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r U.S. OEPUTMEHT OF COMMOCE NiIImwI T*chnkl MnmIIm Strck* Polychlorinated Biphenyls Health Effects and Recommendations Illinois Inst for Environmtntal Quality, Chicago Jun 76 V. HONS 070774 POLYCHLORINATED BIPHENYLS HEALTH EFFECTS AND RECOMMENDATIONS IIEQ Document No. 76/06 ^pOtMATION SfltViCf MCNS 070775 I weuoOAPwc ATA 1, Report No* IIBQ 76/05 Xronsisinr-- Polychlorinated Biphonyla Hoalth Effect* and reoeassendatlone TUU.)---------------------------------------------------------------------------------- Environmental Health Resources Center Staff rra=aMo.,MiM.i~ 4 Mm Environmental Health Reaourcee Center School of Public Health University of Illinois Chicago. Illinois 60680_____________________ IE 3pQ.i*flf Oifuiutin Num .od Minn Illinois Institute for Environmental Quality 309 west Washington Street Chicago, Illinois 60606 IL *00lMMUT M l Mc^wTnemiiMNr 9. Rtppoaptet Daite October 15. 1976 . Pnfmia* OriuiuiiM ** to. Prejtci/Tak/Vo.k U.il N. 90.002 11. CoMfMtTSmaTN*. 13. Tjf. of Report * PirM Cowrvd ________ Pinal 14. 14. AkMIMM Animal studies have revealed that PCBs can have deleterious effects on numerous organ systems including the liver, kidney, adrenal| gland, spleen and skin; abnormal changes in the chromosomes of Ring Dove Embryos and in the reproductive capabilities of female monkeys have also been noted. Environmental levels of PCBs remain quite hlgh.| Polychlorinated biphenyl liquids and electrical units containing PCBs should be destroyed or disposed of in a manner approved By the State and Federal Environmental Protection Agency. 17. Klf Veda Md Damme Aoalr>i>. 17o. Dueripora Polychlorinated Biphenyls Polychlorinated Biphenyls - Environmental Impact Polychlorinated Biphenyls - Health Polychlorinated Biphenyls - Lake Michigan 174. M#atili*ra/Opoo-Eodo4 T.im 17.. COSATI Pi.ld/Gfoup TT^Tvmllebilitr Statement Reltaee Unlimited Available from NTIS OGT Toxicology MTIt-M iAiV. ENDORSED BY ANSI AND UNESCO. 1*. icuiU, Cl... (Tkl. P*1TnCLA3M7ISD THIS FORM MAY SE REPRODUCED [}), ^o.jLEium. uieoMM>oe um>pt MOMS 070776 POLYCHLORINATED BIPHENYLS HEALTH EFFECTS AMD EECQWtWDATICNS This document (EHBC Doowant No. 16) was prepared for tha Illinoia Inatituta for Environmental Quality by Tha Environawntal Health Raaourca Cantar stats of Illinois Inatituta for Bivironmantal Quality Saaual G. Booras, Dlractor June, 1976 lOb HONS 070777 NOTE This report has been reproduced as received from the contractor. No editorial or other changes have been made. Conclusions expressed In this report are the contractor's. Printed By Authority of the State of Illinois Date printed: June, 1976 Quantity printed: 500 This publication has been cataloged as follows: Illinois Institute for Environmental Quality, Environmental Health Resource Center. Polychlorinated biphenyls: health effects and recommendations / by the Environmental Health Resource Center. -- Chicago : Illinois Institute for Environmental Quality, 19T6 ' vi, Uo p. : 30 cm. -- (IIEQ Doc. Ho. 76/05; EHRC Dec. Ho. 16) 1. Polyohlorinated biphenyls 2. Polychlor inated blphenyls-environmental impact 3. Poly chlorinated biphenyls-health U. Polychlorinated blphenyls-Lake Michigan I. Title II, Environ mental Health Resource Center IIEQ Environmental Resource Center Illinois Institute for Environmental Quality - 309 West Washington- Street Cr ` o, IL, 60606 793-3870 11 HONS 070778 FOREWARD This publication deals with "Polychlorinated Biphenyls Health Effects and Recommendations". The Institute's Envi ronmental Health Resources Center has prepared the material based on literature searches. Investigation, and critical reviews. Recommendations for further research are made, both as a guide for research agencies, end as evidence of the state-of-the-art with respect to Polychlorinated Biph enyls. . The Environmental Health Resources Center Is a fac ility of State government established by the Institute for Environmental Quality. Its services are available to anyone Interested In environmental health problems. - Ill MGNS 070779 ENVIRONMENTAL HEALTH RESOURCE CENTER P.O. Box 6996, Chicago, Illinois* Phone* (3X2) 996-7811 STAFF ' Bertram W. Carnow, M.D. Cantor Director Edward J. Calabraaa, Ph.D., Ed.D. Assistant Director of Center Badl M. Bouloa, M.D., Ph.D. Asaociata Professor* Toxicologist Linda Frladnan, M.P.H. Raaaarch Aaaiatant Rodney P. Muaaalman, M.P.H. Research Associate Christina Riddlough, M.S. Raaaarch Associate Alfred J. Sorensen, M.S. Research Associate Edward A. Diersan, B.S. Research Assistant Sally J. Janaan, M.P.H. Raaaarch Aaaociata Sandra Hare, B.S. Research Assistant Milllam H. Kojola, M.S. Raaaarch Aaaociata Janine Roumain, B.A. Research Assistant ADVISORY BOARD R. Stephan Berry, Ph.D, Professor of Chemistry University of Chicago Paul Meier, Ph.D. Professor of Statistics university of Chicago Robert L. Metcalf, Ph.D. Professor of Entomology University of Illinois - Urbans J.E. Quon, Ph.D. Professor of Civil Engineering Northwestern University Arthur HOlff, D.V.M. Professor of Jbivironmental Health Sciences University of Illinois, School of Public Health The Environmental Health Resource Center is an arm of the Institute for Environmental Quality, managed under contract with the Institute by the University of Illinois School of Public Health, Chicago, Illinois 60680. Notat The Environmental Health Resource Center appreciates the efforts of Rustom R. Xhouri in the development of this document. iv MO NS 070760 LIST OP TABLES AND FIGURES Table 1. Whara PCBa were found a*nd in what form prior to 1972. Tabl* 2. PCBa found in edible portIona of epeclee of lake Michigan fiah (1971, 1972). Valuee are axpreeeed in parte per million (ppm) on a wet weight baale. TabU 3. PCBa found'in Lake Michigan sedimenta in lllinoia (1971). Valuta are e^raeeed in parta par billion (ppb) baaed on a dry weight baale* Table 4. PCBa found in aedinenta of aeveral atreaaa and ravinea tributary to lake Michigan (1971). Valuee expreaaad in ppb. Table S. PCBa found in water coupler from lllinoia' ttreama tributary to Lake Michigan (1971, 1972). Valuee are axpreeeed. in parta per trillion (ppt). Table 6. PCBa found in water aamplea from aeveral lllinoia aewage planta tributary to Laka Michigan (1971, 1972). Valuee are expreaaad in ppt. Table 7. The chroaoeome aberration rata in dove embryoe treated with PCBa. figure 1. Biphenyl nucleus shoving 10 possible chlorine positions , figure 2. Locations of aedinsnt sampling stations.along Laka Michigan in Illinois. figure 3. Location of water sapling stations used in 1971 and 1972 for determination of PCS lsvsls in Laka Michigan. vi HONS 0707*1 TABLE Of CONTENTS I. Sunwary and Rsconmandations.............................................................................. 1 IX. Chemical Structure..............................................................................................5 til. Industrial Uses .................................................................................. $ IV. Where PCBi Ara Found and ttiair Mods ofTransport......................................7 V. toutas Into tha Environment,.............................................................. 8 VI. Rata of Loss Into tha Snvironmant ...................................................................9 vil. Rates of Transport Within tha Environment ....................................... ... 10 VIII. PCB Levels in Illinois.................................................................................... XI A. Levels in Lake Michigan Fish Species....................................... .... . 11 B. Levels in the Sediment of Lake Michigan and Some of its Tributary Streams........................................... ... 13 C. Levels in the Water of Streams and Sewage Efflusnt Entering Lake Michigan During 1971 and 1972 ................ 13 IX. Health Effects of PCBst Animal Studies ..................................................... 21 A. Tissue Storage, Metabolism, and Excretion............................... ... . 21 B. Toxic Effects of Various Isomeric Mixtures on Animals and Possible Contamination of PCB Samples by Other Compounds ................................... 22 X. Health Effects of PCBsj "Hunan Exposure Via Food, Air, and Water '............................... 28 A. Occupational Exposure................................................... 28 B. ` Cess History of PCB Poisoning - Japan . ............................................29 C. Consumption via Food and Drink................................................... .... . 30 XI* PCB Lavals in Tissues of Humans in the united States, ........................................................ ........ 32 XII. High Risk Segments of the Population................................................. .... 32 XIII. Appendix...................................................................................................................33 XIV. References . . ........................................................................................ 36 HONS 070782 MOM-TBCHNIQL SUMMARY Polychlorinated biphenyls (PCS*) are a group of chaaioals which contain varying parcantagaa of chlorine arranged on a doubla-ring chemical atructura called biphenyl. Monaanto Cbapany ia the aole U.S. producer of PCBa and oalla ita product* by the trade name AROCLOR. Polychlorinated blphenyla have been manufactured in the U.S. aince 1929 in reaponae to the electrical induatry'a need for an improved lneulating fluid which la more fire reaiatant and alao more raalatent to biological and phyaical degradation. Their uaage ia _ now limited to what are called "cloned ayatama" algniflcantly reducing their lamedlate releaae into the environment. Animal atudiaa have revealed that PCB* can have deleterioue effecta on numerous organ ayatema including the liver, kidney, adrenal, gland, spleen and akint abnormal ohangae in the chromoaomaa of Ring Dove tabryoa and in the reproductive capabilities of female monkeys have alao bean noted, in 1968, two thousand Japanese people suffered various akin and eye disorders after eating PCB-oontamlnated rice oil. Snviromental levels of PCBa remain quit* high, they may be found in certain foods, especially fish in which PCB levels may be as much as a million times higher than the levels of the surrounding waters because PCBa baccara concentrated in fatty tissues. 