Document ym1RwryQn47wzZ4OBkq5QKvqX

r U i DEPARTMENT OF COMMERCE National Technical Inhumation Semico PB -259 26 9 Polychlorinated Biphenyls Health Effects and Recommendations Illinois Inst for Environmental Quality, Chicago G EN F Utmzo Ju n 76 774074 VJl o a NO 31012S ILLINOIS INSTITUTE FOR ENVIRONMENTAL QUALITY "S P 3 2 5 3 2 6 3 ft: POLYCHLORINATED BIPHENYLS HEALTH EFFECTS AND RECOMMENDATIONS I l EQ Document No. 76/05 Reproduced st ' ,m c J P N A L TECHNICAL information service l u.s.oepartment of commercf SPRJNCFiaO, VA. ^161 fiC 774075 5002 BIBLIOGRAPHIC DATA SHEET 1. Report No. IIEQ 76/05 4. Title and Subtitle Polychlorinated Biphenyls Health recommendations Effects and 7. Authorial Environmental Health Resources Center Staff 9. Performing Organization Name and Address Environmental Health Resources Center School of Public Health University of Illinois Chicago, Illinois 60680________________ 12. Sponsoring Orgsnizstion Name sod Address Illinois Institute for Environmental Quality 309 West Washington Street Chicago, Illinois 60606 15. Supplementary Notes >. Recipient' s Accession No. PB-259 269 5. Report Date . October 15, 1976 6 3. Performing Organization Repc. No. I 10. Project/Taslt/Worlc Unit No. 90.002 I 11. Contract/Grant No. 13. Type of Report 4c Period Covered Final 14. 16. Abstracts Animal studies have revealed that PCBs can have deleterious effects on numerous organ systems including the liver, kidney, adrena. 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 high 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. Key Words and Document Analysis. 17a. Descriptors Polychlorinated Polychlorinated Polychlorinated Polychlorinated Biphenyls Biphenyls Biphenyls Biphenyls Environmental Impact Health Lake Michigan 17b. Identifiers/Open-Ended Terms o ra 2! o o U) 17c. COSATI Field/Group 18. Availability Statement Release Unlimited Available from NTIS OGT Toxicology F O R M N T I S - S B i R B V . lo - js i ENDORSED BY ANSI AND UNESCO. 774077 19. Security C lass (This Repon) 1 UNCLASSIFIED 120. Security C lass (This Pa, 1J,NCLASSIFIED THIS FORM MAY B E REPRODUCED 21. No. ot Pages u s c o m m - o c aaos*p74 i POLYCHLORINATED BIPHENYLS HEALTH EFFECTS AND RECOMMENDATIONS This document (EHHC Document No. 16) was prepared for the Illinois Institute for Environmental Quality by The Bivironmental Health Resource Center State of Illinois Institute for Environmental Quality Samuel G. Booras, Director June, 1976 l<L 774078 GENP 005432 NOTE This, report has been reproduced as received from the contractor. No e d ito r ia l or other changes have been made. Conclusions expressed in th is report are the c o n t r a c t o r 's . Printed By A u th o rity o f the State o f I l l i n o i s 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, 1976 vi, UO p. 30 cm. -- (IIEQ Doc. Ho. 76/05; EHRC Doc. Ho. 16) 1. Polychlorinated biphenyls 2. Polychlor inated biphenyls-environmental impact 3. Poly chlorinated biphenyls-health U. Polychlorinated biphenyls-Lake Michigan I. Title II. Environ mental Health Resource Center IIEQ Environmental Resource Center I l l i n o i s In stitu te for Environmental Quality 309 West Washington* Stre e t Chicago, IL, 60606 (312) 793-3870 n 774079 GENP 005433 FOREWARD ' This publication deals with "Polychlorinated Biphenyls Health Effe cts and Recommendations". The I n s t i t u t e 's Envi ronmental Health Resources Center has prepared the m aterial based on lite r a t u r e searches, in v e stig a tio n , and c r it ic a l reviews. Recornnendations fo r further research are made, both as a guide fo r research agencies, and as evidence o f the state-of-the-art with respect to Polychlorinated Biph enyls. The Environmental Health Resources Center i s a fac i l i t y of State government estab lished by the In s t it u t e for Environmental Quality. It s services are availab le to anyone interested in environmental health problems. iii 774080 GENP 005434 environmental health resource center P.O. Box 6998, Chicago, Illinois; Phone: (312} 996-7811 STAFF Bertram W. Carnow, M.D. Center Director * Rodney P. Musselman, M.P.H. Research Associate Edward J. Calabrese, Ph.D., Ed.D. Assistant Director of Center Christine Riddiough, M.S. Research Associate Badi M. Boulos, M.D., Ph.D. Associate Professor; Toxicologist Alfred J. Sorensen, M.S. Research Associate Linda Friedman, M.P.H. Research Assistant Edward A. Diersen, B.s. Research Assistant Sally J. Jansen, M.P.H. Research Associate William H. Kojola, M.S. Research Associate Sandra Hare, B.S. Research Assistant Janine Roumain, B.A. Research Assistant ADVISORY BOARD R. Stephen Berry, Ph.D, Professor of Chemistry University of Chicago Robert L. Metcalf, Ph.D. Professor of Entomology University of Illinois - Urbana Paul Meier, Ph.D. Professor of Statistics University of Chicago J.E. Quon, Ph.D. Professor of Civil Engineering Northwestern University Arthur Wblff, D.V.M. Professor of Environmental 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. Note: The Environmental Health Resource Center appreciates the efforts of Rustom R. Khouri in the development of this document. UfclNJP 005435 iv 774081 TABLE OF CONTENTS I. Summary and Recommendations..........................................1 II. Chemical Structure ................................................ 5 III. Industrial U s e s ...................................................... 6 IV. Where PCBs Are Found and Their Mode of T r a n s p o r t ................ 7 V. Routes Into the Environment............................... .. . . a VI. Rate of Loss Into the Environment................................. 9 VII. Rates of transport Within the Environment......................... 10 VIII. PCB Levels in I l l i n o i s .............................................11 A. Levels in Lake Michigan Fish S p e c i e s ....................... . 11 B. Levels in the Sediment of Lake Michigan and Some of Its Tributary S t r e a m s ........ ' .................. 13 C. Levels in the Water of Streams and Sewage Effluent Entering Lake Michigan During 1971 and 1972 ........ 1-3 IX. Health Effects of FCSst Animal S t u d i e s ............................ 21 A. Tissue Storage, Metabolism, and Excre t i o n .................. > 2 1 B. Toxic Effects of Various Isomeric Mixtures on Animals and Possible Contamination of PCB Samples by Other C o m p o u n d s ................ 22 X. Health Effects of PCBs; Human Exposure Via Food, Air, and W a t e r .......................................................... 28 A. Occupational Exposure .'............ ...................... . . 28 B. *Case History of PCB Poisoning - J a p a n ......................... 29 C. Consumption via Food and D r i n k ............................... 30 XI. PCS Levels in Tissues of Humans in the United S t a t e s . ............ 32 XII. High Risk Segments of the P o p u l a t i o n ............ 32 XIII. Appendix . 35 XIV. References.......................................................... 36 GENP 005436 v 774082 LIST OF TABLES AND FIGURES Table 1. Where FCBs were found and in what form prior to 1972. Table 2. PCBs found in edible portions of species of Lake Michigan fish (1971, 1972). Values are expressed in parts per million (ppm) on a wet weight basis. Table 3. F(2s found in Lake Michigan sediments in Illinois (1971). Values are- stre s s e d in parts per Gillian (ppb) based on a dry weight basis. Table 4. PCBs found in sediments of several streams and ravines tributary to Lake Michigan (1971). Values expressed in ppb. Table 5. PCBs found in water samples from Illinois' streams tributary to Lake Michigan (1971, 1972). Values are expressed in parts pe: trillion (ppt) Table 6. PCBs found in water samples from several Illinois sewage plants tributary to Lake Michigan (1971, 1972). Values are expressed in pptTable 7. The chromosome aberration rate in dove embryos treated with PCBs. Figure 1. Biphenyl nucleus showing 10 possible chlorine positions. Figure 2. Locations of sediment sampling stations along Lake Michigan in Illinois. Figure 3. Location of water sampling stations used in 1971 and 1972 for determination of PCB levels in Lake Michigan. Vi 774083 /rkcnn NON-TECHNICAL SUMMARY Polychlorinated biphenyls (PCBs) are a group of chemicals which contain varying percentages of chlorine arranged on a double-ring chemical structure called biphenyl. Monsanto Company is the sole U.S. producer of PCBs and calls its products by the trade name AROCLOR. Polychlorinated biphenyls have been manufactured in the U.S. since 1929 in response to the electrical industry's need for an improved insulating fluid which is more fire resistant and also more resistant to biological and physical degradation. Their usage is now limited to what are called " d o s e d systems" significantly reducing their inmediate release into the environment. 