl plus 0.0025% DEN (92.3% incidence) aad 0.015% 2-FAA plus 0.0025% DEN (81.8%); after treatment with these combinationa plus PCB, tha incidence of liver tumors was vary lew or saro. Histologic examination showed that PCS inhibited development of noduler hyperplaeies, ovei celt infiltration, and bite duct proliferation as well as hepatocellular carcinoma Induced in the liver by the chemical carcino gens- Ito at at. (1974) induced nodular hyperplasias hut not hepatocellular carcinomas In rata with PCBa. Some of the findings confirmed those of Ulmers and Babe (1973). These studies showed that all hinds of Xanechlor are tumerigenic in tha rat liver. Marked cholengiofibroals fade* aofibrosls) was seen in the rat livar. Kimbrough *t a!., (1975) utilined Sherman strain famala rats (ZOO) fed 100 ppm of a polychlorinated hlphenyl (Aroclor 1260) for approximate ly 21 months, aad kapt 200 famala rata as controls. Tha rat* wars hiHad wham 25 months old. Twenty-six of 184 axparimantal animals and one of 173 control* had lesion* interpreted by histologic criteria as hepetoeallulax carcinomas. Nan* of the controls but 146 of 184 exper imental rata had neoplastic nodules in their livers, ireea of hapato- MONS 213200 cellular alteration war* noted in 28 of 173 control* and 182 of 184 expariaantal anisela. Thu* tho polychlorinated biphenyl Aroclor 1260, whan fed in the diot, wii interpreted sa having a hepatocarcinogome effect in thaaa female rata. It i* worthy of nota that hepatocallular can noma waa baaad on tha controvenial NCI definition. The incidence of tuaor* id other or*ana did not diffar appreciably between tha axpariaantal and control groups. Hapatoeallular alterations wara obaarvad in a high pareantaga of tha control animtla. Nat. Caacar Inat., DHEV Publication No. (NIX) 78-838 C1978) roporxad tha bioasaay of Aroclor 1234 for possible carcinogenicity. Tha blonsany vaa conducted by adainiatarlnf tha teat ehaaienl in faad to Pitch er 344 rata. Groups of 24 rata of each ana vara adaiaiatarad Aroclor 1234 at one of tbraa doaaa, either 23, 30, or 100 ppe, for 104-103 - veeka. Hatched control* eoaaiatad of groups of 24 untreated rata of each tax. All surviving rata war* killed at 104-105 vaaka. Mean body weight* of aalaa and faaalaa receiving aid and high doaaa and faaalaa receiving low doaaa of tha ehaaieal wara conaiatantly below thoa* of tba corraaponding control*, baginnlng at aboat weak 10 of tba ttudy Tha dacraaaa in survival earing aalaa, but not aaong faaalaa, abowod a algnificaat do**-related trend. Adequate nuabsra of anlaala of botb saxes aurvivad for saaaingful ttatiatleal analyast of tb* incidence* of taxors. The coablnad incidancaa of lyapboaan and laukeaiaa abewad a tignifleant dosa-ralntnd trend in aslns (controls 3/24, lew-dose 2/24, aid-don* 3/24, high-doa* 9/24, P 0.009). However, tha direct coa- HONS 213201 psnsons of sach dosed croup with those of the matched controls ware not statistically significant, and tha tumors cannot clearly so re* latad to administration of Aroclor 1254. Hepatocellular adanoaaa and carcinomas vara found in the dosed croups, but not in tha controls (sales: mid-dosa 1/24, high-dose 3/24; fancies: aid-dose 1/24, high-dosa 2/24). Additionally, a ha.jh Incidence of nonaeoplaatie hyperplastic nodules was noted in the dosed animals (ntlaa: controls 0/24, lov-dosa S/24, id*dose S/24, bigb-dosa 12/24; tansies: controls 0/23, lov-doaa d/24, nid*dosa 9/22, high-doae 17/25). Although the incidences of tumors were not significant, the occurrence of the hyperplastic nodules appeared to be rotated to edmmittrit>on of the chemical. In the stomach, jejunum, or cecua, adenocarcinomas vers observed in tvo dosed asles and in two dosad fenelee as vail as s csrclnooa in ona dosed male. None of these lesions vas found in control animals in this study. Historical incidence* of thaaa tumors at tbia laboratory (6/600 oalsa [IS], 2/600 fsmSlss [0.3S] suggest that the lesions, al though not tetistleally significant. ssy be related to cbe adminis tration of Aroclor 1254. It was concluded that under tha conditions of this biossssy, Aroclor 1234 was not carcinogenic in Fischer 344 ret*. i.tl. Tumor initiation Modification. The effects of PCts on earcinofeaielty of various chsmicsls have been investigated by numerous groups. Kanschlor-500 in endblattlon with 3'msthjl4-di*sthylaminoagobsntans, N*2*fluorsnylacsttmlde ( HONS 213202 46 end dlethylnitrosamina la the diets of rats markedly decreased cha formation ot hepetocsreinoass (Mekiura. at at. 1974), Kimure at ll. danonitrated that pre* traetaent with Kanechlor*400 la diats ef rata A Booths prior to tad 2 month* during traataant with 3'methyl-A-dimethylaminoetobefliane protected tha rits against tha formation of hapstoearcinoaas induead by this carcinogen. pC3a wtra shown to add to tha affacts of BHC by Ito at al. (1973). Tbasa findings suggast that in taras of affaets on tuaoriganasia, tialng is iaportant in tha applies* tion of PCS to tha dlata of laboratory animals. Traataant with tha PCIa prior to tha sdalniatration of a carcinogan can rasult in raduction of tha tumor rasponaa. vharaaa traacaant concur rant with a oneogaa can rasult in anhancaaant of tha tuaoriganlc rasponaa. Tha inhibitory offsets of tha PCBa vara assumed to ba dua to tha Induction of hapatie nierosomsl enzymes, vhila tha onhancaaant was aseribad to tha sdditlva hapstotoxie prepareiaa of tha PCIs. Tha tvo*staga systan of mouse skin tuaoriganasia allows ona to evaluate crit ically tha initiation and proaotion phases of eareinoganasis individually. This systaa allows ona to study tha offaeta of aediflara on initiation and proaotion separately in a skin carcinogenesis assay. Tha results of Barry at al., (1979) demonstrate thet PCBa possess th capacity to decrease tumor initiation m a mouse skin assay and that at the doses utilized, PCB* had no initiating or pro* meting properties, lerry, et si. (1979) tatted PCI* for pronotins activity in OUte skin with s high (200 naol) initiating dose of DmBA. In a 30-weak erase* a ant period, tha normal DM1A-initiated, TPA-prowoted controls yielded approxl* merely I papilloess par oouta, PCBa (at dosaa of 100 ug/nousa given twice weakly) did not pronote tha development of skin tumors. Whan tasted without DMBA initiation, PCBa did not demonstrate any carcinogenic activity. PCS* did not produce any observable skin lesions. Tha anticarcinoganlc affects of Aroc- HONS 213203 49 lor 1234 appear eo eorralat* wall with thair ability to indue* aonooxygenas .nryaat of eh* akin. Th*a* axpariaanea suggest chat precraataent gives tut cc in increased rat* of inactivation of eh* DKIA aolecul* relative to tb* cat* of c* tlv*tion in nous* akin. Although eh*a* data point to induction of oxidative biotrani formation aa a poaiibl* aachaniia for eh* inhibitory *ff*eta exhibited, oth*r chanissa could b* op*rating. Possibilities includ* induction in aptdaral tiaiuaa of aonoxidstiv* catabolic pathways auch aa apoxida bydrtcate, glutathiooa-3-transfer***, CDP-glucuronosyltransfaras* and others. Oxh*r possibilities includa affaetx on ONd-repair lyttaaa and on th* distribution of tb* carcinogan to th* critical targat aita(a). 