'Polychlorinated biphenyl liquids and electrical units containing PCBa should be destroyed or disposed of in a manner approved by the State and Pedaral Knviromental Protection Agency to avoid needleaa environmental pollution. Suitable replacements for PCBa are being investigated. Vii MCNS 070783 z. SUH1ARY AND FE00MM5NDATI0NS Polychlorinated biphenyl* .(PCBs) are one member of a class of synthetic chlorinated organic compounds composed of tv*>, six carbon ring structures (Phenolic rings) with 10 possible chlorine attachments. These aromatic compounds encompass a complex heterogeneous group of 210 different chlorinesubstituted isomers, although the number observed in commercial formulations ie much smallar. Polychlorinated biphenyls are also highly toxic agents which have been shown to cause harmful effects in numerous animal species. Including man. They are present in varying amounts in food, drinking water end air. Polychlorinated biphenyls have been used and manufactured in Europe, Japan, the Soviet Union and the United States. The sole U.S. producer la the Monsanto Company which has glvsn the trade name Aroclcr to its products. Animal studies have revealed that PCBs can adversely affect numerous organ systems including the liver, kidney, adrenal gland, spleen, and akin. Other studies have shown that they may cauaa chromosomal aberrations in vivo in Ring Dove Embryos, but no aberrations as studied in Drosophila. Animal studies have also indicated that PCBs suppress tha immune response system. Polychlorinated biphenyls when fed chronically to rats caused hepatic adenofibrosis and biliary epithelial hyperplasia similar to issions caused by butter yellow (p- dimethylamino-asoben sene), a known carcinogen. Contamination of PCS# with compounds such as tits chlorinated dibensofurans (CDPs) and chlorinated naphthalsnss havs bsen suggested as the causative carcinogenic agents. This controversy is unresolved end needs further investigation. Other very recent experiments have indicated that as little as 2.S parts per million (ppm) of a PCB (Aroclor 1242) in tha diet of monkeys has caused loes of heir on the feoe end neck, as well as the development of acne and other skin lesions. Furthermore, the reproductive capabilities of PCB-fad famala monkeys wars affsetad as avldencad by the development of a greater number of both resorbed fetuses and significantly tstdarsised infants. It has also been shown that weanling rets are mors susceptible to Aroclor 1254 and 1260 than adult rats as determined by acute toxicity studies. Despite tha numerous research articles.indicating the toxicity of PCBs for animal species end their possible implications for hvsnan beings, the best 1 HONS 070784 available knowledge of the effect of PCBs on man cornea from the "Yusho" incident in which over 2,000 Japanese people became intoxicated by consuming PCB-contaminated rice oil. Many of the toxic effects which the afflicted Japanese people experienced were elmilar to results reported in animal studies. The lesions of the skin, facial swelling# and neurological disorders were similar to results reported In animal studies. Known toxic effects of PCBs in huaans include chloracne, pigmentation of the skin and hands# distinctive hair follicles# excessive eye discharge, and swelling of the eyelids. Even though there ie considerable evidence that PCB exposure is harmful to human life# the environmental levels of PCB* still remain quite high, For example# two tributaries of Lake Michigan have levels of Aroclor 1234 con sistently exceeding 100 parts per trillion (ppt) while the present EPA recommended water quality criteria is l ppt. Of greater concern is the fact that residents of Chicago draw their drinking water from Lake Michigan which has PCB levels in certain areas of the Lake between 4 and 10 ppt. Fish and 4 other aquatic animals accumulate PCBs to levels of the order of 10 timee higher than those in the ambient water. Predators at the top of the food chain such as birds# seals# and sharks may accumulate PCBs to levels 107 or mors times the levels in the ambient water. Much of the problem with respect to hixnans and Pen intake has to do with the fact that man usually resides at tha top of the various food chains. Once PCBs get into food chains involving birds and maasials# biological magnification seams to occur with the concentration incraasing by a factor of 10-100 at each step. Additionally# PCBs are poorly metabolised and tend to accumulate in ipjd-rich animal tisauas and organs. PCBs have been manufactured in the United States since 1929 in response to the electrical industry's need for an improved dielectric Insulating fluid with increaed fire resistant benefits when used in transformers and capacitors. It has been speculated that 400,000 tons of PCBs were produced between 1940 and 1973. The more highly chlorinated PCB isomers are highly resistant to microbial and physical chemical action in tha environment. Despits the all too apparent environmental problems associated with PCBs# they have remarkable properties which have prompted their use in numerous industrial products such as hydraulic fluids# plasticizers# adhesives ? M0NS 070185 (asphalt and oonorata), printing product* (carbonlaaa carbon papar) and papar coating. They ara atili utilized aa filling agant* on impregnant* in electrical tranaformra and capacitors. Since 1971, Monsanto Company voluntarily restricted its sales to only 'closed'' systems in transformers and capacitorsi this has been a significant factor in restricting the accessibi lity of PCBs to the environment. The action by Monsanto to restrict PCS sales to closed aystmss was a major step in preventing the immediate release of PCBs to the environment. However, Monsanto is still producing about 20,000 tons of PCBs each year. This material must be properly dispoeed of when it is no longer useful. There are 6 major Incinerators in the United States to handle discarded PCB waste. If waste products are sent to these incinerators, anesdless environmental pollution can be avoided, unfortunately, many companies discarding their old electrical units (containing PCBs) are atill discharging many poinds of PCBs into the atmosphere and waterways each day. As a result of the current state of our knowledge concerning the environmental and human health affects of polychlorinated biphenyls, the ftivironmental Health Resource Canter supports the following national policy and research reoosasandationai NATIONAL POLICY HBCOMHBNPATIOHS 1. polychlorinated biphenyls should no longer be penaltted to be discharged into surface and ground waters. 2. polychlorinated biphenyl liquids and electrical units containing PCBs should be destroyed or disposed of in a manner approved by the state and Federal Environmental Protection Agency (BPA). 3. Equipment containing PCSs should be labelled as such. 4. The industrial usage of PCBs in closed systems should be evaluated in light ' of findings of suitable replacements. 5. Proposed tolsranses for PCBs should be mad* with regard to the properties of the different isomers. I 6. The food packaging industry should either cease using recycled psper which contains PCBs, or make use of an impermeable barrier on the inner surface of the packages, thus restricting the transfer of PCBs into food.7 7. Ths food and Drug Administration (FDA) tolerance level for PCBs-ln fish should be lowered from 5 ppa to 2 ppaa. 3 HONS 070786 RESEARCH REOOWCNDATIONS 1. Research on the replacement of PCBs with a substitute chemical in closed electrical systems and capacitors. 2. Further research for the purpose of setting standards with regard to toxicity and carcinogenicity of PCBs in humans. 1. Resea .to determine if the lack of a functional glucuronic anzyms pathway predisposes individuals to unusual accumulation of PCSs. 4. Determination of the relative toxicity of different isomers with respect to standard setting. 5. More research studies on the kinetics of PCBs with regard to absorption and distribution through different organs including the lungs with the development of appropriate animal simulation models which would lead to extrapolative predictions for man. 4 MENS 0707*7 XI. CHEMICAL STRUCTURE Polychlorinated biphenyls are ons msnber of a class of chlorinatsd organic compounds composed of tyo, six carbon ring structures (phenolic rings) with 10 possible chlorine attachmenta. These aromatic compounds encompass a oomplex heterogeneous groiy> of chemicals. Two hundred and ten different chlorine-substituted biphenyl isomers are possible, but the manber observed in comerclal formulations is much smsllar (Figure 1). The dif ferent oomercial products contain mixtures of isomsrs of biphenyls chlorinatsd to diffsrsnt dsgrses to vest specific operational specifications and may vary chemically from batch to batch. 1 ' 2 Polychlorinated biphenyl! have baan uaad and manufacturad in Europe, Japan, tha Soviet Union, and the United States.3 ' The eole U.S. producer ia the IonianCo Company which hat given tha trade name APOCIOR to ita product*.4 Aroclors ara distinguished by using a four digit nunharing ayetarn, me first two digits, 12, specify polychlorinated biphenyl and the last two digits specify approximate weight percentage of chlorine in tha mixture (a.g., hroclor 1254). X'4 Trade name for known PCS containing products produced by foreign manu facturers include Clophan (Germany), Fenclor (Italy), fananhlnr and Santotherm (Japan), phanoolor and Pyralana (France), and Sovol (u.S. s. R.) .X'2 BXPKKtm, Figure li Biphenyl nucleus showing 10 poaalbla chlorine attaohaentsi poaitiona 2-6 and 2'-6' may ba substituted by chlorine. Two hundred and tan different chlorine - substituted biphenyl isomers ara possible. 