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 fenale monkeys have also been noted. In 1968, two thousand Japanese people suffered various skin and eye disorders after eating PCB-contaminated rice oil. Environmental levels of PCBs resain `quite high. They may be found in certain foods, especially fish in which PCB levels may be as mieh as a million times higher than the levels of the surrounding waters because PCBs became concentrated in fatty tissues. 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 to avoid needless environmental pollution. Suitable replacements for PCBs are being investigated. vii 774084 G EN P 005438 I. SUMMARY AND RECOMMENDATIONS Polychlorinated biphenyls .(PCBs) are, one member of a class of synthetic chlorinated organic compounds composed of two, six carbon ring structures (Phenolic rings) with 10 possible chlorine attachments. These aromatic compounds encompass a complex heterogeneous group of 210 different chlorinesubstituted isomerSr although the number observed in commercial formulations is much smaller. 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 and air. Polychlorinated biphenyls have been used and manufactured in Europe, Japan, the Soviet Union and the United States. The sole U.S. producer is the Monsanto Company which has given the trade name Aroclor to its products. Animal studies have revealed that PCBs can adversely affect numerous organ systems including the liver, kidney, adrenal gland, spleen, and skin. Other studies have shown that they may cause chromosomal aberrations in vivo in Ring Dove Embryos, but no aberrations as studied in Drosophila; Animal studies have also indicated that PCBs suppress the immune response.system. Polychlorinated biphenyls when fed chronically to rats caused hepatic adenc fibrosis and biliary epithelial hyperplasia similar to lsions caused by butter yellow (p-dimethylamino-azobenzene), a known carcinogen. Contamination of PCBs with compounds such as the chlorinated dibenzofurans (CDFs) and chlorinated naphthalenes have been suggested as the causative carcinogenic agents. This controversy is unresolved and needs further investigation. Other very recent experiments have indicated that as little as 2.5 parts per million (ppm) of a PCB (Aroclor 1242) in the diet of monkeys has caused loss of hair on the face and neck, as well as the development of acne and other skin lesions. Furthermore, the reproductive capabilities of P OE - f e d female monkeys were affected as evidenced by the development of a greater number of both resorbed fetuses and significantly undersized infants. It has also been shown that weanling rats are more susceptible to Aroclor 1254 and 1260 than adult rats as determined by acute toxicity studies. Despite the numerous research articles.indicating the toxicity of PCBs for animal species and their possible implications for human beings, the best 1 774085 GENP 005439 available knowledge of the effect of PCTs on man comes from tiie "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 similar to results reported in animal studies. Hie lesions of the skin, facial swelling, and neurological disorders were similar to results reported in animal studies. Known toxic effects of PCBs in humans include chloracne, pigmentation of tile .skin and hands, distinctive hair follicles, excessive eye discharge, and swelling of the eyelids. Even though there is considerable evidence that PCB exposure is harmful to human1life, the environmental' levels of PCBs still remain quite high. For example, two tributaries of Lake Michigan have levels of A r o d o r 1254 con sistently exceeding 100 parts per trillion (ppt) while the present EPA recomnended water quality criteria is 1 ppt. Of greater concern is tile 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 other aquatic animals accumulate F Q s to levels of the order of 104 tunes 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 10^ or more times the levels in the ambient water. Much of the problem with respect to humans and PCTl intake has to do with the fact that man usually resides at the top of the various food chains. Once PCBs get into food chains involving birds and mammals, biological magnification seems to occur with the concentration increasing by a factor of 10-100 at each * step. Additionally, PCBs are poorly metabolized and tend to accumulate in 1'-liu-rich animal tissues and organs. PCBs have been manufactured in the Uni ted States since 1929 in response the electrical industry's need for an improved dielectric insulating fluid with increasd fire resistant benefits when used in transformers and capacitors. It has been speculated that 400,000 tons of PCBs were produced between 1948 and 1973. The more highly chlorinated PCB isomers are highly resistant to microbial and physical chemical action in the environment. Despite 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 9 774086 GEN P 005440 (asphalt and concrete) , printing products (carbonless carbon paper) and paper coating. They are still utilized as filling agents on impregnants in electrical transformers and capacitors. Since 1971, Monsanto Company voluntarily restricted its sales to only "closed" systems in transformers and capacitors; this has been a significant factor in restricting the accessibi lity of PCBs to the environment. The action-by Monsanto to restrict PCB sales to closed systens 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 disposed 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, needless environmental pollution can be avoided. Unfortunately, many companies discarding their old electrical units (containing POSs) are still discharging many pounds 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 effects of polychlorinated biphenyls, the Qivironmental Health Resource Center supports the following national policy and research recommendations: NATIONAL POLICY RECOMMENDATIONS 1. Polychlorinated biphenyls should no longer be permitted 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 (EPA). 3. Equipment containing PCTs 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 tolerances for PQ3s should be made with regard to the properties of the different isomers. I 6. The food packaging industry should either cease using recycled paper which contains PG3s, or make use of an impermeable barrier on the inner surface of the packages, thus restricting the transfer of PCBs into food. 7. The Bbod and Drug Administration (FDA) tolerance level for PCBs in fish should be lowered from 5 ppn to 2 ppm. 3 774087 GENP 00544 V RESEARCH RECOMMENDATIONS 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 e n d carcinogenicity of P OE s in humans. 3. Reset- -T; to determine if the lack of a functional glucuronic enzyme pathway predisposes individuals to unusual accumulation of P OE s . 4. Determination of the relative toxicity of different isomers with respect to standard setting. 