8.12. Immunosupprasslv* Effects on Tumor Colla. PCI* have alio b**n raportad to act a* ioBunoiuppraaaiva aganta (Vos and >*** 1971, Vo* and Da RoiJ 19TJ, Keller and Tbigpan 1973). Sine* a auppraaaad inaunologic atat* in th* boat can enhance th* generation and growth of tuner* (Burnet 1970, Oaeti and Good 19 7i, Paan and Starrl 1972, Kabaman 1974), Karkvlait and Kiaaldorf (1977) conducted a atudy eo dataniina tha affacta of boat axpoaura to PCla on tuner growth par i*, utilising a tranaplantabl* tusor in rata. Axocler 1254, diaaolvad in corn oil, vaa incorporatad into apaclally praparad powdered diets at lavals of l, 100, 400 or BOO ppa and fad to group* of asla and ftal* Spragu* Dawlay rats, aight of aach sax par group. Subsequently thzaa ad a ditional groups of 20 aala rata vara placed on diet* containing 0, 5 or 25 ppa ,4 4 PCI. Following 30 days of axpoaura to tha ceataslnatad diata, eh* aalaala vac* inoculated with tha Vtlkar 25* carcinoaarcoo*. Th* tuners war* allowed to grow far aina days, during which tin* tha aniaaU raaainad on chair raspactiv* diets. HONS 213204 SO Tha saaa tuaor waight* of oil PCS*fad iroup* war* *ignifleantly ana liar chan tha aaaa tuaor waight of chair *ax*aacehad control afcar cha nma*dsy tuaor growth pariod, In boch malt and faaala rata, eha aagnicuda of cuoor weight inhibition diraetly corralatad with the eoncantration ol PCS In cha disc. Although fanala rata consistently howad isallar tuaora than chair aala countarperte, tha dagraa of tuaor waight Inhibition obi a rv ad at aach doaa level waa eooptrabli in both saxes. 4 Tha raaulta of thia itudy dasonacrata chat PCS (Aroclor 1234) exposure can in* hiblt cha growth of at laatc ona experimental tuaor, cha Welker 236 careinotar* eoaa la rata. Tha tumor inhibitory raaponaa of PCS waa doaa*ralatad. 6.13. Ara Chlorinated Hydrocarbon* Different? Recent reviews of specific claaaaa of chaaical carelaogaaa indlcata that corn 1atIon with autagaaaala da* panda, la part, on tha chaaical clasa (McCann at al. 1975, Andrawa at al. 1978a j, b, Uano at al. 197g). It haa baaa atatad that cartaia compounds, aapaeially paraiatant ehloriaatad coapouada including TCBa, iacraaia tha ineidanea of only livar tuaora la aica aad that thaaa tuaora aay not ba aaligntnt (Butlar aad Jonas 1978). Saloganatad chaaical* ara tha aoat nuaaroua claat of chaaical* to laduca rat or sous* livar tuaora alosa and aoat ara known not to bo autogenic. Nonauttgaaic chaaical* causing rodaat livar tuaora oust act by opigonotle aach* aa aiaan. Tha following facta aaorgo froa tha NCI bioassay program for polycyclic halogen* atad coapouada: 1. 29 coapouada studiod by NCI roprosanting 7 classos but excluding tha cyclic HONS 213205 31 polychloriaatad saries, produced tumors m novice Uvr as veil n tuaors it other sites; 2. 24 of these 29 compounds were positive la the Aidex Systea; 2. Tea of U chlorinated poijrerelic coapounds tested bp MCI produced only liver tuaore in eiee; ' 4. Four of the 10 chlorinated polycyclic coapounds that produced liver tuaori did so in only one sex; 5. None of the MCI tested chlorinated polycyclic coapounds producing only tu tors in sice produced tuaors tc sites other then the liver; end d. One of tho tested coapounds was positive la the Aaee systea. Vhea cyclic polychlorinated cheaicals are excluded. 63X of the coapounds produc ing tuaore in aouae liver sad et other sites are positive in the Aaee systea. Cyclic polychlorinated coapounds producing either nousa and ret liver tuaore la the MCI bioassay are positive in the Aaee Systea only 12X of the tiae. A review of the carcinogenic, nutagonic, and hepatotoxlc litsratura ravaals that PCls east eaay of tho criteria for producing benign neoplastic lesion and there* fore eey be oucogenic. Cyclic polychlorinated coapounds, however, produce tu* ore and Aaea systea responses different froa aost other esrclaogenie coapounds. PCBs are not positive in the Aaee' systea sad do not produce tuaore it sites oth er than the rodent liver. PCBs are unlikely to produce neoplastic effects through fenotoxie aachaaisea. Several careinoganasis bioatsayt have been con " ducted and, with the exception of Kimbrough et el. (1975), all authors con cluded that PCBs may ba oncogame but not carcinoganic- MQNS 213206 22 8.14. Carcinogenicity Summary. Th# experiments conducted with PCBs r*v**i that * 1. PCS* eusot ba initiator* because ?CB> ara not autageaic; 2. PCB* are not proaottrs of genotoxle initiator* of liver cor* and. in fact, inhibit 3'-Ha-DAB, 2-AAT and DEHA; 3. PCB* ara not promoters of DHBA in oouaa akin and. in fact, inhibit tba car cinogenic proetati 4. PCB* act edditively with tha hapatotoxln BHC in increasing liver tuaors; 5. PCB* do not enhance the carcinogenic proceas through impairment of the u*- aunt eystea e* deaoastreted by inhibition of Walker 254 eercinosircoa* cell*; 4. Liver let ion* produced by PCBt appear to have tha capacity to ragraa*; 7. PCB* only produce neopleatic lesion* of the liver. Ho tuaore have been pro duced et any ocher site; 5. Cxtreordlnery level* of PCB* aunt bo eeeuaulated before aeopleetie cbenges in the liver ere observed; 9. Only on* of oeny etudie*, that of Kimbrough at el. (1975), be* reported PCB Induced cercinoaa. Nona of tha tuaors invaded or aetestesised and the PCB vised, Axoclor* 1240, wo* of unknown purity; end 10. When only livar tuaors are produced by polycyclic chlorinated eoapounds, th* relevance end correlation to hunts cancer risk 1* saell. Tebl* 4 tuMerixe* th* carcinogenicity testing of PCBs. 8.15. Conclusion. The question is, does an experiment utilizing prolonged expo sures et high levels to PCBs, which reportedly increase* th* incidence of liver MOMS 213207 cancer la a single of a single itttla, document a hazard of increased hiutan cancer at environmental axpoaurea. Tha conclusion of this rsvlev is chat ?C3s have not bean damonatratad to b carcinogenic in an aaiaal aodal of aignificanc relevance to man, and do not peasant a caacar hazard at environmental lava Is of axpoaure. . 9. EFFECTS OF PCBS IN HUMANS Possibly tha bast avidanca of what affacts PCBs hava in humans cornea from tha "Yuaho" incident that occurred in Japan. In 1966, epproximetely 1,291 paopla in southwest Japan were affactad by an axposura of 1-2 grans of PCBs that was ing ested in a rice oil contaminated with a Japanese brand of PCBs known as Kanachlor 440 (Kuratsuae 1979, Higuchi 1976, IlJtC 1976). For a breakdown of rha symptoms observed, sea Table 7. Approximately half of tha patients complained of a variety of neurologic dis tresses such as headaches, numbness, hypothesis and neuralgia. Host of tha headaches were transient, but some recurred over a period of months to years. Higuchi (1976) has concluded that most of these probably aroaa from emotional stress or migraine conditions and were not related to PCB exposure. Measure ments of nerve conduction velocities in Yuaho patients revealed, however, that upP to BOS of the 20 patients studied had lower than normal sensory nerve ennduecion velocities but normal motor nerve conduction velocities (Higuchi 1976). Higuchi (1976) originally considered the possibility of adrenocortical hypo- function, but findings in the patients did not support this hypoebesis and post mortem examinations did not reveal any unusual adrenocortical morphology ( HONS 213206 94 Feaale patients-, 60%, did suffer abnormal aenstrual cyelas but tha changes uara ixadi toae suffered prolonged intervals of menstruation whila othara bad short* anad or irregular intervals. Deteralaatlons of urinary estrogens ravaalad a daeraasa; a poasibla axplaaatioa of this finding is as iacraasad degradation of estrogens bacausa of ineraasad liver aetaboliae (Higuchi 1976). Heaatologic exaainationa of Yusbo patiant ravaalad a slight leukocytosis and aonocytosia and larua lavals of Igi sad IgM vara gaaarally dacraasad. Surpris ingly, serua Indicators of livar daaaga such as SOT, GPT and bilirubin vara noral. Thus, although PCSs can causa livar injury in axparinantal aninals, as say haloganatad hydrocarbons do, tha clinical avidaaca at Yusho indicates that this is not a prominent toxicity in huaans (Higuchi 1976, Kuratsuaa 1976). Nonathalass, aicroscopically obsarvad changas have been seen in liver biopsy staples, but tha aajor finding, an increase in tha saooth endoplasaic reticulum, is intarpretad as raprasaativa of tha induction of tha hepatic enzymes for oxi dative aetaboiiaa, a finding ptadictad froa aninal studies and not an indication of toxicity, Analysis of other serua paraaetars also suggested a disruption of noraal lipid aetaboiisa. Serua