5 HONS 070288 Polychlorinated biphenyl. ware first identified in environmental aamplea in 1966. They were established as interference peaks on gas liquid chromatographic analysis of DDT and found to couple with DDT when analyzing the chlorinated pesticide residua.5 III. INDUSTRIAL USES Host individual polychlorinated biphenyls are solids at room temperature, but the mixture may range in consistency from oil's to viscous liquids or resins. ' ' Table 1 denotes how each form can ba used. Polychlorinated biphenyla have vary broad industrial uses because of the following properties non-flammability, high chemical stability, low vapor praasura, inart deoompoaition products, high dialactria strength and low dissipation factor.* TABLE 1 WHERE PCBs WERE POUND AND IN WHAT FORM PRIOR TO 1972 RESIN Protactiva coating Plasticisers and extenders Sealers ini waterproofing compounds and putty Asphaltic materials Printing inks Oynuhetic adhesives LIQUID SOLIDS Dialactrics Hydraulic fluids Thermostats Cutting oils Impregnate carbon resistors Sealers Impregnating agents for electrical apparatus Extrema pressure lubricants | Grinding fluids ! Heat transfer madia! Since 1970, when the first substantial data concerning PCBs in the environment were recorded, Mousanto Company's production has been reduced; from 1960-1970 Monsanto's peek production was 42,527 short tons of PCBs. By ths snd of 1972, it was down to 20,236 ahort tons. 4 r 7 These restrictions which cut production in half resulted in a reduction in uses of PCBs la applications Involving open systems where their loss to the environnvnt had been last controllable. Major applications affected by the Company's program of tsrminatlng aalaa of PCBs to opan application ware in carbonless paper. 6 HGNS 070789 firs resistant hyaraulio fluid*, hast transfer fluid* and plastioissrs. Moncanto n*d* th* decision to ooneinu* supplying PCB* only to tha alactrlcal power diatribution induatry where they ware marketed aa dielactrio fluid* in "closed- or aaalad ayatama auch a* tranaformera and capacitor*. a At ona time, fluorocarbon* war* used in capacitors, but it waa found that they have low dielectric constant* and alao have decomposition products that era toxic. In 1969 , 96% of United States transformers uaad mineral oil. This lasted until it wa* found that PCBa prevented fire and explosion hazard*. Th* major value of PCB liquids with 4 or more substituted chlorines par molecule is tha non-flammability of tha PCB itself, as well as its de composition products. Thay can be uaad as fluids at temperature* up to 700 P without th* danger of explosions or fire. ,In many areas, alactrlcal coda* required th* use of aakarels (PCB capacitor liquids, commonly referred to ae askarsls, ara mixture* of chlorinated biphenyls and chlorinated benzenes). Th* us* of askarals is mors expensive (1.3 x the cost of mineral oil)! however, fir* underwriters will not accept us* of mineral oil. When fluorocarbon* wars tested in th* U.S., their volatility and high cost quickly eliminated them from consideration for continued us*.6 Polychlorinated biphenyls ar* also used as lubricants in hydraulic fluid*. Because possible replacements hav# been found, th* degree to which PCB* ara now being uaad ia unknown. Tricreeyl phosphate, for example, la chamioally stabla aa an additive in lubricants and although toxie, it is nor* biodegradable than tha PCBa.6 With rare exceptions, after compiling eh* properties needed in order to make capacitor*, transform*re, hydraulics, gas turbines and vacuum pump* work efficiently and safely, PCBs ara by far th* best chemical fluid available. IV. WHIR! PCBs ARB POUND AND THEIR MODS OP TRANSPORT Prior to 1970, 60* of sales were for closed system* (electrical and heat tranafar usee)i 25* for plasticiser applications) 10* for hydraulic fluida and lubricant!* lasa than 5* for miacellanaou* applications such as surface coating, adhesives, printing inks and psstlcld* extender*. Exports by Monsanto had averaged 13* of domestic sales for 1963-1970. Imports ara 7 MOWS 070790 thought to be small, comprised primarily of plasticizers in resine and adhesives, transformer oils and capacitor fluid in electrical equipment. Exports to Canada are equivalent to 7% of United States sales. As of 1971, approximately 90% of sales were for closed electrical systems, and by 1972, supposedly 100% of sales were for closed electrical systems. 1, 4, 9 In the sunmer of 1971, Monsanto Conjpany stopped producing Aroolor 1260. They also reduced production of the higher numbered PCBs that are considered more persistent in the environment (l.e., 5, 6, *7 chlorines/biphenyl). The more highly chlorinated isomeric forms of Aroclors (1254 and up) comprised 30% of sales prior to 1971i this fell to 22% by 1972.* (See APPENDIX, P. 35). V. ROUTES INTO THE ENVIRONMENT Data on the amount of PCBs lost into the environment are limited. Possible routes<4ahat have been considered are the following;4 1. Leaks from sealed transformers and heat exchangers. 2. Leaks of PCB containing fluids from hydraulic systems which are only partially sealed. 3. Spills and losses in the manufacturing of PCBs or PCB containing . fluids. 4. Vaporisation or leaching from PCB containing formulations. 5. Disposal of waste PCBs or PCB containing fluids. Any of these possible route* of PCB movements Into tha anvironaent could eventually end up in the food chain. Example* ere the Japaneee rice oil contamination resulting from heat exchanger leaks10 end the Eecambi* Bay area of Florida where leakage of hydraulic fluid from an air compreaeor contaminated chicken feed on the Holly Farms.11 The input into soil by use of Aroclors as pesticide extenders is believed to have been small. Based on purchase reports. It haa been 8 MGNS 070791 estimated that laaa than 10 tons/year are dumped into soil. Direct discharge into oceans by dumping of hydraulic fluids and lubricants from ships has been considered infinitesimal# but may have been locally significant.^ An important factor to consider is which Arcelor isomer is being discharged. This can be determined easily from sales and chemical records. Prior to 1972# most PCBs released into the atmosphere were Aroclor 1248 araS 1260# vaporised from bumihg dumps. Discharge into waters are primarily isomeric fonts of Axoclors that ara used in hydraulic fluids end lubricants# including mixtures of Aroclor 1242- and 1260. The residual in dumps will have ft large fraction of the Aroclor 1242. VZ. RATE OF LOSS INTO THE ENVIRONMENT The following figures represent orders of magnitude estimates of rstss of loss. These estimates are yearly figures# most closely resembling losses incurred during 1970# whiah ves the peek year of PCS production. Transformer! are fairly permanent installations# and therefore# only 10% of sales of transformer fluid is to replace oil that was removed. Ninety percent is for new units. The useful life of capacitors is usually under a decade. It has been estimated that the rate at which capacitors are discarded ie equal to 1/2'the rate of production, a similar figure is assisted for the acrapping of heat exchangers. It is estimated that the rate of evaporation of plasticisers amounts to 10 to 20% of seise. The rate of disposal of plastioisere into dumps is assumed to equal the residual 60 to 90% of sales since numerous plastic objects have short useful lives. Hydraulic fluids and lubricants are rarely re-used) thus# it is assumsd that a major fraction of these fluids used for this purpose# together with those going into miscellaneous applications# were scrapped at rates about equal to those of corresponding sales.* On the basis of these gross approximations# it seems that only about 20% of the 1970 sales in North America, about 7 X 103 tons# represented a net increase in the amount of PCBs in servios {In transformers# heat exchangers and capacitors). The remainder id considered to have been discharged into the environment; 1-2 X 103 tons by evaporation of plas- 9 MOMS 070792 ticlsars; 4-5 X 103 tons by leaks and disposal of hydraulic fluid and lubricants plus small quantitlas by disposal of heat transfsr and tranaformar oils; and 22 X 103 by disposal in incinerators, dumps and sanitary landfill. Of the 22 X 103 quantity, it has been estimated that 10 to 20% were incinerated and 2% were vaporized, mainly by open burning of wire 4 scraps, automobile components and material in dumps. VII. RATES OP TRANSPORT WITHIN THE ENVIRONMENT Transport mechanisms take complex pathways within natural biogeochamical cycles. For example, vaporized PCBs may be absorbed on parti culates, transported with the prevailing wind and deposited on land or. water by particle sedimentation or rain-out. Polychlorinated biphenyls in streams may be absorbed by the waterborne particulates on benthos. Absorbed PCBs may diffuse into bottom sediments, redissolve in the water stream or be entrained into sediment eroded from bottom surface.10,12 xhie whole process is further complicated by the assimilation, transport and degradation of PCBs by the blots.3,3 A major pert of the PCBs discarded irrr dumps is in closed containers or plastic rssins. This rate of loss will oe low until tt< confining materiel vs degraded and cne PCBs subsequently releasee usually dir rosing slowly thru surrounding soil. 4 Polychlorinated biphenyls from discarded non-carbon paper may rapidly be diffused into the environment. However, because much of this paper is recycled, the actual rate rf diffusion into the environment will ofte,. oe Retarded. PCB-impregnatad paper is often used in the packaging of various common food products. This is now recognized as another avenue of food contamination. 