5. More research studies n the kinetics of PCBs with regard to absorption and distribution tnrough different organs including the lungs with the development of appropriate animal simulation models which would lead to extrapolative predictions for man. 774088 GENP 005442 II. CHEMICAL STRUCTURE Polychlorinated biphenyls are one member of a class of chlorinated organic compounds composed of tyo, six carbon.ring structures (phenolic rings) with 10 possible chlorine attachments. These aromatic compounds encompass a complex heterogeneous group of chemicals. Two hundred and ten different chlorine-substituted biphenyl isomers are possible but the number observed in comercial formulations is much smaller (Figure 1). The dif ferent comercial products contain mixtures of isomers of biphenyls chlorinated to different degrees to meet specific operational specifications and may vary 1,2 chemically from batch to batch. Polychlorinated biphenyls have been used and manufactured in Europe Japan the Soviet Union and the United States.3 ' The sole U.S. producer is the Monsanto Company which has given the trade name AROCLOR to its products.4 Arod o r s are distinguished by using a four digit numbering system. The first bra digits 12, specify polychlorinated biphenyl and the last two digits specify approximate weight percentage of chlorine in the mixture (e.g., Aroclor 1254).1,4 Trade name for known PCB containing products produced by foreign manur facturera i n d u d e Clophen (Germany), ffenclor (Italy), jfenechlor and Santotherm 12 (Japan), Phenoclor and Pyralene (France), and Sovol (U.S.S.R.). ' BXPHENL Figure 1; Biphenyl nucleus showing 10 possible chlorine attachments; positions 2-6 and 2*-6* may be substituted by chlorine. Two hundred and ten different chlorine - substituted biphenyl isomers are passible. 5 774089 GENP 005443 Polychlorinated biphenyls were first identified in environmental samples 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 residue. III. INDUSTRIAL USES Most individual polychlorinated biphenyls are solids at zoom temperature, but the mixture may range in consistency from oils to viscous liquids or* 2 45 resins. ' ' Table 1 denotes how each form can be used. Polychlorinated biphenyls have very broad industrial uses because of the following properties: non-flammability, high chemical stability, low vapor pressure, inert decom- 6 position products, high dielectric strength and low dissipation factor. TABLE 1 WHERE PCBs WERE FOUND AND IN WHAT FORM PRIOR TO 1972 RESIN LIQUID SOLIDS Protective coating Dielectrics Plasticizers and extenders Hydraulic fluids Sealers in: waterproofing compounds and putty Asphaltic materials 9^1-tring inks Thermostats Cutting ails Extreme pressure lubricants Impregnate carbon resistors Sealers Impregnating agents for electrical apparatus -yr' h*;tic adhesives | Grinding fluids Heat transfer media Since 1970, when the first substantial data concerning PCBs in the environment were recorded, Mousanto Conssany's production has been reduced? from 1960-1970 Monsanto's peak production was 42,527 short tons of PCBs. By A7 the end of 1972, it was down to 20,236 short tons. * These restrictions which cut production in half resulted in a redqction in uses o f .PCBs in applications involving open systems where their loss to the environnent had been less controllable. Major applications affected by the Conpany's program of terminating sales of PCBs to open application were in cartoole3s paper. GEN P 005444 6 774090 fire resistant hydraulic fluids heat transfer fluids and plasticizers, itonsants made the decision to continue supplying PCBs only to the electrical power distribution industry where they were marketed as dielectric fluids in *^ a "closed" or sealed systems such as transformers and capacitors. At one time fluorocarbons were used in capacitors but it was found that they have low dielectric constants and also have decomposition products that are toxic. 'In 1969 , 96% of United States transformers used mineral oil. This lasted until it was found that PCBs prevented fire and explosion hazards. The major value of PCB liquids with 4 or more substituted chlorines per molecule is the non-flammability of the PCB itself as well as its de composition products. They can be used as fluids at temperatures up to 700 F without the danger of explosions or fire. .In many areas electrical codes required the use of askarels (PCB capacitor liquids, commonly referred to as askarels, are mixtures of chlorinated biphenyls and chlorinated benzenes). The use of askarels is more expensive (1.3 X the cost of mineral oil); however, fire underwriters will not accept use of mineral o i l . When fluorocarbons were tested in the U.S., their volatility and high cost quickly eliminated them from consideration for continued use. Polychlorinated biphenyls are also used as lubricants in hydraulic fluids. Because possible replacements have been found, the degree to which PCBs are now being used is unknown. Tricresyl phosphate, for example, is chemically stable as an additive in lubricants and although toxic, it is 6 more biodegradable than the PCBs. With rare exceptions, after compiling the properties needed in order to make capacitors, transformers, hydraulics, gas turbines and vacuum pumps work efficiently and safely, PCBs are by far the best chemical fluid available. IV. WHERE PCBs ARE FOUND AND THEIR MODE OF TRANSPORT Prior to 197.0, 60% of sales were for closed systems (electrical and heat transfer uses); 25% for plasticizer applications; 10% for hydraulic fluids and lubricants; less than 5% for miscellaneous applications such as surface coating, adhesives, printing inks and pesticide extenders. Exports by Monsanto had averaged 13% of domestic sales for-1963-1970. Imports are GENP 005445 7 774091 thought to be small, comprised primarily of plasticizers in resins and adhesives, traisfoxmer 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 summer of 1971, Monsanto Company stopped producing Aroclor 1260. They also reduced production of the higher numbered PCBs that are considered more persistent in the environment (i.e., 5, 6, *7 chlorines/biphenyl) . The more highly chlorinated isomeric forms of Aroclors (1254 and up) comprised 30% of sales prior to 1971; this fell to 22% by 1972, 4 (See APPENDIX, P.35). V. ROUTES INTO THE ENVIRONMENT Data on the amount of PCTs lost into the environment are limited. Possible routes that 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. Vaporization or leaching from PCB containing formulations. 5. Disposal of waste PCBs or PCB containing fluids. Any of these possible routes of PCB movements into the environment could eventually end up in the food chain. Examples are the Japanese rice oil contamination resulting from heat exchanger leaks^and the Escambia Bay area of Florida where leakage of hydraulic fluid from an air compressor contaminated chicken feed on the Holly Fann?. ^ The input into soil by use of Aroclors as pesticide extenders is believed to have been small. Based on purchase reports, it has been a 774092 G EN P 005446 estimated that less 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 Aroclor isomer is being discharged. This can be determined easily from sales and chemical records. Erlor to 1972, most PCBs released into the atanosphere were Aroclor 1248 and 1260, vaporized from burning dumps. Discharge into waters are primarily isomeric forms of Aroclors that are used in hydraulic fluids and lubricants, including mixtures of Aroclor 1242. and 1260. The residual in dumps will have 4 a large fraction of the Aroclor 1242. VI. RATE OF loss INTO THE ENVIRONMENT The following figures represent orders of magnitude estimates of rates of loss. These estimates are yearly figures, most closely resembling losses incurred during 1970, which was the peak year of PCB production. Transformers 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 is equal to 1/2`the rate of production. A similar figure is assumed for the scrapping of heat exchangers. It is estimated that the rate of evaporation of plasticizers amounts to 10 to 20% of sales. The rate of disposal of plasticizers into dumps is assumed to equal the residual 80 to 90% of sales since numerous plastic objects have short useful lives. Hydraulic fluids and lubricants are rarely re-used; thus, it is assured that a major fraction of these fluids used for this purpose, together with those going into miscellaneous applications, were scrapped at rates about equal 4 to those of corresponding sales. On the basis of these gross approximations, it seems that only about * 3 20% of the 1970 sales in North America, about 7 X 10 tons, represented a net increase in the amount of PCBs in service (in transformers, heat exchangers and capacitors) . The remainder is' considered to have been 3 discharged into the environment; 1-2 X 10 tons by evaporation of plas- 9 774093 GENP 005447 3 ticizers* 4-5 X 10 tons by leaks ana riisposal of hydraulic fluid and lubricants plus small quantities by disposal of heat transfer and trans former 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 biogeo_chemical cycles. For example, vaporized PCBs may be absorbed on parti culates, transported with the prevailing wind and deposited on land o r . 