triglyearidas vara elevated vhila eholastarol vas not. Of 43 affected children axaainad, 23 boys showed daeraasas in height end weight gain cospared to unaffected children, vhila 19 girls did not differ froa the * control group (Higuchi 1976). Also, soaa of the infants bon to voeen affected by Yuaho vara tael 1-for-data. These two findings are felt to suggest that high doeas of KBs nay retard growth in children. Tha other syeptoes in newborns in cluded dark-brown pignantation, parehaant like skin, eruption of teeth and larg er than usual fontanel las indicating trenaplacectal pasaage of KBs to tha fatua HONS 213209 JJ during ga*tat ion. Probably the noat eoooon ayapcona and cha oaaa largoly raaponaibl* for cho idan* tifieation of Yuaho'* diaeaaa vara aya and akin problaaa. Tbaaa eonaiated of aenafon eruption*, follicular accentuation, availing of eh* ayalid* vith dia* eharga fro* tha ayaa and incraaaad pigaaacaeion of eh* ahis. Cnfortunataly, van though cha ehloracaa vaa not a paraaaaae condition, it vaa a diacoafortlag diafiguraaaae that laatad for a period of aontha to yaara. (Kurattua* at al. 1972.) Vbil* tha abova affaeta daacribad in Tuaho paeianta provide a picture of tha pooalbl* coaaa*uaacaa suffarad by ovaraxpoaura to PCBa, the enact cauaa of theae dlaturbancaa la of asai debate. Tha type of PCI alntura contaalnat ing tha rice oil, Kanachlor 400, haa bean diacovarad to eoatala polychlorlaatad dibaaaofu* ran* (PCDfa) at concentration* aa high aa 18 pp* (Xurataun* at al. 1972, Higuchi 1978, EFA 1980). Maaauraaenta of tha rice oil used by Tuaho patient* ravaalod that the PCI* ranged fro* 1 - 3,000 ppo vhil* the PCOFa vara 3 pp* (Xu* rataun* 1978, Nagayaaa *t al. 1978). Tha 2, 3, 7, 8, tatrachlorodibanxofuraa iaoaar i* aa axtraaaly toxie chaaical eauaing liver daaaga, chloracna, birth da* facta and eanear la axp*rln*ntal anlnala (Huff *t al. 1980). Tharafora, it la not known which of tha aid* affaeta aaan in the Yuaho diaaaaa can b* attributed aolaly to PCI* (Vo* at al. 1970) and, if eanear i* found in tha future to have bean aignifleant ly lacraaaad la ehia group tha aoure* of induction will raaain a ' quoatlon. (NOTE*. Tha dibannofurana found In the PCI* in Tuaho incident ar* 1,000 tinea higher than thoa* uaually aaaaurad in PCI*). Baaid** eh* Yuaho incident, thar* ar* other recant report* in tha literature MOWS 213210 38 concerned with th* effects of PClt in humans. Ouv at a). (197$) studied 34 workera froa a factory in which PCBs war* added to capacitors. Air concoctritions inside the plant previous to the study contained PCI* exceeding the allowable limit of 1.0 ng/m* by 30-122% in soso aroaa of the plant requiring the installa tion of a bettor exhaust systas. Although Che induatriai hygiene of the plant hod been last than desirable, with at laeat one ease of ehiorecae and others re porting rsshea or a burning of the eyea, the clinical tests did not reveal any significant health problem. PCI blood levela of tha group averaged over 400 ppb compered to no detectable amounts in the control population, yet the bilirubin, aIkeline phoapbataae, serua protein, a1bunin, SGFT and lmiaoglobullne of the workers wets all within normal Units. Fisehbein at ai. (1979) have elso examined workers employed et a capacitor plant. In their eeudy, 126 employees were exaBined end of these the breakdown for the duration of exposure west 10% had 3 or leas rears, 20.9% had 5*10 years, 17.3% had 10-'.3 years, 11.A% had 13-20 ysars, 29.1% had 20-23 years and 11% bad greater then 23 years of exposure to PCla. Of those employees 10.7% had re ported raahes and 2*.8% had reported e burning aansatios of the skin. Upon phy sical examine:ion, approximately 40% of the group had sobs redness, swelling, dryness or thickening of the skin and 2% had abnormal secrat ions frea the eye. Overall, the clinical chsalstry of the esployees was unreserkeble and this "epaucity of abaormal results" was noted by the authors. Routine neurologic ex animations also did cot reveal any renarkable prevalence of sbootnelitUa There was, however, a decrease in the forced vital capacity of the lungs in 14% of the worksrs eonpared to 3.6% in the normal population, an unusual finding but one of unknown significance et this tine (Vershew et el. 1979). HONS 213211 37 Othtr studise concarnsd with oploy exposure have bean adequately discussed elsewhere (NIQSH 19H, E?A 1930). Theee discus* ions reveal thsc the toxic mes esc often found after occupational exposure are related to the d*ml changes discussed sad indieets lictls or no liver injury or other eysteaic problem*. While these studies indicate thet the liver injury seen la dalasis he* not been correspondingly reflected is huaan* *t the levels of PCI exposure generally en countered occupationally, s study by A1veres sad co-worker* (1977) suggests these eoaeeatretion* sey indeed increese liver oetsbolijo- The antipyrene helf-life oeesured in five workers exposed to PCBe for st leest four yesrs we* two thirds thst of the half-life of the control croup leedlnc to s 50% inereese in antipyrene clearance - Reports of hifh eaneer retee aeons Hobil Oil employees st its Paulshorn, HJ re finery exposed to PCls (Aroclor 1Z3&) hsve been interpreted sa indicative of to a possible link between PCI exposure end skin (nalenona) or pencxestie concur (lehn it el. 15T8). The Mobil study indiosted thst 8 canters developed between 1957 end 19*5 ueong 92 research cad development end refinery workers exposed for 5 or d years in the lets IPAO's and early 1950'* to varylnf levels of Aroclor 1254. Of the I cancers, 5 were malignant aalanomas and 2 were cancers of the pancreas. N10SX said, "This is sicaifieaatly sore skin cancer (nelanosM) and paacreetic eaacar than would be expected in s population of this also, based on the Third National Cancer Survey.*1 However, it it difficult to derive any conelusion* figs this study because of the soell nuabera of individuals exposed and tha variety of other agents to whieh they were exposed. It should b* noted that Monsanto Co. , in contrast to Mobil Oil, could find no ca sual relationship between caacar and PCI exposure at its plant in Sauget, Illi* HONS 213212 58 tt0is. The Monsanto study waa band on a review of the records of nor* than 300 current and foraer enployses it th* Illlnoia plane chat had been engaged in PCS production iuci 1934 (Anon 1974). Finding* of an inertaaod risk of mortality du* to malignant molanoms, canc*r of th* paner*a*. and lung cancar among workara *xpoa*d to PCSs was not corroborat*d in ths itudy of Brown and Jon*t, (1981). Thar* war* no observed d**tha du* to aalignaat aelanona and only 1 oba*rv*d daath from pancreatic cancar, whi1* 1.69 v*r* expected. Th*r* v*r* seven oba*rv*d deaths fron raapiratory systen cancar, wh*r*aa 7.69 w*r* axpeeted. Thar* waa no total relationship between in* creasing durations of eaploynent la Jobs involving FCB exposure and th* risk of aortality due to caaear or cirrhosis of the liver in th* Brown and Jonas study. 