14,15 Theoretically, the rates of transport may be liculated from knowledge of the physico-chemical properties of PCBs and pertinent data on atmospheric conditions, particulate transport, hydraulic dispersion, bottom sediment transport and biological degradation rates. Presently, data are too incomplete and the interactions are too coirplex to attempt formulation of anything more than the crudest of transport models.4 To avoid needless environmental pollution w.:th PCBs and to stop the 10 HONS 070793 discarding of ths* in dumps* rivers and toil, the Monsanto Cbmpeny built an incinerator at their plant in St. Louis* Missouri. It runs on 30 Million B1U per hour and can handle 10 million pounds per year of PCBS and other discardable chemicals. It has been shown that this 10 million pound capacity only requires 5* of use time for repairs and cleaning.7 There are 6 other such incinerators in the United States. They are located in Pittsfield, Massachusetts! Model City, New york; Wilmington* Delaware; Gloucester City* New Jersey; Batten Rouge, Louisiana; and Houston, Texas.7 Those Incinerators, if timed and heated properly, can burn PCBs and not let any toxic pollutants escape into the environment. Federal EPA proposed Effluent Standards for PCBe exist for both fresh and salt water.16'17 Recommended procedures for disposal of PCB-containing wastes (industrial fadlitits) ars outlined by the Federal EPA in the Federal Register. The recommended options for disposal of PCB-containing wastes in order of priority are incineration and controlled land disposal. 18 VIZZ. PCS LEVBUS IN ILLINOIS A. Levels in taka Michigan Fish Species The Illinois EPA initiated a program in 1970 to obtain pesticide residue levels in several species of Lake Michigan fish. In 1971 and 1972* testing included PCBs. A total of 209 fish were analysed over' the 2 /ear period* including samples of yellow perch# chubs* carp* coho salmon* alawlfa and brown trout. Difficulties in obtaining all species in 1972 limited collections to the yellow perch and chubs. Fish were collected from commercial fishermen and the Illinois Conssrvation Department In the Chicago and Waukegan regions of Lake Michigan. Table 2 shows that the edible portions of speciss of fish with ths highest fat content (chubs and alewlves) had the highest level of Aroclor I254.19 Lake Michigan salmon containing PCB levels (regarded by the PDA as a food additive) in excess of the prescribed tolerance level of 5 ppm were seised by the FDA in May 1975.20 The actual amount seised and PCB levels in the fish were not revealed in the reference, however, 1974 data from the Michigan De partment of Natural Resources give values for PCB lsvels in laks trout and cote salmon ranging from 10 to nearly 25 ppm which is in excess of the present PDA maxima alljwable concentration of 5 ppm for fish and shellfish. 11 HONS 070794 TABLE 2 POLYCHLORINATED BIPHENYLS FOOND IN EDIBIE PORTIONS OF SPECIES OF LAKE MICHIGAN FISH (1971, 1972) 19 Values (pjma on a wet weight basis) for approximately 10 fish were used for each measurement. SPECIES SIZE RANGE IN INCHES SAMPLE LOCATION AROGLOR (MEAN VALUES) 1242 1254 Yellow Perch (1971) (1972) Chub (1971) (1972) Carp (1971) Coho Salmon (1971) Alewife (1971) 7.0 - 12.0 8.0 - 9.5 9.0 - 12.0 8.0 - 10.0 17.0 - 27.5 18.0 - 23.5 6.0 - 7.0 Chicago . Waukegan Waukegan Waukegan Chicago Chicago Chicago .1 N.A.a .3 N. A.a 1.0 1.0 N.D.b 0.3 0.3 2.6 2.9 l.S 1.3 3.0 Si.A. - Not analysed for bjl.D. - Not detected MCNS Q 70795 In 1974, the Wisconsin Department of Natural Raaources found lavala se conding S ppm in Lake Michigan Chinook and ooho aalaton, brown trout, tiger trout, laka trout, and carp. Tha lavala wara aa high aa 43.8 ppn In laka trout and 51.6 ppn In carp. The neat contaminated flah In tha u.S. to data hawa baan found In tha upper raachaa of tha Hudaon Rlvar, naar and balow two Sanaral Electric planta. These plants manufactures alactxlcal capacitors in which PCBe ara usad as insulating fluid, aaeples (1974) of yellow parch and shlnnar minnows showed residues of 17 and 78 ppm, respectively) one rock bass sample contained 350 ppn.21 B. Levels In tha Sadlmsnt of lake Michigan and Soma Tributary 8tr-- The results indicated that levels of hrodor'1254 and 1242 found in lake Michigan aedimanta in 1971 ranged between 2.48 and 46.92 ppb and Ml (not detectable) to 106.07 ppb, raapactivaly (Table 3 and Pig. 2). In tributary sadimants, tha lavala for hroclor 1242 ranged from ND to 553.00 ppb with tha maxima values found at an unnamed channel in Haukagan (Table 4 and Fig. 2). hroclor 1254 ranged from 1.54 to 232.0 ppb with tha aaxlanm level found at Pettlbone Creak in North Chicago (Table 4).19 C. Levels in tha water of streams and senega Effluent Entering Laka Miohjqan during 1971 and 1972 Tha results indicated the hroclor 1242 levels were markedly reduced in 1972 compared to 1971 in both tha stream and sewage discharge water, hroclor 1254 lavala also decreased from 1971 to 1972 in aawaga discharge, but stream discharge levels increased slightly (Table 5 and 6). hlao, in most cases, sewage treatment plant affluents wara shown to discharge higher concentrations of PCBs than tha tributary streams in 1971, but in 1972, PCS lavala wars higher in the tributary streams (Figure 3). Highest concentrations of PC9e in sadimants wara obtained in tributary streams and ravines, indicating posalhle contaminations by residential spraying and industrial discharge. 13 HONS 070796 Higheat level! ware obtained in industrial arena in North Chicago and Waukegan. In aadiaanta. KB lavala ware generally higher than peatlcide (DDT, heptachlor epoxide, dialdrln, aathoxychlor, phtalataa and lindana) lavala.19 It i> a'.ao iaportant to point out tha cxtraaa variablility in KB lavala (Tabla 5). In 1971, for example. water froa tha Waukegan River ehowed ovar 1,800 ppt PCS on one day, but lata than a month before, aaaplaa revealed no detectable lavala.19 MONS 070797 TABLE 3 PCfia POUND IN LAKE MICHIGAN SEDIMENTS IN ILLINOIS (1971) Valuaa ar* axpraaand In part* pr billion (ppb) baaad on a dry waight bail*.19 SAMPLE LOCATION 1 to 3 MllnaOffahora *NS8D Park Ava. STP (Highland Park) N8S0 Laka Foraat STP (Laka Foraat) N8SD Laka Bluff STP (Laka Bluff) N8SD North Chicago STP (North Chicago) NS8D Waukagan STP (Naukagan) ' Laka Bad Station 60 Laka Bad Station 55 Laka Bad Station 52 Laka Bad Station 49 Laka Bad Station 46 Laka Bad Station 43 Laka Bad Station 40 Laka Bad Station 37 Laka Bad Station 34 Laka Bad Station 31 Laka Bad Station 28 Laka Bad Station 24 Laka Bad Station 21 Laka Bad Station 18 Laka Bad Station 15 Laka Bad Station 12 Laka Bad Station 8 Laka Bad Station 5 Laka Bad Station 2 ' NSSD - North Shorn Sanitary District A R0 C L0 R 1242 1254 n.ii 10.51 44.36 106.07 17.32 12.42 7.02 14.45 26.54 11.97 4.46 3.58 8.48 13.65 8.63 3.15 3.33 12.42 49.33 83.35 17.23 30.82 38.65 46.92 9.38 33.50 1.24 ND 18.55 2.46 2.48 3.87 '17.25 5.83 8.60 10.53 7.43 19.25 6.64 5.56 5.26 17.45 24.76 46.11 4.98 16.30 34.52 8.36 (23.66) (14.66) 15 HONS 070798 TABLE 4 PCS* FOUtO ZN SEDIMENTS OP SEVERAL STREAMS AND RAVINES TRIBUTARY TO LAKE MICHIGAN (1971) Values expressed in ppb on a dry weight basis 19 SAMPLE LOCATION 10 to 50 Yarda Upstream From Lake Bull Craak (Zion) Daad River (Zion) Unnanad channal (Haukagan) Haukagan Hivar (Haukagan) Pettibone Creek (North Chicago) Stone Gate Lane Ravine (Lake Forest) Barry Hall school Ravina (Lake Foreat) Cary Avanua Ravina (Hlqhland Park) Ravine Drive Ravine (Highland Park) Park Ave Ravine (Highland Park) Barat Ravine (Lake Forest) Ravine Park Ravine (Lake Bluff) Kellogg Creek (Zion) A R0 CLO R 1242 1254 13..00 12..30 553..00 374..00 173..40 2..48 6..34 3..00 ND 4..32 4..37 1..31 1..77 9..10 6 .29 83..04 131..00 232..00 8,.74 12..34 17..90 6..38 1..54 2..91 2 .54 2..56 < 95..77) ( 32..27) 16 MGNS 070799 r MHlffli"------- : gm.toi.4 CHavt.l '* Woukogon Rlvoi^ TF MUD North Chicago STP Poetlboflo Croo RovIro Pork RovInoJ'"'*9 *>* Huff STP VooHorN Prlvo RovlnoJ iForry HoU School fcovli.. * StoRO Roto Loro RovIro orot RovIro 05 Scat* Ir nt Us To UKC MICHIGAN i, k t M,lci4 i. ;.i" |ltfe-taftfe. --______ ICooh Cowity NlgMoRi Pork Pork Avo. sVp t** '* NSSP MlgMiRri Pork Cory Avo. STP Figure 2t Location* of adimant aairpling atationa along Lak* Michigan in Illinoi*.1* 17 MO NS 070000 TABLE 5 PCBa FOUND IN HATER SAMPLES FROM ILLINOIS STREAMS TRIBUTARY IO LAKE MICHIGAN (1971-72) Valuas &r axprassad in parts par trillion (ppt). 19 SAMPLE LOCATION Haukagan Rlvar Waukagan Rivar Pattlbona Craak Pattlbona Creak Waukagan Rlvar Waukagan Rlvar Waukagan Rlvar Waukagan Rlvar Pattlbona Craak Pattlbona Craak Pattlbona Craak DATE COLLECTED AR0 CL0 R 1242 1254 8/18/71 7/29/71 8/26/71 7/29/71 5/24/72 5/23/72 5/25/72 6/29/72 5/24/72 5/25/72 6/29/72 1810.0 ND 388.0. ND 187.0 140.0 (534.2) 194.0 192.0 (193.2) 62.0 120.0 57.0 84.0 114.0 136.0 61.0 119.0 ND ND 653.0 (125.1) 111.0 107.0 841.0 (213.0) 18 HONS 070801 TABLE 6 PCBa FOUND IN HATER SAMPLES FROM SEVERAL ILLINOIS SEWAGE PLANTS TRIBUTARY TO LAKE MICHIGAN (1971-72) Valua* ara oxprasaad in ppt. ' SAMPLE LOCATION NSSD Wauk.gan STP NS8D Waukagan STP NSSD waukagan STP NSSD North Chicago STP NSSD North Chicago STP NSSD North Chicago STP NSSD Waukagan STP NSSD Waukagan STP NSSD Waukagan STP NSSD Waukagan STP NSSD Waukagan STP NSSD North Chicago STP NSSD North Chicago STP NSSD North Chicago STP NSSD North Chicago STP nssd North Chicago STP DATE COLLECTED A R o C LOR 1242 1254 9/17/71 0/04/71 7/22/71 7/23/71 8/04/71 8/25/71 5/16/72 5/19/72 5/23/72 5/22/72 6/17/72 5/22/72 5/23/72 5/16/72 5/19/72 6/17/72 .601.0 2105.0 4020.0 1070.0 266.0 534.0 (1433.0) 139.0 472.0 568.0 250.0 153.0 217.0 (299.6) ND ND ND ND 17.0 139.0 105.0 97.0 118.0 111.0 ND ND ND ND 21.0 104.0 100.0 132.0 161.0 178.0 ( 3.8) (124.0) HONS 070802 19 Figure 3: Location of water sampling stations, used in 1971 and 1972 for determination of PCB levels in Lake Michigan. 