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^ 2 Bils wnole process is further complicated by tne assimilation, transport and 13 degradation of PCBs by the biota. A major part of the PCBs discarded ~r dumps is it close! containers or * plastic resins. This rate of loss will o: low until t*.a confining material is degraded and :ne PCBs subsequently re Leasei usually diffusing slowly thru 4 surrounding soil. Polychlorinated biphenyls from discarded non-carbon paper may rapidly be diffused into the environment. However, oeca.isc much of this paper is recycled, the actual rate r: diffusion into the environment will cftc.. oe retarded. PCB-impregnated paper is often used in the packaging of various common food products. This is now recognized as another avenue of too contamination. ' Theoretically, the races of transport may be .'.icuLated from knowledge of the physico-cnemical properties of PCBs and pertinent data on atmospheric conditions, particulate transport, hydraulic dispersion, bottom sediment transport and niclogical degradation raves, resently, data are too incomplete ana the interactions are too. complex to .ttempt formulation of anything more than the crudest of transport models.^ avoid needless environmental pollution w i h PCBs and to stop the GEN P 005448 10 774094 discarding of them in dumps rivers and soil the Monsanto Company built an incinerator at their plant in St. Iouis, Missouri. It runs on 30 million BTU 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; Batton Bouge, Louisiana; and Houston, Texas.7 These incinerators, if timed and heated properly, can burn PCBs and not let any toxic pollutants escape into the environment. Federal EPA 16 17 proposed Effluent Standards for PCBs exist for both fresh and salt water. ' Recommended procedures for disposal of PCB-containing wastes (industrial facilities) are outlined by the Federal EPA in th Federal Register. The recommended options for disposal of PCB-containing wastes in order of priority 18 are incineration and controlled land disposal. VIII. PCB LEVELS IN ILLINOIS A. Levels in lake 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 analyzed over- the 2 year period, including samples of yellow perch, chubs, carp, coho salmon, alewife and brown trout. Difficulties in obtaining all species in 1972 limited collections to the yellow perch and chubs. Fish were collected from conmerciai fishermen and the Illinois Conservation Department in the Chicago and Waukegan regions of Lake Michigan. Table 2 shows that the edible portions of species of fish with the highest fat content (chubs and alewives) had the highest level of Aroclor 1 2 5 4 . ^ Lake Michigan salmon containing PCB levels (regarded by the FDA as a food additive) in excess of ehe prescribed tolerance level of 5 ppm were seized by 20 the FDA in May 1975. The actual amount seized and PCB levels in tte fish were not revealed in the reference, however, 1974 data from tne Michigan De partment of Natural Resources give values for PCB levels in lake trout and coho salmon ranging from 10 to nearly 25 ppm wiuch is in excess of the present FDA maximisa allowable concentration of 5 ppm for fish and shellfish. 11 774095 GENP 005449 TABLE 2 POLYCHLORINATED BIPHENYLS FOUND IN EDIBIE PORTIONS OF SPECIES OF LAKE MICHIGAN FISH (1971, 1972) 19 Values (ppm on a wet weight basis) for approximately 10 fish were used for each measurement. SPECIES SIZE RANGE IN INCHES SAMPLE LOCATION AROCLOR (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 1.5 1.3 3.0 ^ .A. - Not analyzed for ^N.D. - Not detected 774096 OSfrSOO dNHO In 1974, the Wisconsin Department of Natural Resources found levels ex ceeding 5 ppm in Lake Michigan Chinook and coho salmon, brown trout, tiger trout, lake trout, and carp. The levels were as high as 43.8 ppm in lake trout and 51.6 ppm in carp. Ihe most contaminated fish in the U.S. to date have been found in the upper reaches of the Hudson River, near and below two General Electric plants, ttiese plants manufactures electrical capacitors in which FCBs are used as insulating fluid, samples (1974) of yellow perch and shinner minnows showed residues of 17 and 78 ppm, 21 respectively; one rock bass sample contained 350 ppm. B. Levels in the Sediment of lake Michigan .and Some Tributary Streams The results indicated that levels of Aroclor'1254 and 1242 found in Lake Michigan sediments in 1971 ranged between 2.48 and 46.92 ppb and ND (not detectable) to 106.07 ppb, respectively (Thble 3 and Fig. 2). In tributary sediments, the levels for Aroclor 1242 ranged from ND to 553.00 ppb with the wiav-iTmim values found at an unnamed channel in Waukegan (Table 4 and Fig. 2). Aroclor 1254 ranged from 1.54 to 232.0 ppb with the maximum 19 level found at Pettibone Creek in North Oiicago (Table 4). C. Levels in the Water of Streams and Sewage Effluent Entering Lake Michigan During 1971 and 1972 The results indicated the Aroclor 1242 levels were markedly reduced in 1972 compared to 1971 in both the stream and sewage discharge water. Aroclor 1254 levels also decreased from 1971 to 1972 in sewage discharge, but stream discharge levels increased slightly (Table 5 and 6). Also, in most cases, sewage treatment plant effluents were shown to discharge higher concentrations of PCBs than the tributary streams in 1971, but in 1972, PCB levels were higher in the tributary streams (Figure 3) . Highest concentrations of PCBs in sediments were obtained in tributary streams and ravines, indicating possible contaminations by residential spraying and industrial discharge. 13 774097 GENP 005451 Highest levels were obtained in industrial areas in North Chicago and Waukegan. In sediments, PCB levell were generally higher than pesticide (DDT, heptachlor epoxide, hieldrin, metS-a: xy^rdcr, phtsiates and lindane) 1ieveils.19 It :s a '.so important to point ' trie extreme varrablility it: PCB levels (Table 5). In 1?71, for example water from the Waukegan River showed over 1,800 ppt PCB on one day, but less than a month before, samples revealed no fetectable levels.*'* _4 774098 GENP 005452 TABLE 3 PCBS FOUND IN LAKE MICHIGAN SEDIMENTS IN ILLINOIS (1971) Values are expressed in parts per billion (ppb) based on a dry weight basis SAMPIE LOCATION 1 to 3 Miles Offshore NSSD Park Ave. STP (Highland Park) NSSD Lake Forest STP (Lake Forest) NSSD Lake Bluff STP (Lake Bluff) NSSD North Chicago :5TP (North Chicago) NSSD Waukegan STP (Waukegan) Lake Bed Station 60 Lake Bed Station 55 Lake Bed Station 52 Lake Bed Station 49 Lake Bed Station 46 Lake Bed Station 43 Lake Bed Station 40 Lake Bed Station 37 . Lake Bed Station 34 Lake Bed Station 31 Lake Bed Station 28 Lake Bed Station 24 Lake Bed Station 21 Lake Bed Station 18 Lake Bed Station 15 Lake Bed Station 12 Lake Bed Station 8 Lake Bed Station 5 Lake Bed Station 4 *NSSD - North Shore Sanitary District A ROCLO R 1242 1254 11.11 v 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 2.48 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 774099 TABLE 4 PCBs FOUND IN SEDIMENTS OF SEVERAL STREAMS AND RAVINES TRIBUTARY TO LAKE MICHIGAN (1971) 19 Values expressed in ppb on a dry weight basis SAMPLE LOCATION 10 to 50 Yards Upstream From Lake Bull Creek (Zion) ` Dead River (Zion) Unnamed channel (Waukegan) Waukegan River (Waukegan) Pettibone Creek (North Chicago) Stone Gate Lane Ravine (Lake Forest) Berry Hall School Ravine (Lake Forest) Cary Avenue Ravine (Highland Park) Ravine Drive Ravine (Highland Park) Park Ave Ravine (Highland Park) Barat Ravine (Lake Forest) Ravine Park Ravine (Lake Bluff) Kellogg Creek (Zion) A R 0 C-L O 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) GENP 005454 16 774100 GENP 005455 Figure 2: Locations of Sediment sampling stations along Lake Michigan in Illinois.19 17 774101 TABLE 5 PCBs FOUND IN HATER SAMPLES FROM ILLINOIS STREAMS'TRIBUTARY TO LAKE MICHIGAN. (1971-72) Values are expressed In parts per trillion (ppt). I9 SAMPLE LOCATION Waukegan River Waukegan River Pettibone Creek Pettibone Creek Waukegan River Waukegan River Waukegan River Waukegan River Pettibone Creek Pettibone Creek Pettibone Creek DATE COILECTED ASOCLOR 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 87.0 140.0 (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) G EN P 005456 18 774102 TABLE 6 PCBs FOUND IN HATER SAMPLES FROM. SEVERAL ILLINOIS SEWAGE PLANTS TRIBUTARY TO LAKE MICHIGAN (1971-72) Values are expressed in ppt. 9 SAMPLE LOCATION NSSD Waukegan STP NSSD Waukegan STP NSSD Waukegan STP NSSD North Chicago STP NSSD North Chicago STP NSSD North Chicago STP NSSD Waukegan STP NSSD Waukegan STP NSSD Waukegan STP NSSD Waukegan STP NSSD Waukegan 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 8/04/71 7/22/71 7/23/71 8/04/71 8/25/71 .601.0 2105.0 v 4020.0 1070.0 268.0 534.0 (1433.0) 139.0 472.0 568.0 250.0 153.0 217.0 (299.6) 5/16/72 5/19/72 5/23/72 5/22/72 6/17/72 ND ND ND ND 17.0 139.0 105.0 97.0 118.0 111.0 5/22/72 5/23/72 5/16/72 5/19/72 6/17/72 ND ND ND ND 21.0 104.0 100.0 132.0 161.0 178.0 ( 3.8) (124.0) GENP 005457 19 774103 I Reproduced\ from I bast available copy igure 3: Location of water samplino stations, used in ^ 7 1 and 1972 for determination of PCB levels in Lake Michigan. 