9.T. Summary of Human Hnslth Effects, The literature on hunaa toxicological effects on reproduction, birth defects, nutsgaaicity and general toxicity, has bean reviewed, as well as the literature relevant to hunan occupational exposure end eeeideatal poisonings. Th* following conclusions have been wads: PCBs rep* resent a low, acute, expoaur* hazard; nutsgenic, teratologic, and reproductive risks are ninmal; natabolisa in nan is likely lass aggressive than In rodents; end th* low levels of PCBs generally experienced in th* anvironnent pose little risk and no obvious hazard. However, there have been reports of PCIs containing highly toxic contaminants, a.g., polychlorinated dibanxofurans, and tha pres* * ence of the** contaminants could modify PCB toxieity and the health risks asso* dated with exposure- * MOHS 213213 59 m 10. SUMMARY ANO CONCLUSION Poitou ar* agents thet can produet adverse effects on t biological system Ad' vera# tf facet oay vary fro* an alteration of normal function to the date ruction of lift, ill chtBicals art capable of altering aom# function in oat organien at a large enough dote; therefore, all ehMieala could be defined as poisons. Because the definition of a poison can be broad and does not describe chose cir cumstances and condition* under which *n adverse effect can be expected to be produced, a more useful definition of the toxicity of a choaical focuses on thoee conditions predicted to develop at likely expoaurea to the chemical. Evaluation of experimental evidence end establishment of relavance to aan ia ne cessary before defining riak or haxard to aan and the ugnitude of that risk or haxnrd. Safety la relative and is dsfinsd as the probability that a substance will not produce an unacceptable alteration of normal function under e given tee of specified condition*. The success of predictions of safety depends on the type* of experiments performed, the adequacy with which thoy have been performed, end, moat importantly, the appropriateness of extrapolating from ex perimental reeclta to man. To maximise the utility of the date, the toxicity of the material should be determined under controlled circumstances relevant to de fining the minimum conditions necessary to produce adverse effects. PC Is can be toxic. PCS* can be used safely under controlled conditions. PCI* under known conditions of sxposurs to aan, have not, with the exception of evert poisonings, produced significant adverse health effects. The litsreture ef PCI toxicity in both animals and humans has bean reviewed to predict those rendi tions under which PCS* may be considered poisonous or unsafe. Included in the literature review were studies on reproduction, birth defects, snieagenieity, HONS 213214 60 czrcincgeniCity. tad general systesic toxicity. In Addition, the literature `.as reviewed for data relevant to human occupational expoaura and accidental poison* mga. Analysis of publishsd sniasl dsts Usds to tha conclusion that, in sat* mala, pura PCBi raprasant a low acuta exposure hazard, that mutagenic, teratogenic and raproductiva risks ara ainiael, asd that the carcinogenic potan* tial of this compound has cot baan convincingly demonstrated la an aalnal nodal ralavant to ran. Tha metabolism of PCBs in nan is auch lass aggrassive than in rodants, tharafora bioactivation, nodals proposad as explaining chronic toxieitias in rodants ara inappropriate to predict siailar hazards in nan. Analysis of hunan PCI sxposura snd offset data ravaals a spactrun of toxieitias fairly eonsistant with those induead in aalnal tests. Acuta human exposures have not produced tha sigaificant liver damage seen in ehronio exposures of rodents, as evidenced by the Tusho incident. Human occupational apidaniology itudias with substantial ou^ bars of axposad workers indicate niniaal systamie toxicity and no inereasa in caacar incidanca. PCBs raprasant no tnusual hssard whan coaparad to nany "lafa" chamicali with tha exeaption of ehloracna sad sdvarsa dsrmal raspoosas. Kiaan axposura to tha PCBs that ara gensrally prasant in ehe environment is at auch lower levels and/or far shorter periods of time chan chose exposures documented for Tusho' or la capacitor plants. Iharefore, it is concluded chat low lavola of Pda post little risk and no obvious hazard. Tha chemical analysts of PCBs have shown that they often contain polychlori nated dibansofursns (PCDfs) at low levals. Tha concentrations of these toxic contaminants are generally in ehe pares-per-oillion range ia pure Pd mix . cures, but parcane of coneinaeion can be substantially increased as e result HONS 213215 61 of induteriil u*a. S^oea l**alt of KBt gofiorally foun4 io eh* *wirar.s*F,t or* t eh* ?*rt*-fir-r'iUioo roof* or Uvt, th* concomitant eonctntrttiont af mt would ba axpoctat co ho !**e*uT*bl*. For chit rooton and bacauta th* toxiciey d*c* of all PCI* axpoturaa hav* probably iceludod chi* cooetxunant, cho concern foe loo loval ax90auras to PCSF* i* (till aapectod to bo mia'ioal. Although cho frtaanea of choto eonceminenta could modify cho eoxieity of FCla and cho health riiki associated with exposure, choir axpeccsd leu ltvala should represent no wusual hatar0. MOHS 213216 il U*t of Tablw I HONS 213217 { Tofcta I ismcm or rca I (klcrlMi inaaaauoaooaoauooaoai'Ooi>aatoiotooa*ooootoo33oaat*kcBai * w CktanklpkMgfl lammra 1 Chlarloa ay MalplK i! i^ 1 ~~ _ 1 IN) 2 01 12 221.1 1 irl 2a 29? ( a utri Hi . 292.0 9 ^MU ao 120. a 0 haxa a2 . ica.a ? hapta 2a m.) MU 12 . . 129.? 9 nova ) aoi.t 10 Oaca t an.) Map mo rraa HuruiDHr at al., I9?a, NIOStf 191? ami imc lira. 10. ? )i.?? ai.io ao.M 9a. io 90.91 02.1? 09.90 00.?) ?l.?0 1 MONS 213218 n TabU 2 . mviiCM. rMHincs or cohncocial rco MOCUMS* freparty 1221 101* 1202 125* 12*0 Appearance ciaar, otita ati ciaar, o*ll* alt Clear. o*lla all lloht yallow, thick all atlchy raolha Specific ftnvliy 25*C 1.12 I.M I.M I.M 1.5/ platlllattap ana |*C| 2/5*129 121-15* 125-14* 1*5-190 105-020 Vaporization Kata at IOO*C (9/ca>/hr| -orX loat 100'C/t hr t.Tb -- o.M 0.05 0-0.21 0-0.If Water Solubility at 25*C lai/l) O.* *A -- ------------------------------------------------------------- ------------------ --------------------------------- ------r IriMairk af HMaanta Mapte* f rM Hurtilhpar at a I l(?t, HiOSN lT7 Mt (MIC I*?* ***** 12*0 l.*l 015*050 0-0.11 HONS 213219 Illtl ) (MB US(S OF MOCIMS* IV TYK tM hM :0I6 1221 Currant - C|tdirt - IriMtarMrl Urair * ita*i Irmiftr Mytfratal lci/6ubrleiii* - Hydraulic MMi - Vicwuf fua^i - Fiiuleliin lltiMMira 6)t*ilImiIc Main* CftrlNuilati fi^ar - Nltcilancii AMwihk * Wax (4i<W*ra Mubllny Afiflti Ink! * Cml.ll9 Oils - FtfUlvlAi (Kinndari * Stalams aM Catalfclnf CaapMMi x tt K X x * IraiMirh af Mmimia M*m< Fran Miriil*Hr at al l>n and IMG ItM 1212 X M l2 x X X X X X X X X IMI X 12*6 X !2 X X X X 1262 X XX 1262 X HONS 213220 Tbl* 4 peat w pooo Fst*t 9t tiapiM witn ?C|* Product* 1975 1974 Flab ut Chao* Faad Coopooaat* i&iaal Faad Proca*ad fruit l*t>f food Haata, Poultry 40.4 1.2 l.l 0.9 12.7 7.2 4.5 1.1 1.9 44.0 26 4.2 2.4 0.0 0.0 0.0 0.0 1.2 AxUptad from JUsfc and Com*Uu**n 19*4. 1973 flaxiaal Concentratiea 17. 0.7 0.0 0.0 0.3 0.0 0.0 0.0 0.3 122.0 2.3 11.0 2.9 9.0 199.5 19.2 traea > 3 ppa MONS 213221 Table 5 TOXICITY RATING CHART Ratine Probable Oral Lathal Doaa for Kuaana* Aniae! LDjq Expected Hvuaaa Dosa .1 Nontoxic 1. Weakly toxic 3. Moderately toxic i>. toxic .5. Cxtraaaly toxic 6 Supartoxic 15,000 ag/kg 5,000-15,000 sg/kg 500*5,000 Of/kg 50-300 ag/kg 5-30 ag/kg t 3 ag/kg * Average Adult of 70 kg Adapt ad froa Doull at al. 1980. A 1 Quart 1 Pint-1 quart 1 Ounca-1 Pint 1 Tecapoon-1 Ounea 7 Oropa-1 Taaspooa Laaa Than 7 Oropa HONS 213222 Table ACTUAL TOXICITY AND THE TOXICITY RATING CHART Of SOME SELECTEO CHEMICALS Agcata AniMl L0J0 rest Alcohol Ttbla celt Izoo DDT Strrehaiao Hleocisc TO lotuliau* toxia 14.000 ag/Xg 10.000 of/fcg 4,000 ag/Xg 1,300 ag/Xg 100 * 1 0.001 0.00001 * Average Adult of 70 kg Adapted froa Ooull ot cl. i960. Expected Huaca Dose* 1 Quart 1 Mn*l Quart 1 flat 1 0uacc-l Plat 1 Tcaapooo'l Ouacc 4 Orepc 1 Drop Lose Thoa 1 Drop toes Thao. 1 Dt^p MOWS 213223 MJk11 va OCMftAl SYMFTOMS OF "HWBHO* PAT IfNIS sssstSiatoMttaBt>atBii*aa OljKlIvt SmtMl I. Canaral Fatl|w Z. BiBriw 1. Brandi His* Him 2. Santa ry nawropatby 1, IWaalMI Hi** ' I. IMmii *r pain af IM IIAi (wallInf ana Hi* I* Ida Jalnta t. Cayffc ana tfntua 7. Chanyat la Mnitnai loa Mtt*a f ran Aura I tana ||M 1. Bnraltla 0. Indian Ian af frmnb In cdliaran ). Snail far data baalat B. Acmrara anmtlan* an chin. 7. incraataa algnaniailan af ylnyiva, akin ana Mitt. B. Iliclnria Fran nalbanlan lanB*. 