20 HONS 070803 IX. HEALTH EFFECTS OF PCBet ANIMAL STUDIES A. Tissue Storage Metabolism and Excretion Experimental exposure of rats to dietary PCBe has revealed that the isomeric forms are retained to various degrees (as tissue residues) in most body fluids and tissue, with the highest value in adipose (fat) tissue. The adipose tissue often contained more than ten times the concentration-of other tissues with the second highest PCB concentration (liver, usually) and more than 100 times the levels in other tissues including the blood, heart, kidney and brain.23*33'34 Why Isomeric forms are retained to various degrees is still not resolved. A possible explanation includes the differential absorption of the isomers through the digestive tract.33 The turnover rate of PCBs in tissue will vary with the degree of chlorination. The higher isomers are usually retained the longest in mamnals and other vertebrates. It is still uncertain whether PCBs are stored in tissue until a specific point when a steady state is reached and the concentration does not increase further. The given level at which this equilibrium may be reached in adipose tissue could vary with the amount fed to the animals and the type of compound. 22 ' 2% The urinary excretion of biphenyl and 4-chlorobiphenyl has been studied in rabbits. Biphenylglucosiduronic acid and 4-hydroxybipheny1 were isolated from the urine. The rabbits fed the 4-chlorobiphenyl excreted 4-(p-chlorobiphenyl)-phenol and 4-chlorobiphenyl glucosiduronlde. Twice as much 4-chlorobiphenyl as biphenyl was excreted as the glucosiduronic acid derivative. It was suggested that other low chlorinated biphenyls are excreted in a similar manner. Of dogs injsctsd with 2,4,4'-trichloro-2'-hydroxydiphenyl sther, nearly 100% of the material is recovered es the glucuronide or sulfate in urine and feces over a 5-day period.. Humans similarly exposed excrete 65% in urine and 20% in feces after Intravenous injection. It is excretsd sither as free compound or es a glucuzonlds. other evidence suggests that some chlorinated biphenyls ere hydroxylated HOMS 070804 21 by species such as the rat and pigeon, mo evidence of reductive 27 dechlorination was observed in either the trout, rat, or pigeon. Pish and other aquatic animals accumulate PCBs to levels of the order 4 of 10 times higher than those in the ambient water. Predators at the top of the food chain such as birds, seals, and sharks may accumulate PCBs to levels 107 or more times the levels in- the ambient water. B* Effects of various Isomeric Mixtures and Possible Ccn*-"inaUon of PCB Samples by Other Compounds There is no consistent relationship between toxicity and the degree of chlorination which is valid for different species and * different routes of exposure. For example, in rats, acute oral toxicity decreases with increasing chlorine content, while in rabbits, acute dermal toxicity appears to be highest for aroclors of intermediate chlorine content. Also, as will be seen later, most of the data on mammals concerning reproductive effects, demonstrate that toxicity decreases with increasing degrees of chlorination.1 A study on White Leghorn hens using Aroclors 1221, 1232, 1242, 1240, 1254, 1268, 5442, and BP-6 (at the 20 ppm level) additionally,1242, 1240 and 1254 ware fed at the 2 ppm level) showed that feeding 20 ppm Aroclors 1232, 1242, 1248 and 1254 reduced hatchability and caused teratogenic effects in the embryos (edema and unabsorbed yolk). It was determined that adverse effects of the PCBs were not directly related to the degree of chlorination of biphenyls, or the amount of the total residue since Aroclors 1221 and 1268 did not adversely affect the embryonic development. Another study showed that weanling rats were jre susceptible to Arocior 1254 and 1260 than adult rats as determined by acute toxicity studies. 25 An experiment comparing Aroclors 1254, 1242, and 1221 (respectively, 54, 42, and 214 chlorine) was conducted to determine the effect of varying chlorine content on rabbits (oral administration, 300 mg of the PCBs Arocior 1221, 1242, 1254, once a week, for 14 weeks). The livers of the 1254 and 1242 treated rabbits were significantly enlarged compared to the control animals. The study suggests that the higher chlorine content of Arocior 1254 causes the most toxicity of these mixtures. Arocior 1242 22 HONS 070805 has a leaser, though significant effect on the liver. No significant Itssion* were found in the 1221-treeted 29 rabbits. This would suggest that the PCB mixtures with the lowest chlorine content should be used commercially, but factors such as biodegradability and bio-accumulation should be taken into consideration, as well. Chlorinated dibenzofurais (CDF) and pentachloro a&pthalenes have bean idantifled by coirbined gas chromatography/mass spectrometry In a polychlori nated biphenyl of Japanese manufacture (KC-400). The question of whether chlorinated dlb^nsofuran in KC-400 may have contributed to the reported "Yusho" incident (see section on Case History of PCB Poisoning--Japan) has bssn raised. 30Controversy exists on two important factors in ralation to the CDIbt 1) whether contamination, occurrred during manufacture of the PCBa or during the use of the PCB mixture as a heat exchange fluid in the rice oil plant. High temperatures may have led to its formation through tha hydroxi- lstion and oxygen ring bridging of chlorinated biphenyl molecules, and 2) there ia as yst no direct experimental evidence linking dibenxofuran derivatives with the long-term chronic affects similar to those which have been demonstrated with P_CBs. 21,25,31 Chlorinated dibenaofurans have been detected in several PCB preparations (Clophen A60, Phenoclor DP-6, Aroclors 124b, 1254, 1260) and have been shown bo be acutely aanbryotoxic.21* Other organochlorine compounds which my be present in food webs include the chlorinated dibencodioxlns in addition to the chlorinated dibenaofurans which are toxic to eatoryos in amounts less than 1 ug. 33'33 1. Effacts on tha liver and spleen The most significant effect of PCSs to the liver for birds and a variety of mammals (s.g., rats, rabbits, dogs) included weight increase, fatty degeneration and necrosis. Increased liver weights are probably caused by the proliferation of smooth endoplasmic reticulum. Along with such structural changes, there are increased activities of soma drug metabolising ensymes such as nitroreductase and aromatic hydroxylase.35,33 In a study testing the effect of PCBs on pentobarbital metabolism and alteration of sleeping time in rats, it was found that Aroclors 1254 and 1260 reduced sleeping time. Such results suggested an acceleration of pentobarbital metabolism caused by liver enzyme induction. 34 HONS 070806 23 In rata exposed to Aroclor 1242, vitamin A storage in the liver waa reduced by as much as 50%, although no toxic or deficiency symptoms were seen. If only marginal amounts of vitamin A were in the diets of some rats, it has been theorized that avitaminosis could result. 35 This suggests that PCBs may alter lipid metabolism and/or affect preferential absorption from the gastrointestinal tract. Histopathological effects observed in pheasants fed 210 mg of PCBs daily included loss of appetite, degeneration of liver cord cells and depletion of lymphatic nodules in the spleen.36 2. Carcinogenesis and Tumorigenesis Polychlorinated biphenyls when fed chronically to rats caused hepatic acfenefibrosis* and biliary epithelial hyperplasia** elrtdlar* to lesions caused by butter yellow (p-dimethylamino-azobenzene), a known carcinogen. Contamination of PCBs with compounds such as polychlorinated dibanzofurans and chlorinated naphthalenes have been suggested to be causative carcinogenic agents. This controversy is unresolved and needs further investigation. Studies indicatsd that when various Kanechlor mixtures were fed to rats liver weight increased and certain histopathological findings were observed these included the induction of nodular hyperplasias (increase in hepatic cells, forms nodes), but no heputocellular carcinomas were observed. The authors suggested that all kinds of Kars chlors have . tunorlgenlc action in the rat liver. Other studies had shown hepatocellular carcinomas were Induced in the liver of mice by Kanechlor - 500 which contains a high proportion of chloride groups, but not by Kanechlor - 400 or-300.37 This study also showed marked cholanglofibrosis (fibrous formations In lobules of the liver) in the rat liver. Further investigations are required of the difference in the tumorigenic actions of the PCBs since this was not observed in mice treated with PCBs.37 Evidence exists that soma hepatocellular carcinomas may originate from nodular hyperplasias. The histopathological patterns of nodular hyperplasias *Adenofibroslst glandular formation surrounded by proliferating fibrous tlsue; benign, yet difficult to distinguish from cancerous tissue. **b.i Mary epithelial hyperplasiat an increase in the number of cells in the 1 it whereby the bulk of the liver is Increased. 24 HONS 070807 nan in that aeudy were similar to thoss induced by known chemical carcinogens such as 3'-methyl-4-(dimethylamino) -azobeniene, N-2-flmrorenylaentamide, DL-ethronine, m- toluenediamine, and diethylnitrosamine.37 Findings suggested that hepatocellular carcinomas can be induced by administration of Kanechlor -500,-400, -300 for a longer period of tlM.37 Increased liver weisfit, adenofibroeis and hepatomas were induced in mice fed 300 ppm Aroclor 1254 in diet for 11 months. Hepatocellular carcinomas were observed in 26 of 184 rats fed 100 ppm Aroclor 1260 in their diet for 21 30 months in contrast to 1 of 173 control rats. 3. Effects on adrenal gland Rats receiving 200 ppm Aroclor 1221 in their drinking water for 6 weeks showed morphological alterations in the zona fasciculata of the adrenal gland, as well as increased levels of corticosterone. Such results have been in terpreted as possible evidence of the need for a higher level of glucosteroids 40 in defense against tha stressor action of Aroclor 1221. 