20 774104 GENP 005458 IX. HEALTH EFFECTS OF FCBs: ANIMAL STUDIES Tissue Storage, Metabolism and Excretion Experimental exposure of rats to dietary FCBs has revealed that the isomeric forms are retained to various degree (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 concentratiop-of other tissues with the second highest PCS concentration (liver, usually) and more than 100 times the levels in other tissues including the blood, heart, kidney and brain.22'2 2 4 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. 22 The turnover rate of FCBs in tissue will vary with the degree of chlorination. The higher isomers are usually retained the longest in mammals 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 r 25 The urinary excretion of biphenyl and 4-chlorobiphenyl has been studied in rabbits. Biphenylglucosiduronic acid and 4-hydroxybiphenyl were isolated from the urine. The rabbits fed the 4-chlorobiphenyl excreted 4 - (p-chlorobiphenyl)-phenol and 4-chlorobiphenyl glucosiduronide. Twice as much 4-chlorobiphenyl as biphenyl was excreted as . the glucasiduronic acid derivative. It was suggested that other low 26 chlorinated biphenyls are excreted in a similar manner. O f dogs injected with 2,4,4'-trichloro-2'-hydroxydiphenyl ether, nearly 100% of the material is recovered as 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. 25 It is excreted either as free compound or as a glucuronide. Other evidence suggests that some chlorinated biphenyls are hydroxylated 21 774105 GENP 005459 by species such as the rat and pigeon. No evidence of reductive ^ dechlorination was observed in either the trout, rat, or pigeon. Fish and other aquatic animals accumulate .PCBs to levels of the order 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 IO7 or more t i the levels in_the ambient water. B * Toxic Effects of Various Isomeric Mixtures and Possible Contamination of PCS 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. ^ A study on White Leghorn hens using Aroclors 1221, 1232, 1242, 1248, 1254, 1268, 5442, and BP-6 (at the 20 ppm level; additionally,1242, 1248 and 1254 were 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 P O s 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 enbryonic development. 28 Another study showed that weanling rats were .tore susceptible to Aroclor 1254 and 1260 25 than adult rats as determined by acute toxicity studies. An experiment comparing Aroclors 1254, 1242, and 1221 (respectively, 54, 42, and 21% chlorine) was conducted to determine the effect of varying chlorine content on rabbits (oral administration, 300 mg of the PCBs Aroclor 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 Aroclor 1254 causes the most toxicity of these mixtures. Aroclor 1242 22 774106 GENP 005460 has a lesser though significant effect on the liver. No signincant lessions 29 were found in the 1221-treated rabbits. Hiis 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 dibenzofura-is (CDFs) and pentachloro napthalenes have been identified by contained gas chroma tography/mass spectrometry in a polychlori nated biphenyl of Japanese manufacture (KC-400). The question of whether chlorinated dibenzofuran in KC-400 may have contributed to the reported "Yusho" incident (see section on Case History of P OE Poisoning-- Japan) has 30 been raised. Controversy exists on two important factors in relation to the CD&: 1) whether contamination occurrred during manufacture of the PCBs or during the use of the PCS mixture as a heat exdhange fluid in the rice oil plant. High temperatures may have led bo its formation through the hydroxi- lation and oxygen ring bridging of chlorinated biphenyl molecules, and 2) there is as yet no direct experimental evidence linking dibenzofuran derivatives with the long-term chronic effects similar to those which have been demonstrated wth 21,25,31 PCBs. Chlorinated dibenzofurans have been detected in several PG3 preparations (Clophen A60, Phenoclor DP-6, Aroclors 124a, 1254, 1260) and have been shown to be acutely embryotoxic.23, Other organochlorine compounds which may be present in food webs include the chlorinated dibenzodioxins in addition to the chlorinated dibenzofurans which are toxic to embryos in amounts less than 1 ug. 32,33 1. Effects on the liver and spleen The most significant effect of PQ3s to the liver for birds and a variety of mammals (e.g., rats, rabbits, dogs) included weight increase, ratty 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 some drug o5 metabolizing enzymes such as nitroreductase and aromatic hydroxylase.*" * 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 34 of pentobarbital metabolism caused by liver enzyme induction. GENP 005461 23 774107 In rats exposed to Aroclor 1242, vitamin A storage in the liverwas 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 | j 2. Carcinogenesis and Tumorigenesis Polychlorinated biphenyls when fed chronically to rats caused hepatic adenofibro sis* and biliary epithelial hyperplasia** oifrdlar* to-lesions caused by butter yellow (p-dimethylamino-azobenzene) , a known carcinogen. Contamination of PCBs with compounds such as polychlorinated dibenzofurans and chlorinated naphthalenes have been suggested to be causative carcinogenic agents. This controversy is unresolved and needs further investigation. Studies indicated that when various Kanechlor mixtures were fed to rats liver weight increased and certain his topathological 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 37 that all kinds of Kaifi chlors have . tumorigenic action in the rat liver. Other studies had shown hepatocellular carcinomas were induced in the liver, of i mice by Kanechlor - 500 which contains a high proportion of chloride groups1, but not by Kanechlor - 400 or-300.^ This study also showed marked cholangio- fibrosis (fibrous formations in lobules of the liver) in the rat liver. ! Further investigations are required of the difference in the tumorigenic actions 37 of the PCBs since this was not observed in mice treated with PCBs. Evidence exists that some hepatocellular carcinomas may originate from, nodular hyperplasias. The histopatho logical patterns of nodular hyperplasias GENP 005462 ^denofibrosis: glandular formation surrounded by proliferating fibrous *.i sue; benign, yet difficult to distinguish from cancerous tissue. b.'Hary epithelial hyperplasia: an increase in the number of cells in the 1 :r whereby the bulk of the liver is increased. 24 774108 seen in that s^udy were similar to those induced by known chemical carcinogens , ^such as 3'-methyl-4-(dimethylamino) -azobenzene/ N-2-fluororenylacetamide, DL-ethronine, m-toluenediamine and die thylni trosamine. Findings suggested that hepatocellular carcinomas can be induced by administration of Kanechlor -500,-400, -300 for a longer period of time. Increased liver weight, adenofibrosis 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 months in contrast to 1 of 173 control rats. 39 3. Effects bn 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 the stressor action of Aroclor 1221. 