1, Ctftant ar raca ana ayat IO. tlvar cnlaryanant Clinical tamlti I. Mlyb ICI Cnncantratlan In rat ana blaoB. _ Z, lacraata ar tarua natural llplat, ), AnnaI a b. BaBiiCaa ctAductIan valaclty ar tantwry narvnt. ), ABraiiocari leal bynorunci Ion I HONS 213224 MIIMI La U U- llakraufk (| |). Naaiakl 21 it. VtM on orceito Nlea >riL i*/% Nlaa MM *%* u fti. 1*15 Nlaa 11aura a 0*Oa i*/i Maklara || u, tlaOraopk (| |j. irtk 1915 IhiumM || |], 1lavra || |), Alloa 0 Raraack 910 19/0 1911 Allan 0 Aklakaaaaa 1*11 llckraoffc o llnOar 19 n hrawkl u u. 19/2 RarfcvllaL 0 llaaiaarf to u o|. */% > *L It. Klvarava |( al 912 IULi RILL m|f) tonin ail Mu Klca Hlca(N) Ran Hair Mutm Raltffl * n l i ! IMU lomaiocoic crrtcra or rco'a CONTOUR*, ROSACf Raatcklar-509 la Rial 500 rrmtn a Araclar 125% taaacMar-500 500 ppai/ R -M 250 aaa/2% v% RaaacOlai-500 100 |fa * O-ORC 50 ppo Toma- lain- ar LrlaOli Olukanrll, 10a, 250, 500 apa ror 2% WO Tania- aaO Latra-cOlara klH~^l*a ppo * SI Raaacklar-%00 (1000* ISaO ap--Lka LOial far aoo rayi) ' Ranacklar-500 Araclar 1200 100 ppo/21/a Araclar 125% 200 ppo/25 a rco'i Araclar I2%0 MO ap/k* fCO'a 5000 af/kf Araclar !2%0, 125%, *201 Araclar 125% aaacfclar 500 Araclar 125% Maaacklar 5o0, %00, MO ,'rvcla- I2%2. la 10 Araclar 1240, 125% 20- 1000 rritci* RaOular knaiflnln a*T wall OlffaranLlaiaO kapaLacallvIar carclaoaaa la ika llvar AOOIllva af carclaaiaaaala lya-IMC aa* fl-muc. MaMtaaai mT lOwniraili 12 wH Utopian Ic chtityai la llar 12 wh Mtoplatilc ihiapa* la llvar 12 all Raaplaitlc ckangai la llvar Llvar iMaarlaa*i11 la klfkor laclOaaco al kl|lar Paia mat. Llvar tuavr !* I1 afa-OMC war rrmlal alia ky rn chlarlMIrl Vlpkainrla. alattlc aaOwlaa ckaapa la 0/10 9/M aalaa. . ilai ana lAblkUaO Lfca Mki In ar llvar liaorl ay aavaral llvar carelaogaat, RapaLocal lalar carclaoaaa N/IH R*parplaailc aaOulat Ikt/IM AOcaallkraala MailLocallular aPanaaaa. AMl*praooLari la aaparlaaatol aaralaataaaaia, %parplacla aa Oytploala af fnirlc aacau vltk lavaalaa af aOJaaaat tliaaai, raproialva aOaafaa kaffatilai af kapaLaaaa Mia kipuaaii |M* * MO Oafatlva) IrklkUaT MBlfcar 250 cartlaatareaaa RaOolar kyrarrliiii. clwianplaf ikratla Llvar call imrvili 125% aara iriuaurd cwiiiainiiir albanrviuran HONS 213225 JJ*jL4'*MNTACHL0Ot^HNYL ajrjj-.rrniAeMLOiHMiMitMw *^,*>rrnAOitoo*iPHKYL MOT >Ar>nTIUCHLOROWPHNYL NO* rA4'J'-TITtUCHI.O(IOIPHMYL Plfur* 1 PCB STRUCTURES AND NOMENCLATURE . HONS 213226 R*f*rnc* HONS 21322? REFERENCES Albro, P.U. and Fishbein, L., Intestinal Absorption of Polychlorinated 3i' phenyls in Rets,'3ull, Environ. Corream. Toxicol. 8.26, 1972. Allan, J.R. and Sorback, D.H., Pachobiological Responses of Pciaetes to Polychlorinated Iiphenyl Exposure, Iri National Conference on Polychlorinat ed Biphpriyls , Proceedings, "3, 1973. Allen, -7.lt, and Norback, D.H., Carcinogenic Potential of the Polychlorinat ed Biphenyls, in National Conference on Polychlorinated Biphenyls . Pro ceedings, *3, 1973. ' Allen, J.R., Carstens. L.A., and Abrahaason, L.J , Responses of Rats Exposed to .Polychlorinated Biphenyls for 32 weeks, 1. Comparison of Tissus .Lavsls of.PCB and Biological Changes, Arch. Env. Contaa., 4;*04, 1976. Allen, J.R. and Barsotti, 0-A., The Effeeta of Transplaeantal and Mammary Movement,of.BCB*.on Infant Rhesus Monkeys., Toxicology.6:331, 1976. . a a. . -....................... r * Allen, J.R. and Norbaek, O.H., Polychlorinated Biphenyl and Triphenyl In* ddded Gastric Mucosal .Hyper?laa ie in Primates, Science 1979--498, J.RT3. a** ' - i * - * * " , Allan, J.R., Carxtans. L.A. and Barsotti, O.A., Residual Effects of '[ShpXtrTera Low-Lave 1 Exposure of NoiAuaian. Friaates ;to Polychiorusojcced Bi* -Toxicol". Appl. Pharesco 1.30:lco, 1974. Allen, J.R. and Abrahaason, L.J., Morphological and ;Riochaeieai Changes m 'We*" Liver ,of Rats -Fed .Polychlorinated Bipnenyls, Arvch. Environ. Contaa. *G#xiMl! 1:3, 1973. ' ' :*'1 '* ' Aly^res, A.P., -Tischbain, A., Anderson,. ICE. end Copp.es, A.. Alterrt ion ui 27rug'`Malabo lisa*`In' Workers Exposed to .Polychiorj(ft*te(l Bipbeoyls, Clin. A.cpl: Thar., '22 : W0. '19 7 7. '- * Apes, J.N., Darntfln, U.E., Ysaosaki,,E., end Lae, f.J)., Carcinegen* are MuVaVeM'"; A Simple" .Tea* 'tax Combining. LiVef Hooogenacee for Activation and Jttjejip jfp.plOajfeatjim. fame. Natl-.r-*cxd. Sci., 70:^31, ;973. Aftlrevs. A.V., Jbibaulr, I I. and. Li.) insky, W-, -The Relationship Between tAjtippgajaifijiy'an3`3u.tagenicityof-Some Polynuclear Mydroeeroons, Mutat. :31i, i?*8a............ ' ': ; ' Rptfxiw. A-V.. Thibaulr. L.H. and .LiJinsky, V., Thp Relationship Between fWMWldiPI Add Carcinogenicity'ofr^Scae Nitrossmlnpp, Mutat. Res. 51:319. 197$?^.................................. *" ' :r.* ` Afipp, Vfpuisope pci Levels Found in Mothers' Milk |n 10 States. Toxic Mat. tSWf. ?tw.- ' Appp, The Rising Clamor About PCBe, fnv. Sci. Technol 10:U2, 1976. Apofi, High Cancer Rates Aaiong Workers Exposed to PdBs, Cheo. tng. News, 54:26, 197$, ' .................... :: r MONS 213226 1  Anon, Monsanto "inds So Link Between Canetr and PCI* in korksrs, Occup Hlth. Safety Letter, 5:5, 1976. Behtt, A.Jt., Rosenweike, I , Herrxanfl, N., *c tl., Melenoxe Aft*r Expo*ur* to PCI*, New Engl. J. Ned., 295: 450, 1976. Baraotti, D-A., Msxlaz, R.J., tad Allan, P.J., Reproductive Dysfunction m Rhesus Monkey* Exposed to Low Lovell of Polychlorinated Biphenyl* (Aroclor 1244), Fd. Cosset. Toxicol. 14:99, 1976. Berry, D.L., 51i|t, T.J., DiSlovuml, J. end Juctutt, M.R., Studies with Chlorinated Dibenxo-p-dioxin*, Polybroxinated Biphenyls, and Polychlorixited Biphenyl* in * Two-state Systea of Mouse Skm Tuxorigsnssis: Potent Anticercinogsnic Effects, Ann. N.Y. Acad. Scl. 1979. Biros. F.J., Walkar, A.C., and Hedbery, A., Polychlorinated Biphenyl* in Hu nan Adipo*e Ti**ue, Bull Env. Centex. Toxicol., 5:317, 1970. Brown, O.P. and Jonaa, It., Mortality and Industrial Hytlene Study of Vorkars Exposed to Polychlorinated Biphenyl*, Arch. Env. Health. Vol. 36 3:120. Burnet, F.M., The Concept of Ixxunological Surveillance, Pro*. Expel. Tuner Re*. 73:1, 1970. Bur**, V.V., Kixbrough, R.D., et el., Storege, Distribution, Excretion and Recovary: Liver Morphology after Prolonged Dietary Ingestion, Arch. Envi ron. Health, 29: 1974. Butler, v.K., Long-ten Effects of Fhaibarbiton*-Ns on Malt Fischer Rats, Brit. J. Cancer, 37.415, 1976. Butler, V.H. and Jon**, G., Pathological and Toxicological Data on Chlori nated Pesticides and Phenobarblcal, Seoeoxicol. Environ. Saftty, 1:51.3, 197*. Butler, V.H. and Mevbeme, P.V., Mouse Hepatic Neoplasia, Elsevier, Aastwrdaa, pp. 193, 1973. Calendra, J.C., Suaaary of Toxicological Studies on Conertisl PCIs, Na tional Conference on Polychlorinated Biphenyls (EPA-S40/6-73-004) pp. 33, 1976. Cletley, A., Burse, V.V., Jennings, R.V. Villenuevc, E.C., Evidence of Tecrxchloredibenxofurea (TCDF). In: Aroclor 1254 *nd the Urine of Rats fol lowing Dietary Exposure to Aroclor 1234, Bull. Environ. Centax. Toxicol. 14:135, 1973. Dely, J.V., Jertna, D.M. and Vitkop, I., Aran* Oxides and the NIK Shift: The Metabolite, Toxicity and Carcinogenicity of Aroxacic Coapounda, Expar* entia 28:1129, 1972. Dept. HEW, Final Repost of the Subconxitea* on the Health Effects of Poly chlorinated Biphenyl* and Polybroxinated Biphenyls, Washington, D.C. July 1976. HONS 213229 2 DKEV/EPA, Masting to Review and Evaluate ?A's Stapling of PCSs in the "at of Mother*' Milk, DHEV Committee to Coordinate Toxicology and Related Pro gram ia Cooperation with Environmental Protection Agency, Bethesda, 1 :D, Sept, 23, 19*6 Dikshith, T.S.S., Rockvood, V., Abraham, X. and Coulaeon, F., Efface of Po lychlorinated Biphenyl (Aroclor 125-) on Hat Testis, Exp. Mol. path. 22:376, 1975. Doull, J., Kltassan, C 0. and Aadur, M.O., Caaarott's and Ooull* Toxicology: Tha Basic Science of Poisons, MacMillan Publishing Co-, saw York, New York, i960. Ecoblchon, D.J. and Coneau, A.M., laonarically Pure Chlorobiphsnyl Congenerf and Hepatic Function in the Rat: Influence of Foaition end Degree of Chlorination, Toxicol. Appl- Pharmacol. 