4. Effect! on the raproductive system (not including, primates) Rats wars exposed to Aroclors 1242, 1254, and 1260 in the diet at lavala of 1, 10, and 100 ppm. It was found that Aroclor 1242 did not affect the first generation, but mating indicas were decreased in the second generation at 100 ppm. With Aroclor 1254, the number of young delivered and the number surviving to weaning were decreased in both the second and third litters. Aroclor 1260 was found to increase the number of stillbirths at 100 ppm. No effects were seen at concentrations of 1 and 10 ppmA Studies with chickens indicated decreased egg production at 100 ppm with Aroclors 1242 and 1254, but not with Aroclor 1260. Decreased egg shell thickness occured at 10 and 100 ppm of Aroclor 1242 , but only at 100 ppm with Aroclor 1254; however, such effects were not seen with Aroclor 1260 even at 100 ppm. Pheasants have also been reported to have their reproductive capacities decreased by PCBs with reduced numbers of eggs laid and reduced developmental success of those that did hatch. Biochemical studies have indicated that PCBs are capable of inducing the microsomal hydroxylating activity in the liver so as to affect the 25 MOftS 070808 hydroxylation of both progesterone and testosterone. 41 Such biochoslcel findings may provide the basis for understanding how PCBs interfere with reproductive processes. Such information may also shed light on the possible effects of PCBs on the depression of secondary sexual characteristics. 5. Effects on chromosomes The effects of Aroclor 1254 (10 ppm in the diet) on dove embryo chromosomes were examined. The experiments studied the largest 8 chromosome pairs occurring in metaphase cells of allantoic sac and limb bud origin with 365 metaphase cells examined per embryo. Parameters, observed were aneuploidy, polyploidy and breakage rearrangement. The results, as summarized in Table 7, provide evidence that PCBs may act 43 as clastogenic agents. The studies showed that PCfte may cause chrowset aberrations^in vivo in Ring Dove Embryos, but no aberrations as studied in Drosophila. TABLE 7 THE CHROMOSOME ABERRATION RATE IN DOVE EMBRYOS TREATED WITH PCBs Control PCB Treated Rate 0.8% 1.8% Range 0-2% 0-9.4% Total # Sampled 6 17 6. Synergistic and Additive Effects In a study where male rats were orally dosed with carbon tetrachloride (OClj) used in conjunction with Aroclor 1254, the Aroclor potentiated the toxicity of CCl^. This study indicated that the liver is the main site of Aroclor 1254 metabolism and rats with 0C14 damaged livers are not able to metabolize this compound as rapidly as rats with normal livers wider the conditions of the experiment. The residues in the blood, testes, liver, kid- 26 HONS 070809 ney and heart of CC14 traatad rata was higher. 23PCBb given to laying phaaaant hena adversely af{acted egg production, hatchability, and viability of the embryo about the time of hatching but did not affect fertility or eggahall thickneae. However, whan phaaaanta were fed 50 mg PCBa along with dieldrin36 or DOB, 45 only additive and not aynergiatic interactions were found. A study waa done to determine the effects of PCBa on neoplastic changes induced by isomers of benzenehexachloride (BHC) in the livers of mice fad a diet containing BHC with or without PCBa for 24 weeks. Researchers observed that PCBa promoted the induction of hepatic neoplasms in mice by Isomers of BHC.46 7. Immunosuppression A reduction in lyzphoid tissue and the presence of amyloid or amyloid like material in the liver of PCB exposed chicks has been reported.47 (Amyloid formation has been found to be stimulated by certain imnunosipprasslve drugs). Also, lymphopenia has bean reported in rabbits,48 while in guinea pigs, 33 PCBa decreased the number of antibody-forming cells after stimulation of the humoral lymphoid system with tetanous toxoid. Such immunosuppressive actions by PCBs may help to explain the increase in susceptibility of PCB exposed fish to fungal disease, 49 PCB exposed ducks to viral hepatitis 30 and the onset of liver cancer in PCB exposed rats. 20 (see section on Carcinogenicity) 8. Primate studies Racent studies have indicated that very low levels of PCB exposure are toxic to primatss. For example, in one experiment rhesus monkeys which ate food containing 25 ppm of Aroclor 1248 for 2 months developed facial swelling, loss of hair and acne lesions within a month, (hie monkey died from PCB intoxication 2 months after going off the experimental diet.*** Another experiment utilized 2 groups of rhesus monkeys which ate food containing 5 and 2.5 ppm of Aroclor 1248. Within 2 months both groups had lost hair from the face and neck and their akin was of HONS 070810 27 "a andpapar-llX* taxtura". Both groups davslopad sons, although tha 2.5 fp" groups davalopad tha laslons latsr. In 6 months, both groups rtachad a stsady stats concentration of PCBs In adipoaa tissue. Test monktys were then mated with monkeys which had not been fed PCBs. Six of the 9 female monkeys which had eaten food containing 5 pf of PCBs became pregnant, in contrast to all 12 females in the control group. In the test group 4 of the 6 pregnant females aborted or re sorbed the fetus, 1 gave birth to a stillborn and 1 to a vary undersised infant.51b Zn the 2.5 ppm group, all 8 females in the test group conceived and of . aiw then, 3 resorbad and S gave birth to undersized Infanta. Z. nun BTSCT6 OF PCBat HUMAN BXFOSUBB VIA FOOD, AIR AND MATER A. Occupational Exposure Known toxic effects of PCBa in humans includa an acneliks akin eruption callad ohloracna, pigmentation of tha akin and naila, diatlnctiva hair follicles, axcaaaiva ay. discharge, and availing of eyelids. Several 'oarea of htnan tocicity to PCBa in an industrial! acting -- have been reported. SJ53 Exposed workers .developed small dermal cyet. and ccaiados (blackhaada). These wars usually found on tha face and ears, although auch aoraa have bean reported on numerous other parts of tha body. Darmal aoraa generally persisted for several months after removal from the source and in soma instances, lasted four years.54 Systemic affects have also occurred in several cases. These effects includa nausea, lassitude, anorexia, digestive disturbances, impotence and hematuria.*'5* ' A study dona on PCB concentration in tha plasma of refuse workers found that 32 out of 37 (81%) of tha refuse workers had detectable lavala as compared to only lit (6 out of S4) of the controls. Median PCB concentrations for thosa with datactabla amounts wars similar in tha two groupsi rafuaa workers - 2.6 ppb, controls - 3.7 ppb. The higher frequency of measurable plasma PCB lavala in refuse workers (l.a., 81% of refuse workers with detectable lavala as opposed to only 11% of controls with datactabla levels) 1:. thought to raflact their increased PCS exposure from incinerated materials.55 28 MGNS 070811 The American Oonferenc* of Governmental Industrial Hygienist* hu Mt a TLV of 1 mg/mJ for occupational exposure to vapor* of Aroclor 1242, with lowar valuaa for hiqher Aroclor*. Based on an 8-hour axpoaura, thia would rvault in tha inhalation of approximately 5 mg/day. iha currant Occupational Health and Safety A&nlnistration, Department of Labor atandarda for chlorinated biphenyl* aura 1 mg/m3 for 42% chlorine mixturaa and . 5 mg/m3 for 54% chlorine mixturaa, baaed on tha TLVat. fraagntly, it 1* not ' Known how much of tha inhaled.fCBa human* abaorb...through theMung*.1'3 . . . B. caaa Hiatory of PCB Poiaonino - Japan Tha moat wall known caaa of PCB contamination ha* occurred in Japan, with documented toxic affect* in over 2,000 Japan*** exposed to rice oil contamination. Kanauri Rica Oil was polluted with Kanachlor 400, which la equivalent to Rroolor 1248. This contamination incident, which was finally traced to a rica oil shipment in February, 1968, was called "Yusho" and occurred in western Japan in the area of Fukuoka prefecture. The first affected people showed the development of dermal cysts pre dominantly on the face and ears, but also on most other parts of the body. In severely intoxicated individual*, nausea, lassitude, anorexia, impotence and haemturl* were observed. It is apparent that the severity of symptoms are directly related to the amount of ICBs ingested.56 It is known that the concentration of JCanechlor 400 in the rice oil waa 2,000-3,000 ppm and the average quantity of rice oil con*laved by patients in a first epidemiological study (325 eases) was IN ml. over a period of approximately 8-9 months.S7 Consequently, the average dose of PCB ingested by affected individuals was approximately 2 g. The smllest dose ingested by a patient mis estimated to be 0.5g.56 Tha children of 13 woman (9 of whom consisted between 0. >-2.-6 liters of rice oil during pregnancy) were studied for possible teratogenic effects. Eleven children were born alive while 2 war* stillborn. 56,63 Tha infants had a charctaristic grayish, dark brown skin pigaentationi 5 had dark nails and gingivae (the gumsi the tissues.whiab surround tha necks of the teeth and cover the alveolar procassesof the mamllla and mandible) and 9 had increased eye discharge. A detailed study of 29 M0NS 07C812 4 infant* ravtalad Abftomalitift* which included enlarged frontal sagittal suture. Paces were edematous, and there was an abnormal protrusion of eyeballs. ' As a result of such symptoms, it has been generally ooncluded that placental transfer of PCBs had occurred affecting tha.fetus. The growth of school children afflicted with Yusho has also been studied. Both height and weight gain of boys with Yusho illness were v significantly leas than a control group, while the girls of Yusho did 57 not differ ignificantly from the control group. C. Consumption Vl Food and Drink Band on market basket samples of PCS levels In food, an adult la estimated to Ingest approximately 5-10 tg PCB/day. This figure was baaed. In part, on an asaumad level of 0.1 ppm In 3t of the food. Such a calculation may lead to an inaccurate representation of the total PCB intake of various coninner groups. It is known that human fish censusption and PCB levels in fish vary considerably.* although the FDA tolerance for PCB residues in fish is 5 ppan,it la not uncommon to find PCB lavals between 10-20 ppm in fish found in the Great bakes, especially Lake Michigan. 60 Thus, individuals who habitually eat large quantities of. fish, especislly from such arses as the Great takes, will have much higher intakes than the general population. For example, an individual who eats 50 g of fish par day (1.8 or./day) containing 2 ppm of PCB. will lngs.t 100 pg/day of PCBs. For a person following the reaommanded "weight watcher's diet", the levels of PCBs in the diet may be even significantly higher. The "weight watcher diet" suggests 5 fish meals/waak, which is approximately 98 g (3.5 ox.) of fish consisted par day.