4. Effects on the reproductive system (not including- primates) Rats were exposed to Aroclors 1242, 1254, and 1260 in the diet at levels of 1, 10, and 100 ppm. It was found that Aroclor 1242 did not affect the first generation, but mating indices 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 ppmJ' 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.1 Biochemical studies have indicated that PCBs are capable of inducing the microsomal hydroxylating activity in the liver so as to affect the GENP 005463 25 774109 hydroxylation of both progesterone and testosterone, 41 Such biochemical 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. 42 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 PCBs may cause aberrations in vivo in Ring Dove Embryos, but no aberrations as studied in 44 Drosophila. t 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 GENP OUi404 6. Synergistic and Additive Effects In a study where male rats were orally dosed with carbon tetrachloride (CCl^) 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 CC14 damaged livers are not able to metabolize this compound as rapidly as rats with normal livers under the conditions of the experiment. The residues in the blood, testes, liver, kid- 26 774110 ney and heart of C d 4 treated rats was higher .^^PCBs given to laying pheasant hens adversely affected egg production, hatchability, and viability of the embryo about the time of hatching but did not affect fertility or eggshell thickness. However, when pheasants were fed 50 mg PCBs along with dielarin^0 45 or DDE, only additive and not synergistic interactions were found. A study was done to determine the effects of PCBs on neoplastic changes induced by isomers of benzenehexachloride (BHC) in the livers of mice fed a diet containing BHC with or without PCBs for 24 weeks. Researchers observed that PCBs promoted the induction of hepatic neoplasms in mice by isomers of BHC.46 7. Immunosuppression A reduction in lymphoid tissue and the presence of amyloid or amyloidlike naterial in the liver of PGB exposed chicks has been reported. (Amyloid formation has been found to be stimulated by certain immunesuppressive drugs). Also, lymphopenia has been reported in rabbits,46 while in guinea pigs, 66 PCBs 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, 46 PCB exposed ducks to viral hepatitis 66 and the onset of liver cancer in PCB exposed rats. 20 (see section on Carcinogenicity) 8. Primate studies Recent studies have indicated that very low levels of PCB exposure are toxic to primates. 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. One monkey died from PCB intoxication 2 months after going off the experimental diet.51a 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 skin was of 27 774111 GENP 005465 "a sandpaper-like texture". Both groups developed acne, .although the 2.5 ppm groups developed the lesions later. In 6 months, both groups reached a steady state concentration of PCBs in adipose tissue. Test monkeys were then mated with monkeys which had not been fed PCBs. Six of the 6 female monkeys which had eaten food containing 5 ppm of PCBs became pregnant, in contrast to all 12 females in the control group. In the test groups 4 of the 6 pregnant females aborted or resorbed the fetus, 1 gave birth to a stillborn and 1 to a very undersized infant.51*3 In the 2.5 ppm group, all 8 females in the test group conceived and of these, 3 resorbed and 5 gave birth to undersized infantsJ*1*3 X- HEAL3H S T E M S OF PCBs: HUMAN EXPOSURE VIA FOOD, A IR AND HATER A. Occupational Exposure V* Khown toxic effects of PCBs in humans include an acnelike skin eruption called chloracne, pigmentation of the skin and nails, distinctive hair *** follicles, excessive eye discharge, and swelling of eyelids. Several "cases -of human bocicity to PCBs in an industrial-Setting have been reported. 52,53 Exposed workers .developed m a n dermal cysts and comedos (blackheads) These were usually found on t-hp* face and ears, although such sores have been reported on numerous other parts of the ' body. Derma l sores generally persisted for several months after removal from the source and in some instances, lasted four years.54 systemic effects have also occurred in several cases. These effects include nausea, lassitude, anorexia, hv,emat*.uria. i'54 - digestive disturbances, impotence and A study done on PCB concentration in the plasma of refuse workers found that 32 out of 37 (81%) of the refuse workers had detectable levels as compared to only 11% (6 out of 54) of 'the controls. Median PCB concentrations for those with detectable amounts were similar in the two groups; refuse workers - 2.6 ppb, controls - 3.7 ppb. The higher frequency of measurable plasma PCB levels in refuse workers (i.e ., 81% of refuse workers with detectable levels as opposed to only 11% of controls with detectable levels) i thought to reflect their increased PCB exposure from incinerated materials.55 28 774112 GENP 005466 The American Conference of Governmental Industrial Hygienists has set a TLV of 1 mg/m for occupational exposure to vapors of Aroclor 1242, with lower values for higher Aroclors. Based on an 8"hour exposure, this would result in the inhalation of approsnately 5 mg/day. The current , Occupational Health and Safety Administration, Department of Labor standards 33 for dilorinated biphenyls are ! mg/m for 42% chlorine mixtures and;.5 mg/m for 544 chlorine mixtures, based cn. the TLVs*.. ,resntly, it is not. * 1,2 Known how much of the .inhaled..PCSs humans absorb...through -thevlungs. . . . . B. Case History of FCB Poisoning - Japan The most well known case of FCB contamination has occurred in Japan, with documented toxic affects in over 2,000 Japanese exposed to rice oil contamination. Kaneuri Rice Oil was polluted with Kanechlor 400, which is equivalent to Aroclor 1248. This contamination incident, which was finally traced to a rice 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 cars, but also on most other parts of t-tio body, in severely intox icated individuals, nausea, lassitude, anorexia, impotence and hematuria were observed. It is apparent that the severity of symptoms are directly related to the amount of FCBs ingested.56 It is known that the concentration of Kanechlor 400. in the rice oil was 2,000-3,000 ppm and the.average quantity of rice oil consumed , by patients in a first epidemiological study (325 cases) was 300 d . 57 1 over a period of approximately 8-9 months. Consequently, the average dose of PCB ingested by affected individuals was approximately 2 g. 56 The smallest dose ingested by a patient was estimated to be 0.5g. The children o f 13 women (9 of whom consulted between 0.3^2.6 liters of rice oil during pregnancy) were studied for possible teratogenic effects. Eleven children were b o m alive while 2 were stillborn. 56,57 The infants had a charcteristic grayish, dark brown skin pigmentation; 5 had dark nails and gingivae (the gums; the tissues-.which surround' the necks of the teeth and cover the alveolar processes'-of the maxilla and mandible) and 9 had increased eye discharge, A detailed study of GEN P 005467 29 774113 4 infants revealed abnormalities which included enlarged frontal sagittal suture. Faces were edematous, and there was an abnormal protrusion of 58,59 .L eyeballs. As a result of such symptoms/ it has been generally concluded that placental transfer of PCTs 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 significantly less than a control group, while the girls of Yusho did *' 57 not differ significantly from the control group. C. Consumption Via Food and Drink Based on market basket samples of PCB levels (in food, an adult is estimated to ingest approximately 5-10 yg PCB/day. This figure v* was based, in part, on an assumed level of 0.1 ppm in 3% of the food. Such a calculation may lead to an inaccurate representation of the total PCB intake of various consumer groups. It is known that human fish consunption and PCB levels in fish vary considerably. ^ Although the FDA tolerance for PCB residues in fish is 5 ppa, ^ it is not uncommon to find PCB levels between 10-20 ppm in fish found in the Great Lakes, 60 