33:94, 1975. Edwards, J.E. and Whitt J., Pathologic Changaa with Spacial Rsfsrancs to Plantation and Claasification of Hepatic Tuner* in Rets Fed F*ditthyiamino**ob*nx*n* (Butter Yellow), J, Nat. Cancer Inet., 2:157, 1941. Environmental Protection Agency (EPA), Aableat Vater Quality Crltsria for PCIa, (EPA 440/5-60-068), I960. . riacbbeia, A., Wolff, M.S.. lilis, R., Thornton. J. and Stlikoff, I., Clin* leal Finding! Among PCI Exposed Capacitor Manufacturing W'orkara, Ann. N.Y. acad. Sci. 320-703, 1979. Fiahbaia, 1,., Toxicity of Chlorinated Biphenyls, Ann. Rav. Pharmacol. 14:139, 1974. Frith, C-X. and Ward, J.M., A Morphologic Cleat ifteation of Proliferative and NtopUstie Kapetlc Las ions in Mica, J. Environ. Toxicol. Pathol, (in press), 1979. Oaffnay, P.E., Chloxobiphenyls and PCIa: Fotmtioa During Chlorination, J. Vator Pollut. Control, 49:401. 1977. Gaines, T.B, and Kimbrough, R.D-, Orel Toxicity of Mirex ia Adult end Suck ling Rate, Arch. Environ. Health 21:7, 1970. Gardner, A.M., Chen, J.T., Roach, J.A.G., end Rage11a, E.P., liocheo. 3iophya, Ras. Com.. 35:1377, 1973. Getxl, P.A. end Good, R.A., Occurrenca of Malignancy in Imuaodeflcieacy Disauas, Cancar 23:89, 1971. Ghieauddln, S.M.. Sanxar, R.E., and Nalaon, J.0-, Matebelisn of 2,3,2'*Trlcbloro-, 2,5,2',J'-Tatraehloro- end 2,4,J,2*5'-Pentaealoco* biphenyl in Rat Hepatic Microsonal Syatam, Toxicol. Appl. Pharaseol., 36:167, 1976. HONS 213230 . Gilbartaon, fl., and Hal*, ft. , Early Embryonic Mortality in a Karting Cull Colony ia Lake Ontario, Canada, Fiald-'iaturaliit, 35:334, 1974, Coldatain, J.A., Hiefcnan, P and Jua, 3 L., Experimental Hepatic Porphyria Induced by Polychlorinated 3ipn#nyl*, Toxicol. Appl. Pharmacol 27 .37, 1974. So Id* ram, J.A., Kickaar, P., Sargsan, K., McKinney, J.D., andValkar, 1 P , Separation of Pur* Polychlorinated liphanyl laomari incoTwo Type* of Indue* ar* on the Sail* of Induction of Cytochroa* P--30 or P*44g, Chan. Biol. In* taract. 17:69, 1977. Grant, D.L., Villanauv*, D C . McCully, K.A., and Phillip*, V.E.J., Placan* tal Tran*far of Polychlorinated liphanyl* in tha Babbit, Eav. Phyaiol., 1 1, 1971. Graan, S., Sauro, F.M., and Friaaann, L., Lack of Dooinant Lathality in Bat* Tractad with Polychlorinated Biphanyla, Food Coaoat. Toxicol., 13.507, 1973. Graan, S-, Carr, J.V., Palaar, R.A., and Oavald, E-J-, Lack of Cytogenie Ef* facta in Bona Marrow and Sparmatagoniel Call* in Kata Traatad with Polychlo* rinatad Biphenyl* (Aroclor* 1242 and 1234), Bull. Environ. Cent. Toxicol. 13:14, 1973*. Groan, $.. Sauro, F.M., and Friadaun, L., Lack of Dooinant Lethality in Rata. Traatad with Polychlorinated Biphanyla (Aroclor* 1242 and 1234), Fd. Coa*t. Texicol. 13:307, 1973b. Grbver, PL., Siaa, P., Mitchlay, 8.C.V., and Roe, F.J.C., Tha Carcinogenic ity of Polyeyclie Hydrocarbon Epoxide* in Newborn Mica, Br. J. Cancer, 31:182, 1973. Haaaond, A.L., Chaoical Pollution: Polyeblorinatad Biphanyla, Scianca, 175:135, 1972. Mabaroan, R.B., Call`Mediated Inounity to Tuaor Call*, Adv. Cancer Baa. 19:207, 1974. Kiguchi, K., PCS Poiaoning and Pollution, Academic Praia, New York, 1979. Rirayoa, T., Meatin* on Ori*ia* of Kuaan Cancer, Cold Sprln* Harbor, N.Y., fapt. 7*14, 1979. Roopingaraar, R., Saoual, A., and Krauae, 0., Polychlorinated Biphenyl In* tarnotiona with Tiaau* Culture Calla, Environ. Health Parspact. 1:153, 1972. Hnu, I.C., Van Millar, J.P., Sayoour, J.L., and Allan, J.R., Urinary Mata* bo lita* of 2,5,2',5'`Tatrachloroblphanyl in the Nonhuaan Prinata, Proc. Bee'. Exp. Biol. Mad., 150:185, 1975. Hubbard, H.L., Chlorinated Biphenyl and Related Compounds, In: Kirk*Othm*r'a `'Encyclopedia of Chaaical Technology," 2d ad. 5:289, 1964. HONS 213231 4 Huff, J.E., Moors, J A , Sarscci, R- and Toraatia, L., Long-Tann Hazards of Polychlorinated Oibenzodioxms and Polychlorinated Dibenzoiurena, Environ Haalth Perspect. 36.221, I960. Kutzinger, 0., Jamieson, W.D., Safa, S., Paulmann. I,., and Aanon, R., ;j,n. tification of Metabolic Dachlorination of Highly Chlorinated Bipnenyl m Rabble, Nature, 251-698, '971. Hutzingar, 0., Safa. S., and Sitko, V., Tha Chemistry of PCB*. CRC Praas, Clavaland, Ohio, 1971. Inagami, E., Koga, T, , Tomita, Y,, Poisoning of Chloroblphaayls, Shokuhm Eiaai Gaku Zasani, 10:-13, 1969. Inearnaelonal Agency for Rasaarch on Cancar ClARC), IARC Monographs on tie Evaluation of cha Carcinogenic Risk to Humans: Polyehlorinatad Biphanyls, Volume 18, World Haalth Publications, Albany, Now York, 1978 Ito, N., Hananoucbl. M., Sugihara, S., Shlral. T., Tsuda, H-, Fukushiaa. S. and Nagasaki, H., Reversibility and Irreversibility of Liver Tumors In Mice Induced by the x-isomer of 1,2,3,4,3,6-hextchloroeyclohexsne, Cancar Res. 36:2127, 1976. Ito, N., Nagasaki, H., Makiura, S., and Aral, Masayuki., Hlstopaehologlcal Studies on Liver Tumonganeais in Rats Treated with Polychlorinated Biphe nyls, Gann, 65:343, 1974. Ito, N. , Nagasaki, H., at al-t Histopathologic Studies on Liver Tumorigenesis Induced in Mica by Technical Polychlorinated Biphenyls and Its Promoting Effect on Liver Tumors Induced by Benzine Hexachlonde, J. Natl, Cancer Inst. 31:1637, 1973. Jelinek, C.F. and Coraeliussen, P.E., Levels of PCBa In the U.S. pood Supply, National Conference on Polychlorinated Biphenyls (EPS-560/6-7J004) pp. 747, 1976. Jensen, $., and Siwdstroa, G-, Metabolic Hydroxylation of a Chlorobiphenvl Containing Only Isolated Lnsubstituted Positions-2,2'4,4'3, -3'-Hextcalorobiphenyl, Nature, 251:219, 1974. Johnstone, G.J., Ecobichon, D.J. and Hutzinger, 0., The Influence of Pure Polychlorinated Biphenyl Compounds on Hepatic Function in the Rat, Toxieol. Appl. Pharmacol. 28:66, 1974, Kapitalnik, J., Levin, V., Couney, A.HG., Yogi, H- and Jerins, D.M. , Beano(a)pyrone 7,8-Dihydrodiol Is More Carcinogenic Than 3anzoCa)pyrene in Newborn Mica, Nature, 266:378, 1977. Keplinger, M.L., at al., Toxicological Studies with Polychlorinated Biphe nyls PCB Confarenca, Quail. Roost., Conf. Cantar, Rougemont. NC, Dec., 1971. Kerkvliat, N.I. and Kimeldorf, D.J., Antitumor Activity of a Polychlorinat ed Biphenyl Mixture, Aroclor 1234, in Rats Inoculstad with Walkar 236 Carci nosarcoma Calls, J. Natl. Cancar Inat. 59:931, 1977. HONS 213232 5 . Kiabrough, R.D., Lindir, 3.E.. and Gain**, T 3 , Morpnologieal Chang** :n Livers of Rats Fad Polychlorinated Siphanyl*. Light Microscopy and lltrastruecur*. Arch. Env. Hl:h., 23.354, 1972. Kiabrough, R.D., Th* Toxicity of Polychlorinated Polycyclic Compound* and Ralacad Chemicals, CRC C::t. Rev. in Toxicol. 2.445, 1974, Kiabrough. R.O., Gain**, T.3., and Lindar R.E., Th* L'ltrsstructur* Livtrs of Rat* fad DDT and Dialdrin. Arch. Environ. Health 22.460, 1971. ' Kiabrough, R.D. and Lindar, U., Induction of Adanofibroai* and Haoatomas of tha Livar in 3*lb/cd Mica by Polychlorinatad Biphenyl (Arocior 1254), Hat. Cancer Inat. 53;547, 19*4. Kiabrough. R.D., Squire, R.A.. Lindar, R.E., Standbarg, J.D., Nontali S J and luraa, V.Y., Induction of Livar Tuaors in Shaman Strain Faaal* S*cs by Polychlorinated Biphenyl Aroclor 1260, J. Nat. Cancar Inst. 55:1453, 19*}. Kiabrough, R.D., Squire, R.A. , at af.. Reproduction of Livar Tumors in Shar* an Strain Faaal* Rats by Polychlorinatad Biphenyl Aroclor 1260. J. Nat. Cancar Inst, 55:6, 1975. Kiaura, N.T, and Baba. T. , Neoplastic Changes u> tha Rat Livar Induesd by Polychlorinatad 3iph*nyl, Gann 64:103, 1973. Kojlaa, T,, Fukuaoto, H., Makisuai, S., Chloro*liph*nyl Poisonings, G*a*Chraaatogrsphie Detection of Chloro-Biphenyla in, the Rica Oil and Bi ological Materials, Jap. J. Legal Mad., 23.415, 1969. Roller, l.D. and Thigpen, J.E., Biphenyl-Exposed Rabbits, Aa. J. Vat. Res. 34:1603, 1973. Kuratsun*, M., Yoshiaura, T., Matsuxaha, J., and Yaaaguehi, A., Epidemio logic Study on Yusho, a Poisoning Caussd by Ingestion of Rics Oil Contaainstad with a Commercial Brand of Polychlorinatad Biphenyls, Environ. Health Parspaet. 