*' Assuming a contamination of 2 ppm, the "faithful weight watcher" would consuna about 200 pg/day of PCB just from fl.h alone. In addition to high level# of PCBs in fish, considersbla concentration, may also be founjl in human milk. For example, samples of himtan milk from two cities in California contained average PCB levels of 60 ppb, while average levels In hisnan milk in Sweden and Germany ware 16 ppb and 100 ppb, respectively. Baaed on a daily milk Intake of 150 ml/Kg, breast fad Infants In California would ingest about 9 pg/Kg/day of PCB (at least ' X more than a rsoosmendad reasonable dose). Sporadic instance! of 30 M0NS 070813 contamination of other foods such is milk and poultry aay also load to higher in takaa for short pariods. 1,62 A rsport of measurement of aablant PCS atmospheric Iavala ranTad from 1-50 ng/ra3. This would rasult In tha inhalation of laaa than 1 ug/day by an adult. 2 Bie intaka from drinking PCB-contaminatad water, asaiaing 10 ppt as tha concentration, would rasult in about 2-5 ug/day by an adult. Laka Michigan levels ara usually lass than 10 ppt.20 A ranga of 1-3 ug/Kg/day (70-210 ug/day for an adult) has bean suggested ae a "reasonable" level for an Acceptable Daily Intake.2 One ug/Xg/day has bean reported as being 100 tines lass than tha lowest "no-affact level" reported in animal studies.33 . The Federal Drug Adminiatratlcn established PCS tolerance levels In a ntraber of food products as follows!22'03 Food Concentration (PPm) Milk * 2.5 Dairy Products * 2.5 Poultry * 5.0 Fish and Shellfish * . 5.0 Eggs 0.5 infant fi Junior Food 0.2 Complate and finished Animal Feed 0.2 AnistaL Faad Conponants 2.0 Papsr food-Packaging Matarial 10.0 * on fat basis However, toxicity data obtained subsequently showing reproductive abnormalities with concentrations of tda in primates ranging from 2.5 to 5.0 ppm and tha recant demonstration of adenofibrosis and other toxic offsets in rate indicate a need for revisions of the present FDA tolerance limitations of PCBa in foods. The FDA is expected to enforce its guidelines more 'forcefully in the 'future based on a recent legal decision that allows tha FDA to define pesticide residues in foods as an Indirect food additive.22 ' 31 M0NS 070814 Studies have also shown that migration of PCBs from packaging materials does occur. 21* 64 In the abseioe of an effective barrier, Aroclor 1242 was shown to migrate from paperboard to food in measurable amounts when food was purchased in paperboard containing a significant amount of Aroclor 1242. It is considered an absorption phenomenon dependent primarily on the surface area of the food and secondarily on the fat content of the food, the study suggestsd that materials of low gas permeability could be effective barriers to PCS migration. XI. PCB LEVELS IN TISSUE Of HUMANS IN THE UNITED STATES Adipose samples were collected from tissues withdrawn for therapeutic surgery or from post-mortem exams. Positive samples were obtained from 10 states, one of which was Illinois. The other 17 states include eastern, western and southern states, thus indicating that PCBs are widespread. It wee reported that 165 of 637 (25.9%) samples of human adipose tissue contained 1-2 ppm. Thirty-three of the samples (5.2%) contained greater than 2 ppmi 125 (19.6%) contained between a trace and 1.0 ppmi the remaining 314 (49.3%) were negative at the level of pen identification. 65 XII. HIGH RISK SEGMENTS OF THE POPULATION Embryos, fetuses and neonates ( 2 to 3 months old ) Often lack tha liver microsomal enzyme systems that oxidise various natural and foreign chemicals, including those of a biphenolic nature. The activation of such enzyme systems often facilitate the detoxification and excretion of such substances. Usually by the age of 2 to 3 months, adult levels of 66,67 the enzyme systems are achieved. Unfortunately, this "developmental inmaturity" in the unborn and the very young may predispose them to ths toxic effects of certain substances since they may be unable to detoxify end excrete them as quickly as necessary. Clinical experience has shown that Infants may respond differently to doses of drugs which are easily tolerated by older children and adults. Presumably, this is bacausa older children and adults have fully functioning enzyme detoxi66,67 licetion systems while the neonate lacks such development. 32 MCNS 070615 On* such microsomal enzyme system includes the glucuronldation pathway which functions in tha detoxification and axcration of a variety of chemicals 66 including alcohols and phenols. Inefficient glucuronidative machanlmts in infants have broad significance since the absence of such mechanisms prevents the prompt elimination of toxic substances from the body. Since some young children have been shown to consuee more PCBs per unit of body weight than adults {since PCBs have appreciable concentrations 62 in human milk), the lack of appropriate detoxification enzyme systems compounds ths PCB problem for the very young. A tragic example of toxicity arising from the inability to form glucuronides hae been reported. The drug chloramphenicol, which is known to be metabolized in himans by the action of the glucuronic pathway, caused the death of more than 30 premature babies who had been treated with the antibiotic for infectious dlseasss. 68 Thsoretically, the premature babies were not able to conjugate the drug with glucuronic acid and thus the drug could only be slowly excreted end so tended to accumulate in the body to toxic proportions eventually leading to death. An additional problem encountered by many neonates is that approximately five percent of the mothers of normal infants secrets milk which inhibits ths activity of glucuronyl transferase (and thus the glucuronldation process) by more than 20% via the action of a steroid present in the breast milk. Inhibition of this glucuronyl transferase has been reported for up to 49 days after birth. Clinically, these children have been reported to develop unusually severe neonatal jaundice. Thia condition develops because glucuronide formation, which assists in the elimination of bilirubin (breakdown product of hemoglobin), is partially inhibited. Oow's milk does not contain sufficient amounts of this steroid to effect a noticeable inhibition of the glucuronideconjugation process.69 Consequently, about 5% of the breast-fed neonates would be expected to have their ability to excrete PCBs impaired. Administration of ths antibiotic novobiocin has also been associated with unoonjugated hyperbilirubinemia in infants.70 Novobiocin is a noncompetitive inhibitor of glucuronyl transferase activity in vitro.^ Thus, children receiving concomitant exposure of novobiocin and PCBa would be expected to have their ability to detoxify and excrete PCBs impaired. MONS 0 30616 33 After the neonatal period, a broad range of conditions is Associated with the improper or incomplete development of the glucuronide conjugation system. The usual physiologicaa problem associated with these conditions is the inadequate detoxification of bilirubin. This spectrum extends from the frequently occurring "mild" condition known as Gilbert's syndrome, 72 to the very rare, but severe and often fatal Crigler and Najjar syndrome. Since the clinical effects associated with these syndromes are considered to be caused by metabolic disturbances of the glucuronide conjugation scheme, it is expected that PCB elimination in these individuals would be impeded. Although Gilbert's syndrome has been mentioned as being "encountered relatively often" in a clinical sense, no estimates of the gene frequency of such a trait has been reported.' Concomitant exposure to PCBs and other compounds may enhance the toxic effects of PCBs. For example, rats and monkeys given 0-diethylaminoethyl-2,2-diphenylpentanoate (SXF525A, a non-specific inhibitor for many of the microsomal enzyme activities, especially hepatic microsomal enzymes) during the initial 24 hours of exposure to PCB, succumbed rapidly as compared to the control group. 51 Of possible significance is the fact that SKF525A inhibits the proper functioning of the glucuronidation pathway. 68 Individuals with liver infections may also be at high risk with respaot to PCBs. For example, depression of glucuronide synthesis has been observed in hvsnans with Infectious hepatitis. 68 HONS 070813 XIII APPENDIX AROCLOR PRODUCTS MANUFACTURED IN THE UNITED STATES CUWffiOT 1221 10X6 1242 1254 .... . . , DISCONTINUED 1232 1248 1260 1262 1268 PERCENT Cm^RINE 21 32 41* 42 48 54 60 62 68 / Aroclor products ars idantifiad by a four digit numbering coda In which tha first two digits, 12, indicata tha parent Molecule is biphenyl and the last two digits specify tha weight percent of chlorine. The exception is Monsanto's newest product, hroclor 1016 (41% chlorine), which retained the 1016 designation by whioh it was known during develop ment. 35 MONS 070818 XIV. REFEW5NCBS 1. Sellkoff, I. J. (ed.)i "Polychlorinated Biphenyl--Environmental Intact: A Review of the Panel on Hazardous Trace Substances." Environ. Research 31249. 1972. "-------------------------- 2. Lloyd, J. W., Moore, R. M., Woolf, B. s., and stain, H. p. i ''Polychlorinated Biphenyls." J.O.M. 18il09, 1976. 3. Cook, j. w.> "Some Chemical Aspects of Polychlorinated Biphenyls (PCBe)." Environ. Hlth. Persp. Ii3, 1972. 4. Nisbet, I. C. T., and Sarofln. A. P. "Rates and Routes of Transport of POs in the Bivironmant." Environ. Hlth. Persp. Ii21, 1972. 5. Reynolds, L. M. i "Polychlorobiphenyls (PCBs) and Their Interference with Peetlcide Residue Analysis." Bull. Environ. Oontemin. and Toxicol. 4(3) 1128, 1969. |---------------------------------- 6. Broadhurst, M. G.i "Use and Replaceability of Polychlorinated Biphenyls." Environ. Hlth. Persp. Ii81, 1972. 