especially Lake Michigan. Thus, individuals who habitually eat large quantities of. fish, especially from such areas as the Great Lakes, will have much higher intakes than the general population. For example, an individual who eats 50 g of fish per day (1.8 oz./day) containing 2 ppm of PGJs will ingest 100 yg/day of PCBs. For a person following the reconmended "weight watcher's diet", the levels of PCBs in the diet may be even significantly higher. The "weight watcher diet" suggests 5 fish meals/week, which is approximately 98 g (3.5 oz. J of fish consumed 61 per day. Assuming a contamination .of 2 pm, the "faithful weight watcher" would consume about 200 yg/day of PCB just from fish alone. In addition to high levels of PCBs in fish, considerable concentrations may also be found in human milk. For example, samples of human milk from two cities in California contained average POJ levels of 60 ppb, while average levels in human milk in Sweden and Germany were 16 ppb and 100 ppb, respectively. Based oh a daily milk intake of 150 ml/Kg, breast fed infants in California would ingest about 9 yg/Xg/day of PCB (at least X more than a reconmended reasonable dose). Sporadic instances of 89K00 rlNiTn 30 774114 contamination of other foods such as milk and poultry may also lead to higher . ,, 1*62 intakes for short periods. A report of measurement of ambient PCS a toospheric levels ranged from 1-50 ng/m2. This would result in the inhalation of less than 1 yg/day by an adult. ^ The intake from drinking PQ-contaminated water/ assuming 2010 ppt as the concentration/ would result in about 2-5 yg/day by an - adult. Lake Michigan levels are usually less than 10 ppt. A range of 1-3 yg/Kg/day (70-210 yg/day for an adult) has been suggested as a "reasonable" level for an Acceptable Daily Intake.^ One yg/Kg/day has been reported as being 100 times less than the lowest "no-effect 33 level" reported in animal studies. The Federal Drug Administration established P OE tolerance levels in a number of food products as follows:2^-'2 Food Concentration (PPm) Milk * Dairy Products * 2.5 2.5* ! Poultry * 5.0 Fish and Shellfish ** 5.0 Eggs 0.5 Infant & Junior Food 0.2 Complete and Finished Animal Feed 0.2 Animal Feed Components 2.0 5 Paper food-packaging Material * on fat basis 10.0 ! ** on edible oortion _! However/ toxicity data obtained subsequently showing reproductive abnormalities with concentrations of P Q s in primates ranging from 2.5 to 5.0 ppm and the recent demonstration of adenofibrosis and other toxic effects in rats indicate a need for revisions of the present FDA tolerance limitations of p c t s in foods. The FDA is expected to enforce its guidelines more -forcefully in the -future based on a recent legai decision that allows the FDA to define pesticide residues in foods as an indirect food additive.2^ GENP 005469 31 774115 Studies have also shown that migration of PCBs from packaging materials does occur. ^ absence 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 anount 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 suggested that materials of low gas penneability could be effective barriers to PC3 64 migration. XI. FCB 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 vwere- obtained from 18 states, one of which was Illinois. The other 17 states include eastern, western and southern states, thus indicating that PCBs are widespread. It was reported that 165 of 637 (25.9%) samples of human adipose tissue contained -2 ppm. Thirty-three of the samples (5.2%) contained greater than 2 ppm; 125 (19.6%) contained between a trace and 1.0 ppm; the remaining 314 (49.3%) were negative at the level of ppm identification. 65 XII. HIGH RISK SEGMENTS OF THE POPULATION Embryos, fetuses and neonates ( 2 to 3 months old ) eften lack the liver microsomal enzyme systems that oxidize 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 immaturity" in the unborn and the very young may predispose them to the toxic effects of certain substances since they may be unable to detoxify and 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 because older children and adults have fully functioning enzyme detoxi- 66,67 ication systems while the neonate lacks such development. GENP 005470 32 774116 One such microsomal enzyme system includes the glucuronidation pathway which functions in the detoxification and excretion of a variety of chemicals 66 . . ... . including alcohols and phenols. Inefficient giucuroniaative mechanisms in infants have broad significance since the absence of such mechanisms prevents the prompt elimination of toxic substances from the body. Since some young 7 have been shown to consume more PCEs per unit of body weight tten adults (since PCBs have appreciable concentrations 62 , in milk), the lack of appropriate detoxification enzyme systems compounds the PCB problem for the very young. A tragic example of toxicity arising from the inability to form glucuronides has been reported. - The drug chloramphenicol, which is known to be metabolized in humans by the action of the glucuronic pathway, caused the death of more than 30 premature babies who had been treated 8 with the antibiotic for infectious diseases. Theoretically, the premature babies were not able to conjugate the drug with glucuronic acid and thus the drug could only be slowly excreted and 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 secrete milk which inhibits the.activity of glucuronyl transferase (and thus the glucuronidation 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. This condition develops because glucuronide formation, whicn assists in the elimination of bilirubin (breakdown product of hemoglobin), is partially inhibited. Cow's milk does not contain sufficient amounts of this steroid to affect 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 the antibiotic novobiocin has*also been associated with unconjugated hyperbilirubinemia in infants.^ Novobiocin is a noncompetitive inhibitor of glucuronyl transferase activitv ir. v i t ro.^ Thus, children receiving concomitant exposure of novobiocin and PCBs would be expected to have their ability to detoxify and excrete PCBs impaired. GENP 005471 33 774117 Af>.'r t he n e o n a ta l p e r io d , a b ro a d ra n g e o f c o n d itio n :; i - a s s o c iatci-i with the improi^:r or inccxnpletL- cl'jv*-lopment o f the g lu cu ro n ia e corouqatLon .yijtera. The usual physiologica-1 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 PCSs and other compounds may enhance the toxic effects of PCBs. For example, rats and monkeys given B-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, 51 a succumbed rapidly as compared to the control group. Of possible significance is the fact that SKF525A inhibits the proper functioning 68 of the glucuronidation pathway. Individuals with liver infections may also be at high risk with respect to PCBs. For example, depression of glucuronide synthesis 68 has been observed in humans with infectious hepatitis. 34 774118 GENP 005472 XIII. 1. APPENDIX AROCLOR PRODUCTS MANUFACTURED IN THE UNITED STATES CURRENT 1221 1016 1242 1254 DISCONTINUED 1232 1248 1260 1262 1268 PERCENT CHLORINE 21 32 41* 42 48 54 60 62 i 68 / Aroclor products are identified by a four digit numbering code in which the first two digits, 12, indicate the parent molecule is biphenyl and the last two digits specify the weight'percent of chlorine. The exception is Monsanto's newest product, Aroclor 1016 (41% chlorine), which retained the 1016 designation by which it was known during development. UTHirv / 35 774119 XIV. REFERENCES 1. Selikoff, I. J. (ed.): "Polychlorinated Biphenyl-- Environmental Impact: A Review of the Panel on Hazardous Trace Substances." Environ. Research 5:249, 1972. 2. Lloyd, J. W., Moore, R. M., Woolf, B. S., and Stein, H. P .: "Polychlorinated Biphenyls." J.O.M. IS:109, 1976. 3. Cook, J. W.: "Some Qiemical Aspects of Polychlorinated Biphenyls (PCBs)." Environ. Hlth. Persp. 1:3, 1972. 4. Nisbet, I. C. T. ,'and Sarofim, A. F . : "Rates and Routes of Transport of PCTs in the Environment." Environ. Hlth. Persp. 1:21, 1972- 5. Reynolds, L. M.: "Polychlorobiphenyls (FQs) and Their Interference With Pesticide Residue Analysis." Bull. Environ. Contamin. and Toxicol. 