1:119, 1972. Kuratsuna, M., Soa* of th* Recent Findings Concerning Yusho, Naciontl Con ference on Polychlorinated liphanyla, (SPA 560/6-75-004) pp. 14, 1976. Kuratsun*, M,, at al., Morikawa, Y., Hirshata, T., Nishizuai, M., Kochi, S . An Epidaaiologic Study on "Yusho" or ChlorobiphanyLs Poisoning, Fukuka Acta Mad., 62:20, 1971. Kurataun*. M., Yosbioura, T., Matuaaka, J , at al., Yusho, A Poisoning Canaad by Rica Oil Contaainated with Chlorobipnanyls, Env. Hlth. Panp. , 1iIIP, 1972. Kuratsun*, M., Morikawa, Y. , Hirohata, T.. Nishizuai, M., and Kochi, S., An Epidsaiologie Study on "Yusho" or Ch1oroblphenyl* Poisoning, Fukuka Acta Mad, 60:513, 1969. Lindar, RiE>> Gaines, T.B., and Riabrough, R.D. Th* Effect of Polychlori nated Biphenyls on Rat Rsproduction, Fd. Cosast. Toxicol. 12:63, 1974. HONS 213233 6 Litterat, C.L., Terser, T , Baker, A.M. and Van Loon, E.J., Effect 0f ?0. lychlorinated Biphenyls on Hepatic Microsomal Enzymes in the Rat, Toxicol Appl. Pharmacol, 13:112, 1972. Litterat, C.L. and Van Loon, E.J., Enzyma Induction by Polychlorinated 3i- phanyls Relative to Known Inducing Agones, Proe, Soc. Exp Bio. "so 141:763, 1972. ` Lutz, R.J.. Dedrick, R.L. , Matthews, H.|. , Ellng, T.E., and Andarson, '[ V, , A Preliminary Pharmacokinetic Modal for Several Chlorinated Biphenyls .n the Rat. Drug Metab. Oiap. 5:384, 1977. Makiura, S., Aoa, It., Sugihara. S-. Kirao, X., Aral, M., and Nobuyukilto Inhibitory Effect of Polychlorinated Biphenyls on Liver Tumorigenesis .n Rats Treated with 3`Nethyl**dimethylaainoazohenzene, N-2-TluorenylaeetaBide, and Oiethylnitrosaaine, J. Natl. Cancar. Inst. 33:1233, 1974 Matthews, HI., and Anderson. M.U., Effect of Chlorination on the Distrib ution snd Excretion of Polychlorinated Biphenyls, Drug Metab. Dispos , 3:371, 1975. Matthews, H.l. and Kato, S., The Metabolism and Disposition of Kalogenatad Aroaatics, Annals, N.Y., Acad- Sci. 320:131, 1979. Matthews, X., Tries, G. , Gardner, A., Garchoff, L., Goldstein. J., Xu, Y and Moore, J., Metabolism and Biochemical Toxicity of PCls and Plls, Envi ron. Health Perspect. 24.147, 1978. McCann, J. and Ames, 3.N., Detection of Carcinogens as Mutagens in the Salnoneila/Mierosoiee Test: Assay of 300 Chemicals: Discussion, Proe. Nat Acad. Sci. USA, 73:930, 1976. ' McCann, J , Choi, E. , Yamaaaki.E. and Amat, 9 N., Detection of Carcinogens as Mutagtas in the Selmonelli/Microsome Test: Assay of 300 Chsmieals, Proe. Nat. Acad, Sci. USA 72.5133, 1973. Mltzutani T., Kidaka, X., Ohe, T. and Matauaoto, M,, A Comparative Study on Accumulation and Elimination of Tatrachlorobiphanyl Isoaars in Mica, Bull. Environ. Concern. Toxicol- 18:452, 1977. Moilanen, X.V., and Crosby, Amer. Chem. See. Masting, 165th, Dallas, TX April 1973. Momsanto, Polychlorinated Biphenyl* A Report on L'aes, Environmental md Health Effects, and Disposal, Monsanto Publications, St. Louis, MO, 1979. Nagasaki, H,, Tomii, s.. at el., Hepatocarcinogemcicy of Polychlorinated Biphenyls in Mica, Gann 63:805, 1972, Nagayama, J., Kuratsune, M., and Maauda, Y., Decsralnation of Chlorinated Dibenzofurani in Kanechlors and "Yuaho Oil", Bull. Environ. Contam Toxieol. 13:9, 1976. MOMS 213234 7 . Nation*! Cancer laatitute, Bioassay of Aroclor* 1254 for Possible Cirei.no* genicity, Circi.iO|nuu Turin* Prograa Division of Cincor Ciuh ino Pre vention, DHEV Pub. Vo. (NIH) 78. National Institute for Occupational Safoty and Health (NIOSK), "Criteria for Recenend Standard. Occupational Exposure to Polychlorinated Biphenyls (PCBs)'', DHEV Publ. Co d 77, 1977. Neeley, V.B. , A Material Balance Study of Polychlorinated Biphenyl* ui Lake Michigan, Sci. Total Environ., 7.117, 1977. Nilsson, B., and Raael, C-, Genetic Tests on Drosophila Melenogester w-.ih Polychlorinated Bipnenyls (PCB), Kereditas, 77:319, 19*4. Nlsbizumi, M., Light and Electron Microscope Study of Chlorobiphenyl Poi soning in .Mouse and Monkey Liver, Arch. Environ. Health. 21:o20. 19*0 Orberg. J. and Lundberg, C., Son* Effects of DDT and PCB on the Horsonal Systea in the .Male Mouse, Environ. Physiol. Biochea. 4:116, 1974, Ow, H.K-, Siopson, G.R. and Siyali, D.S. , Use and Health Effects of Aroclor 1242, a Polychlorinated Biophenyl, In: An Electrical Industry, Arch. Envi ron, Health 31:189, 1976. Panel on Hazardous Substances, Polychlorinated Biphenyls-Environmental lapact, Environ. Res., 249, 1972 Peakall, D.I., PCI* and Their Environaental Effects, CRC Crit. Rev Environ. Cont. 3:469, 1975. Peakall, D. and Lincer, J. , Polychlorinated Biphenyls: Another Long-life Widespread Chemical in the Environment, Bioscience, 20:958, 1970. Pena, I. tad Starsl, T.E,, Malignant Tumors Arising De Novo in lamunosuppressed Organ Transplant Recipients, Transplantation 14-407 1972. Periano. C., Fry. R.J.M., and Staffaldt, E., Enhancement of Spontaneous He patic Tuaorigeaosia in C3H Mice by Dietary Phtnobarbital, J. Nat. Cancer last. 31:1349, 1973. Plimeer, J.R., end Kligebeil, U.L., PCB Fornetlon, Science, 181.994, 1973. Panel, C., Mutagenicity Research and Testing in Sweden, Mutation Res., 33:79, 1975. tisehrough, R.V. end deLappe, R.W., Polychlorinated Biphenyls in Ecosystems, Eav. Hlth. Persp., 1:39, 1972. Risebrovgh, R.V., Relche, Nature 220:1098, 1968. Peeksll, D.I., Hemen, S.G. end Kirven, M.N. : Roach, J A,<3,, end Poaerenta, I.H., The Findings of Chlorinetsd Dibtrucofurans in iroclor PCI's of Recant Manufacture. Paper No. 53, Presented at 88th 8 HONS 213235 1 Annual Meeting of Assn, of Official Analytical Chavises, Washington 0 c October U-17, 1974 '' Roach, J.A.G. and Powers.-iti, [ H , The Finding of Chlorinated Oibenzofjrirs In a Japanese Polychlorinated Biphenyl Saaple, Bull. Environ. Conte*. Toxi col., 12:33$, 1974, Ross 1, L. , Ravers, 71,, Repettl, 0., and Sant 1, L, Long*cam Ad*Iniscration of DDT or Phanobarbital-Se m k is tar Rats, Int. J. Cancer, 19:179, 1977 Saekl. S., Tsutsul, A , Oguri, X., Yoshimura, H. , and Haaana, M , isolation and Structure Elucidation of the Aain Conponent of KC~*vO (Chlorobiphenyls) Fukuoka, Act. Med,, 60:513, 1969. Sehwetx, B.A., Morris, J.M., Sparschu, G.L., Rowe, V.JC., Gehrlng, P. J., Ea- arson, J.L., and Garbig, C.G., Toxicology of Chlorinated Dibsnxo-p-dioxms, Env. Hlth. Parsp. 5:67, 1973. Squire, R.A. and Lavitt, M.H., Report of a Workshop on Classification of Kapatocellular Lasiona in Rats, Canear Raa. 35:3314, 1975. Stewart, H L., Comparative Aspect* of Certain Caneara, In- Cancer*-A Conpreheoslve Treatise, F.F, Becker, ed., Plenua Press, 4:320, 1973. , Stewart, H.L. and Snell, K.C., The Histopathology of Experimental Tuaers of the Liver of the Rat. A Critical Review of the Histopathogenesis, Acta On. Int. Contr. Canear 13:770, 1957. Suadatron, G., Hutginger, 0., and Safa, S., The Metabolise of 2,2',4,4',J,J'Kextchlorobiphanyl by Rabbits, Rats and Mice, Chaaoaphere, 4:249, 1976. Takagi, Y , Ctak*. T., Xatsokt, M. Murats, Y., Aburada, S., Akaseka, S , Hashiaoto, R., 0d, H,, and Ritaura, T., Studies on the Transfer and Dis tribution of lkC-Palychlerinated Biphenyls fro* Maternal to Fetal and Suck ling Rata, Toxicol. Appl. Pharmacol., 38-549, 1976. Taste, B, and Jannat, P., Onus Metabolism: Chemical and Biochemical Aspects., Marcal Dekker Inc., Maw York. 1976. Toaruek, Effect of PCI on Developing Mouse, Cheoosphere 2:175, 1973. Tomatla, l., Agtha, C., lartsch, H., Huff, J., Monteaaeo, R., Saracei, R , ` Valkar, E. and Wilboum, J., Evaluation of the Carcinogenicity of Chemicals: A Review of the Monograph Prograa of the International Agency for Reaeareh on Cancer (1971 to 1977), Cancer Res. 38:377, 197$, To**ti, L,, Partensky, C. , and Montaaano, R.. The Predictive Value of Mouse Liver Tumour Induction in Carcinogenicity Testing -- A Literature Sur vey, Int. J. Cancer, 12:1, 1973. Tuhey, D.B. and Matthave, R.I., Pharmacokinetics of 3, 3', 5, S'-Tetrtchlorobiphenyl in the MaleRtt, Drug Matab. Diep. 5-144, 1977. MONS 213236 9 . Tulp, Sunditran, G., and Hutcinger. 