7. Papageorgs, W. B.i Monsanto Industrial Chemicals Co., 800 North Lindbergh Blvd., St. Louis, Missouri. November, 1974. Personal Comaunicatlon. 8. Monsanto Companyi "Polychlorinated Biphenylsi A Risk/Benefit Dilesnm." St. Louis, No., January, 1976. 9. Interdepartmental Task Force on PCBs (Depts. of Agriculture, HEW,' EPA, and other participating agencies)i Polychlorinated Biphenyls and the Environment. NTIS No. C0M-72-10419. Washington, D.C., May, 1972. 10. Rlsabrough, R. W., Rische, P., Peakall, 0. B., Herman, S. G., and Kirven, M. N. "Polychlorinated Biphenyls in the Global Ecosystem." Nature 220tl098, 1968. 11. Duka, T. W., Lowe, J. J., and Wilson, A. J., Jr.i "A Polychlorinated Biphenyl (Aroclor 1254) in the Water, Sediment, and Biota of Escasbia Bay, Florida." Bull. Biviron. contamln. and TOxlcol. 5(2) 1171, 1970. 12. Vaith, G. D., and Lee, F. G.t "Chlorobiphenyls (PCBs) in the Milwaukee River." Water Research 6,1107, 1971. 13. Risebrough, R. w., and deLappa, B.i "Accuaulation of Polychlorinated Biphenyls in Eoosystems." Environ. Hlth. Persp. 1<39, 1972. 14. Trout, P. E.i "PCS and the Paper Industry--A Progress Report." Environ. Hlth. Persp. 1,63, 1972. !5. Subpart B - Tolerances for Added Poisonous or Deleterious Substances, 122,100 Polychlorinated Biphenyls (PCBs), Federal Register 39(236) ,42747, Friday, Deoesber 6, 1974. 16. Subpart 1 - Proposed Toxic Pollutant Effluent Standards 129.09 Effluents Standards for Polychlorinated Biphenyls (PCBs), Federal Racistsr. 38(247),35395 ihursday, December 27, 1973. 36 MCNS 070819 17. Subpart II - Proposed Effluent Standard. (H) Tha Proposed Effluent Standard for PCBs. 40 CFR 129i Draft Advance Notice of Proposed Rule Making tor Toxic Pollutant Effluent Standards. Environ. Reporter 1342, Noveotoer 12, 1974. 18. Federal Register 41(64),14134, Thursday, April 1, 1976. 19. Schacht, R. A. i "Pesticides in the Illinois Water of Lake Michigan." Ecological Research Series. EPA-660/3-74-002. Project No. 16050 ESP. January, 1974. 20. FDA Consumer 9 (7) t 32, September, 1975. 21. Ahmad, A. K.i "PCBs, in the Environment." Environment 18i6, 1976. 22. Burse, V. W., Kimbrough, R. D., Villanueva, E. C., Jennings, R. w., Linder, R. E., and Sovocoal, 0. W.t "Polychlorinated Biphenyls Storage, Distribution, and Recovery, Liver Morphology After Prolonged Dietary Ingeation." Arch. Environ. Hlth. 29,301, 1974. 23. Grant, D.. L., Phillips, W. E. J., and Villanauve, D. C.i "Mstabolism of a Polychlorinated Biphenyl (Aroclor 1254) Mixture in tha Rat." Bull. Environ. Content, and Tox. 6(2),102, 1971. 24. Curlay, A., Bursa, V. W., Grim, M. E., Jennings, R. W., and Linder, R. E., "Polychlorinated Biphanyla, Distribution end Storage in Body Fluids and Tissues of Shaman Rata." Environ. Research 4,481, 1971. 25. Goldberg, L. (ad.), "The Toxicity of Polychlorinated Polycyclic corpounda and Related Chamicale." Critical Reviews in Toxicology. 2(4),445, 1974. 26. Block, W. D., and Cornish, H. H., "Metabolism of Biphenyl and 4Chlorobiphenyl in the Rabbit." J. Biol. Cham. 234(12),3301, 1959. 27. Hutsingar, O., Nash, D. M., Safe, S., DaFreltas. A. S. W., Norstron, R. J., Wildish, D. J., and Zitko, V., "Polychlorinated Biphenyls, Metabolic Behavior of Purs Isooars in Pigeons, Rats and Brook Trout.' Science 178,312, 1972. 28. Cecil, H. C., Bitman, J., Lillis, R. J., and Fries, G. F.i "Enfcryotoxic and Teratogenic Effects in unhatched Fertile Eggs from Hens Fed Polychlorinated Biphenyls (PCBs)." Bull. Environ. Contam. Toxicol. 12,489, 1974. 29. Zlnkl, J. G., and Keller, L. D.t "Pathology of Polychlorinated Biphenyls in Rabbits." Vat. Pathol. 12,63, 1975. 30. Roach, J. A. G., and Pomsrantz, I. H., "The Finding of Chlorinated Dibensofurans in a Japanese Polychlorinated Biphenyl sample." Bull. Environ. Contam. Toxicol. 12,338, 1974. ' M0NS 070820 37 31. Kuratauna, M., Masuda, Y.. and Nagayami, J.: "Soma of the Recent Finding. Concerning Yusho Papers Fraaantad at National Confaranca on Polychlorinated Biphenyls." Chicago, Illinoia, Novambar 19-21, 1975. 32. Bowes. 6. W.. Mulvhill, M. J.. Siooneit. R. T., Burlingame. A. L.. and Risebrough. R. W.: "Identification of Chlorinated Dibenzofurana in American Polychlorinated Biphenyla." Nature 256305, 1975. 33. voa, J. G., "Told.oology of PCBa for Haamala and for Birda." Environ, tilth. Perap. 1:105. 1972. 34. Vill.n.uva, 0. C., Grant, D. L., and Phillips, W. E. 3.1 "Modification of Pentobarbital SI*.ping Tina in Rat* Following Chronic PCB lngastion." Bull. Environ. Contan. and To*. 7(5),264. 1972. 35. Cscil, H. C., Harris, S. J., Bitman, J., and Pries, G. F. t "Polychlorinated Biphenyl-Induced Decrease in Liver Vitamin A In Japanese Quail and Rats." Bull. Environ. Contestin'. and Tex. 9(3) >179. 1973. 36. Dahlgran, R. B., Lindar, R. L., and Carlson, C. W., "Polychlorinated Bioh.nvlsi Their Effects on Panned Pheasants." Environ. Hlth. Perso. 1,89, 1972. i " Ito, N., Hiroshi, N., Makiura, S., and Aral, M.t "Hiatopathological Studlas on Liver Tunorlganaais in Rats Treated with-Polychlorinated Biphenyls." Gann. 651545, 1974. 38. Kinbrough, R. D., and Lindar, R. E.t "Induction of Adanofibro.is and Hepatomas of the Liver in BALB/cl Mice by Polychlorinatad Biphenyls (Aroclor .1254)." J. Nat'l. Cane. Inst. 53i54 7. 1974. 39. Kimbrough, R. D.. squire, R. a., and Linder. R. E., et al * "Induction of Liver Tumors in Rats by Polychlorinatad Biphenyl Aroclor 1260." J. Nat'l. Cane. Inet. December. 1975. (Cited in Reference 2). 40. Was Barman, D., wassarman, M., Cucos, 8., Djaraharlan, H.i "Function of Adrenal Gland - Zona Fasciculata In Rata Receiving Polychlorinated Bishenvls." Environ. Research. 6i334. 1973. 41. Ptakall, D. B.i "Pastlcida-Inducad Enzyme Breakdown of Steroids in Birds.' Nature 216,505, 1967. 42. Rehfeld# Be He, Bradley. R. L., end Stands. M. L.i "Tbxicity Studies on Polychlorinated Biphenyls in the Chick." Poultry Science S0(4)il090. 1971. . 43. Faakall, D. B., Linear, J. L., and Bltm, S. S.: "Embryonic Mortality and Chromosomal Alteration. Caused by Aroclor 1254 in Ring Doves." Environ. Hlth. Perap. 1,103, 1972. ' 38 MONS 070821 58. Okueiura, M., and Kateuki. 8. i 'Clinical Obaervatlon on ruatio (Chlorobiphenyl Poisoning).' rukuoks lets Mad. 60 (6) i 440, 1969. 59. Soto, M, and Higuchi, K. i '"Hie Symptomatology of Yusho (Chloroblphenyle Poisoning) In Dermatology." rukuoka Acta Mad. 60(6) 1409, 1969. 60. stalling, D. L., and Mayor, p. L.: "Toxicltias of PCBe to Flah and ' Environmental Realduea." Environ. Hlth. Parao. 1<159, 1972. 61. Barland, T.i Rating tha Plata. Skokis, 111., p. 286, 1974. 62. Sarglund, p.i "Levels of Polychlorinated Biphenyls In Pood in Sweden." Environ. With. Parap. Ii67, 1972. 63. Padaral Baglatar 38(129)I18096, July 6, 1973. 64. Stanoviek, B. Shahiad, S. I., and Mlsaa^ii, B.i ''Determination of Polyahlorlnatad Blphanyl (Aroclor 1242) Migration into Pood Typas." Bull. Environ, Contax. Toxicol. IOiIOI, 1973. 65. Yobs, a. B.i 'Lavals of Polychlorinated Biphanyla in Adipose Tissue of tha General Population of tha Nation." Environ. Hlth. Parap. It 79, 1972. 66. Gillette, J. R.i "Individually Different Responses to Drugs Recording to Age, Sax, and Functional or Pathological State.* Ini Drue Responses In Man. Wblatanholme, G. and Porter, R. (ads.) Churchill, London, p. 28, 1967. 67. Nyhan, w. L.t "Toxicity of Drugs in tha Neonatal Period." J, Padiat. 59(1)tl, 1961. . 68. Balth, R. L., and Mllliaas, R. T. t "IMplication of tha Conjugation of Drugs and Other Exogenous Compounds." Ini Glucuronic Acid, Dutton, G. J. (ad.), Aceded,c Prase, M.y:, p. 457, 1966. 69. Gartner, L. N., and Arias, I. M.i "studies of Prolonged Neonatal Jaundica in tha Breast-Pad Infant." J. Padiat. 68(1)i54, 1966. 70. Sutherland, J. N., and Keller, W. H.i "Novobiocin and Neonatal Hyparbllirtblnemla.' An. J, Die. Quid. 101t447, 1961. 71. Loklets, B., Dowben, R. M., and Hsia, D. Y. i "Studies on tha Rffact of Novobiocin and Gluouxonyl Transferase." Padlatrice 32t47, 1963. 72. Las tar, R., And Schadd, R. i "Bilirubin Metabolism." New Eng. J. Med. 270(15).779, 1964. t I HONS 070822 44. Nillaon, B., and Ramel, C.i "Ganatic Teata on Droeophila Malanogaetv with Polychlorinated Biphanyla (PCB)." Haradltaa 77.319, 1974. 45. Heath, R.G., ej: al_i "Stfacts of Folychlorinatad Biphanyla on Birde." Frooeedlnga XV Intarnational Ornithological Oongraaa, The Hague, 1970. (Citad in rafaranca 36). 46. Ito, N. Nagasaki, H., hrai, M., Makuira, 5., Sugihara, S., and Hirao, K.i "Hiitopathologic Studiaa on Liver Tunerigeneaia Induced in Mion by Technical Folychlorinatad Biphanyla and lta Promoting Bffact on Livar Tuaore Induced by Banxana Hexachloride." J. Mat'l Cane. Inat. 51.1637, 1973. 47. voa, J.B., and Hoeman, J.H.t "Comparative Toxicological Study with Folychlorinatad Biphanyla in Chlckana with Special Rafaranca to Porphyria, Edema Formation, Livar Nacroaia and Tiaaue Raaiduea." Toxicol. Appl. Pharmacol. 17.565, 1970. 48. Voa, J.B., .and Bataa, R.B.i "Dermal Toxicity Sttldiae of Tadhnlcal . Folychlorinatad Biphanyla and Fractiona Thereof in Rabbita." TOxicol. ADpi. Pharmacol. 19.617, 1971. ' 49. Hannan, D.J., Parriah, P.R., Lowe, J.I., Wilaon, A.J. Jr., Wilaon, F.i "Chronic Toxicity, Uptake, and Retention of Aroclor 1254 in Two Eatuarine Fiahaa." Bull. Environ. COntam. and TOxlool. 6.113, 1971. 50. Friend, M., and TTainar, D.O.i "polychlorinated Biphanyl. Interaction With Duck Hapatltia Vlrue." Science 170.1314, 1970. 51a. Allan J.R.t "Reaponaa of tha Non-Hwen Primate to Polychlorinated Biphanyl Expoaura." Federation Frocaadlnda 34(8).1675, 1975. 51b. Baraotti, D.R., Marlar, R.J. and Allan, j.r.i "Reproductive Dyafunotion in Rheaua Monkeya Bipoaed to Low Levela of Polychlorinated Biphanyla (1248). Pood and Ooam. Toxicol. 14.99, 1976. 52. Maiga, J.W., Albom, J.J., and Xkatln, B.L.i "Chloracna From an Unuaual Ixpeaura to Chlorine." JAMA 154.1417, 1954. 53. Pack, s.m.i "Dermatitle Free. Cutting olla, Solvanta, and Dialactrice, Including Chlorlna." JAMA 125.190, 1944. 54. Jonea, A.T.t "Tha Etiology of Acne with Special Rafaranca to Acne of Occupational Origin." J, Ind. Hyg. Toxicol. 23.290, 1941. 55. 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