0 , The Metabolisms 0f A,i`-Dichlorobiphenyl in Diet nd Frogs, Chemosphere., 6:i25, 1976 Tumasonis, C.F., 3ush. 3., and 3akar, F 0., PCS Levels in E*j Yolks Associ ated with Embryonic Mortality and Deformity of Hatched Chicks. Aceh. Inv Contarn. Toxicol., 1.31J, 1973, Ueno, Y., Kubota, Jt., Ito, T., and Nakamura. Y.. Mutagenicity of Cerci.-io(Hie Mycotoxins in Salmonella Tymphimurium, Cancor Res. 38:53d. 1978. L'meda, C-, Kanan 1 Yus ho: PCS Poisoning In Japan. Ambio, 132, 197.. Uyeta. M., Taut, S-, Chikasawa, 1C., and Maxaki, M. , Photo format ion of Poly chlorinated Biphenyls from Chlorinated Santanas. Nature, 264; Jj], 1976 Van Millar, J.P., Hsu, I.C. and Allan. J.R., Distribution and Matabollsm of *K-2, 3. 2'. J'-Tatrachlorobiphanyl in Rats. Proc. Sot. Exp. Biol. 'lad. 148.662, 1975. VUlsnsuva, D.C., Grant. D.L., (Chart, K,, Cleg*, D.J., Saar, H. and Phillips. W.J., Tha Fatotoxicity of a Polychlorinated Biphenyl Mixture (Aroclor llii) in tha Rabbit and in tha Rat, Eavir. Physiol. 1:67, 1971. Vos, J.G., and Koeman, J.K., Comparative Toxicologic Study with Polychlori nated Biphenyls in Chickens with Special Rafaranca to porphyria. Edean For* metion, Liver Necrosis, and Tissue Residues, Toxicol. Appl. Phans. 17:565, 1970. Vos, J.S., Koasan, J.K., Van dar Maas, H.S.. Debraun, M.C., and DaVos, K . Identification and Toxicological Evaluation of Chlorinated Dlbeiuofuran and Chlorinated Naphthalene in Two Commercial Polychlorinated Biphenyl, Food Cesaet. Toxicol., 8:625. 1970. Voa, J.G., and Koaman. J.H., Daraal Toxicity Studies of Technical Polychlo rinated Biphenyls and Fractions Thereof in Rabbits, Toxicol. Appl.. Pharma col.. 19:617, 1971. Voa, J-G. and Baaas, R.B., Dermal Toxicity Studies of Technical Polychlorinatad liphanyls and Fractionj Thereof in Rabbits, Toxicol. Appl. Pharmacol. 19:617, 1971. Voa. J.O. and Da loij, Th., Ismnanosuppressive Activity of a Polychlorinated llphanyl Preparation on tha Humoral Response in Guinea Pl*s, Toxicol. Appl. * Pharmacol. 21:J<*9, 1972. Vos, J.O, Koeaan, J.H., Vsn der Maas, X.L., Ten Noever de Srauw, M.C., and ds VOS, X,A., Identification and Toxicological Evalutlos of Chlorinated Dihenmsfuran and Chlorinated Napthalene in Two Commercial Polychlorinated Bi phenyls, Fd, Cosmet. Toxicol. 8:625, 19*0. Vsrd, J.M. and Vlahakis, G,, Evaluation of Hepatocellular Neoplasms in Mies, J. Nat. Cancer last. 81:607, 1978. HONS 2X3237 10 Vard, 3.M., Bernal. E-, Buratto, 3 . Goodaan, D G., Strj.ndberg. ; 3 lnd Schuelar, R., Histopathoiogy of Neoplastic ar.d N'onneoplistic Hepatic Le- ion* in Mice Fad Diets Containing Tetraeluorvmphos, J 'it Canee- r-it 69:llli 1979. *" ' Varshav, R., Fischbein, A., Thornton.J., A. and Selikoff, I , De crease in Vital Capacity m PCB*E.tpo*ed Workers :n a Capacitor .Manufactur-,ig Facility, Ann.N-Y. Acad- Sci. 320:ZT7. 19T9. Uatiman, M , W'asaarsan, D , Cucos, S., and Millar, H.J., World PC3i Mao Storage and Effects in Man in His Biologic Environment, Annals. N.Y. Acad. Sci. 320:69, 19*9. WilliaBt, 5.M., Tha Dataction ot Chemical Hutagens/Carcinogens by Dna Re* pair and Mutagenesis m Liver Cultures, In: Chenical Mutagens, F.J. Dasarras and A. Kollaandar, ads., Planus Press, New York (in press) 1979, Villiass, Cl, Hirota, M., and Rice, J.M., Tha Resistance of Spontaneous House Hepatocellular Neoplasss to Iron Aecunulation During Rapid Iron load* in a by Parenteral Administration and Their Transplantability. An. J, Pathol.. 94:65, 1979. Wyndhas, C., Deveaish, J., and Safa, S., Tha In Vitro Metaboliss, Macroao* lacular Binding and Bacterial .Mutagenicity of i-Chlorobipnenyl, a Modal PCB Substrata, Res. Cosh. Chas. Path. Pharmacol. 15-563, 1976 MONS 2X3238 11 rI Glory HONS 213239 GLOSSARY OF TERMS Oncogen Carcinogen Teratogen Mutagen kt * 1 ug <*g 1 * aao 1 !*/' of PCt NIOSH NCI EPA 1ARC it* page 28 im pi|( 29 agent causing abnormal development of embryo or fetus any change In eha character of the jane that is perpetuated la subsequent call divisions kilogram (2.2 pounda) jcaa (1/1,000 of a kilogram) illljraa (1/1,000 of a grin) microgram (1/1,000,000 of a graa) naaogram (1/1,000,000,000 of a jraa) litar (0.91 quarts) cubic saear (of air) nanomoles (1/1,000,000,000 of a solo of a aubataaea) approximately aquala 0.0815 ppm (assuming a molocular weight of 300) National Institute of Occupational Safety and Health National Cancer Institute Environmental Protection Agency International Agency for Research on Cancer HONS 2X3240 Biographical Information on tho Authors MOWS 213241 BIOGRAPHICAL sketch of AUTHORS Robert C. James, PhO Dr- Janes if the Corporate Toxicologist for Ecology and Environment, lac. Ha it responsible for assessing tha impacts of toxic and hazardous materials on tha environment and on human health- Dr- Janes has had several years axparitnca skin* s^b assessments as wall as davalopins tachsical transfar documents and coursas concerned with mutagenicity, carcinogenicity, haxardous aacarials, has* srd evaluation/risk assessment, industrial toxicology, and tha basic principles of toxicology for sponsors like Vanderbilt University, Georgia Institute of Technology and tha United States Environmental Protection Agency. In addition, Dr. James has coaductsd basic research in toxicology and published over 20 arti cles in the areas of xenobiotic metabolism, regulation of metabolism during chemical injury, the disposition of chemicals, and chemically induced toxici des caused by metabolic activation. Or. Morris Cranmtr, PhO Dr. Cranmer is currently the President of Jefferson Professional Services, which provides consulting, tearing and management services to clients worldwide. He is also a Professor is the Department of Interdisciplinary Toxicology at the University of Arkansas. His expertise in the field of toxicology lies oeinly In those areas of: techniques for identifying carcinogens; risk estimation proce dures; face and effects of chemicals in the environment; management of applied research laboratories; and federal environmental and health effects legislation. In the course of his work he has publlshsd over 150 papers, books, manuals and presentations. In past years he functioned not only as Diractor of HONS 213242 the National Cancer tor Toxieotofic.il Research, but he has also served with tha Environmental Protection Aftney, tha Food and On* Administration, tha Canter For Disease Control, and at the University ot JSiaoi and Michigan. Ha is aff.tiatad with thirteen scientific or professional societies and is on tha editorial board of four setanttfic journals. 4a a selantist, ha haa racalvad additional recognition by having racalvad tha highest awards fivan by tha Dapartaent of Haalth, Education and Welfare (the Diettnguiehed Sarvlca Award, 1976); tha Soci ety of Toxicology (National Achievement Award, 1974); and tha Food and Oruf Administration (Award of Merit, 1973). Raymond Harbison, PhD Dr. Harbison is currantly Chairman of tha Interdisciplinary Toxicology Progran at tha University Arkansas. His axpartisa in tba field of toxleology cover* tha araaa of; carecology (i.e. birth dafacte as wall as reproduceiva, embryo and fetal toxicology); bioactivatlon and detoxification mechanisms; hatard/safety analysis of toxic wastes; fata and effects of chemicala In the snvironaent; and industrial/occupational hasLth and safety. Dr. Harbison has praviously taught at both Vandarbilt and Tulin* Medical School* and dev*loped the National Kaaardous Materials Training program for the Environmental Protection Agency which has been also used to train tha CT. S- Coast Guard, Navy and induatrltl clients in the safe handling of toxic material*. Or. Karbieon has published over 90 pepere, boolta and prasantations and eurrantly *rv* on eh* adltorlal board of thraa si* caneiflc Journals. H# is affiliacad with savtn different scientific and profet* * tonal eocietie*. Dr. Harbison haa received further recognition by his peers, in having received the Society of ToxicoLogy'e Metion*i Achievement Awerd in 1976. HONS 213243