4(3) :128, 1969. '6. Broadhurst, M. G-: "Use and Replaceability of Polychlorinated Biphenyls." Environ. Hlth. Persp. 1:81, 1972. 7. Papageorge, W. B.: Monsanto Industrial Chemicals Co., 800 North Lindbergh Blvd., St. Louis, Missouri. November, 1974. Personal Communication. 8. Monsanto Conpany: "Polychlorinated Biphenyls: A Risk/Benefit Dilemma." St. Louis, Mo., January, 1976. 9. Interdepartmental Task Force on PCBs (Depts. of Agriculture, HEW,* EPA, and other participating agencies): Polychlorinated Biphenyls and the Environment. NTIS No. C0M-72-10419. Washington, D.C., May, 1972. E N p 005474 10. Risebrough, R. W., Rieche, P., Peakall, D. B., Herman, S. G., and Kirven, M. N . : "Polychlorinated Biphenyls in the Global Ecosystem." Nature 220:1098, 1968. 11. Duke, T. W., Lowe, J. J., and Wilson, A. J., Jr.: "A Polychlorinated Biphenyl (Aroclor 1254) in the Water, Sediment, and Biota of Escambia Bay, Florida." Bull. Environ. Contamin. and Taxicol. 5(2):171, 1970. 12. veith, G. D., and Lee, F. G.: "ChiorobiphenyIs (PCBs) in the Milwaukee River." Water Research 5:1107, 1971. 13. Risebrough, R. W., and deLappe, B . : "Accunulation of Polychlorinated Biphenyls in Ecosystems." Environ. Hlth. Persp. 1:39, 1972. 14. Trout,- P. E .j "PCS and the Paper Industry-- A Progress Report." Environ. Hlth. Persp. 1:63, 1972. !j . Subpart B - Tolerances for Added Poisonous or Deleterigus Substances, 122:100 Polychlorinated Biphenyls (PCBs), Federal Register 39(236)42747, Friday, December 6, 1974. lb. Subpart 1 - Proposed Toxic Pollutant Effluent Standards 129.09 Effluents Standards for Polychlorinated Biphenyls (PQs) ( Federal Register, 38(247) :35395, Thursday, December 27, 1973. 36 774120 17. ; Subpart II - Proposed Effluent Standard. (H) The Proposed Effluent 1 Standard for FCBs. 40 CFR 129: Draft Advance Notice of Proposed Rule Making for Toxic Pollutant Effluent Standards, Environ. Reporter 1342, November 12, 1974. 18. Federal Register 41(64)14134, Thursday, April 1, 1976. 19. Schacht, R. A.: "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).S 32, September/1975. 21. Ahmed, A. K.: "PCBs-in the Environment." Environment . 18:6, 1976. 22. Burse, V. W., Kimbrough, R. D., Villanueva, E. C., Jennings, R. W . , Linder, R. E., and Sovocoal, G. W . : "Polychlorinated Biphenyls Storage, Distribution, and Recovery: Liver Morphology After Prolonged Dietary Ingestion." Arch. Environ. Hlti. 29:301, 1974. 23. Grant, D. L . , Phillips, W. E. J., and Villeneuve, D. C.: "Metabolism of a Polychlorinated Biphenyl (Aroclor 1254) Mixture in the Rat." Bull. Environ. Gontam. and Tox. 6(2) 102, 1971. 24. Curley, A., Burse, V. W., Grim, M. E . , Jennings, R. W . , and Linder, R. E.: "Polychlorinated Biphenyls: Distribution and Storage in Body Fluids and Tissues of Sherman Rats." Environ. Research 4:481, 1971. 25. Goldberg, L. (ed.): "The Toxicity of Polychlorinated Polycyclic Conpounds and Related Chemicals." 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. Chem. 234(12) :3301, 1959. 27. Hutzinger, 0. , Nash, D. M . , Safe, S., DeFreitas, A. S. W., Norstrom, R. J., Wildish, D. J . , and Zitko, V.: "Polychlorinated Biphenyls: Metabolic Behavior of Pure Isomers in Pigeons, Rats and Brook Trout. " Science 178:312, 1972. 38 Cecil, H. C., Bitman, J . , Lillie, R. J., and Fries, G. F . : "Embryotoric and Teratogenic Effects in Unhatched Fertile Eggs from Hens Fed Polychlorinated Biphenyls (PC3s) ." Bull. Environ. Contain. Toxicol. 12:489, 1974. 29. Zinkl, J. G., and Koller, L. D.: "Pathology of Polychlorinated Biphenyls in Rabbits." Vet. Pathol. 12:63, 1975. 30. Roach, J. A. G., and Pomerantz, I. H . : "The Finding of Chlorinated Dibenzofurans in a Japanese Polychlorinated Biphenyl Sample." Bull. Environ. Contain. Toxicol. 12:338, 1974. 37 774121 31. Kuratsune, M., Masuda, Y., and Nagayami, J . :. "Some of the Recent Findings Concerning Yusho Papers Presented at National Conference on Polychlorinated Biphenyls." Chicago Illinois November 19-21, 1975. 32. Bowes, G. W., Mulvhill, H. J.,' Simoneit, R. T.r Burlingame, A. L., and Risebrough, R. W . : "Identification of Chlorinated Dlhenzofurans in American Polychlorinated Biphenyls." Nature 256:305, 1975. 33. Vos, J. G.: '"Toxicology of PCBs for Mamnals and for Birds." Environ. Hlth. Persp. 1:105,'1972. 34. Villeneuve, D. C., Grant, D. L., and Phillips, V. *E. J . : "Modification of Pentobarbital Sleeping Time in Rats Following Chronic PCS Ingestion. " Bull. Environ. Contain, and Tox. 7(5):264, 1972. 35. Cecil, H. C., Harris, S. J., Bitman, J., and Fries, G. F.: "Polychlorinated Biphenyl-Induced Decrease in Liver Vitamin A in Japanese Quail and Rats." Bull. Environ. Contamin. and Tox. 9(3): 179, 1973. 36. Dahlgren, R. B., Linder, R. L . , and Carlson, C. W . : "Polychlorinated Biphenyls: Their Effects on Penned Pheasants." Environ. Hlth. Persp. 1:89, 1972. 37. Ito, N., Hiroshi, N., Makiura, S., and Arai, M.: "Histopathological Studies on Liver Tumorigenesis in Rats Treated with*Polychlorinated Biphenyls." Gann. 65:545, 1974. 38. Kimbrough, R. D., and Linder, R. E-: "Induction of Adenofibrosis and Hepatomas of the Liver in BALB/cl Mice by Polychlorinated Biphenyls (Aroclor 1254)." J. Nat1!. Cane. Inst. 53:54 7, 1974. 39. Kimbrough, R. D., Squire, R. A., and Linder, R. E., et al: "Induction of Liver Tumors in Rats by Polychlorinated Biphenyl Aroclor 1260." J. Nat11. Cane. Inst. Decenber, 1975. (Cited in Reference 2). 40. Vasserman, D., Vasserman, M., Cucos, S., Djaraherian, M . : "Function of Adrenal Gland - Zona Fasciculata in Rats Receiving Polychlorinated Biphenyls." Environ. Research. 6:334, 1973. 41. Peakall, D. B.: "Pesticide-Induced Enzyme Breakdown of Steroids in Birds." Nature 216:505, 1967. 42. Rehfeld, B. M., Bradley, R. L . , and Sunde, M. L.: "Toxicity Studies on Polychlorinated Biphenyls in the Chick." Poultry Science 50(4):1090, 1971. 4 3. Peakall, D. B., Lincer, J. L., and Blbom, S. E.: "Eabryonic Mortality and Giromosaraal Alterations Caused by Aroclor 1254 in Ring Doves." Environ. Hlth. Persp. 1:103, 1972. 38 774122 GEN P 005476 44. wNiitlhls oPno,lyBc h.,loarninda tReadmeBl,ipCh e.:n y ls"G(ePneCticBT)eHstesreodnitaDsro s7o7p:h3i1la9, M1e9l7a4n.o gaster 45. HP(Creoaicttehed,edRiinn.gGsr.e, fXeVerteInnacl_tee: r n3"aE6t)fi.foencatsl oOfr nPitohloy clohgloicrainl a tCeodngBreipshs,enTyhles oHnagBuei,rd1s9."70. 46. bPI"ytHooli,ByscteoNnhpz.leoanNtrheianogaHlaotesegaxdikacicB,hSilHpotuhr.,idedineeAys.lr"saoina, nJ dL.Mi.vNi,tesaMrt'alPTkruuoCmimaroano,reti.ignSegI.n,neEssSitfs.fuegIcin5htd1aou:r1nca6e, d3L7Siv,i.n,e1r a9Mn7Tid3cuem. HobriysraoTIn,edcuKhcn.e:idcal 47. TVPP oooosrlx,ypichcJohy.llrB.oia.rA,,inpaaEpntdlede.md PaKBhoFaeimpormhramena,ncayotJillo.s.Hn ,i.n:1L7C:i5v"h6eCi5crok,mNe1npe9sac7rraw0ot.isivtihse aTSnpodex ciTci aiosllsouRgeiecfRae lreesnSi cdt ueudeytso. w " i t h 48. AVP oopslp,yl.cJh.PlBoha.r,irnmaaantcedodlB. Beeimp1h9s,e:6n1Ry7l.sB, .a1: n9d71"FD. rearmc tailo nTso xTihc ietryeoSf .tuind ieRsa bobf itTs .e"chTnoicxailc o l. 49. FH"Ciasnhhsreoenns,.i"c DT.BJo.ux, lilcP.itayEr,rnivsUihrpo,tnakP. e.RC, o.a,nntadLronwR, eea,tnedJn.tIiTo.on, x iWocfoillA.sorno,6c:l1Ao1r.3J1,. 251J49r 7. ,1in. WTwilosoEn,s tuPa.:rin e 50. WF riitehn dD,ucMk .H, eanpda tiTtirsa iVn eirr,u sD.".O .S: cie"npcoely c1h7l0o:r1in31a t4e,d 1B97ip0h. en yl: I n te r a c tio n 51a. BAiplhleennyJl .RE.x:p o s"uRrees."ponFsee doefratthioen NPonro-Hcuemedanin gPsrim 3a4te(8t)o:1 6P7o5l,y c1h9l7o5r.in a te d 51b. FinBooadRrhsaeonstdutsi,CMoDsom.nR.ke.,yTsMoExaxirpclooasrle,. d R1t.o4J.:9Loa9wn, d L1A9e7vl6lee.lns , o Jf . RP o. :ly c"hRloerpirnoadtuecdtivBeipDh eynsyfulsn c(t1io2n48). 52. UMneuigsus,al J.EWxp.o, sAu rlbeomto, JC.hJ l.o, rianned." K aJAsMtiAn , 1B5.L4:.1: 41"7C,hl1o9ra5c4n. e From an 53. PIneccklu, d iSn.Mg .:C h"lDo reirnme .a"titisJAMFArom1C2 5u:t1t9in0g, O19i4ls4,. S o lv e n ts, and D ie le c tr ic s , 54. OJocnceusp, atAio.nTa.:l O"rTihgeinE."tio lJo.g yInod f. AHcynge. TWoitxhicSopl.e c ia2l3:2R9e0f,ere1n9c4e1. to Acne o f 55. SHH.aaHmir.m, eoraf, ndDR e.BfIu.r,side bFWoinrdok,rlkeeaKr,s.:."J . F"EP. ,novlPyircroihnel.sotreHinrl,athteL.d.EPBe.,ripshKoe.eniyl,1l :8Jin3.E, t.h,1e97S2Pa.lnasdmifae ra, nd 56. WTYhaomme iearng uHBcaahvib,iinegAs .."C, oYnFsouusmkhueidmokuaRraiAc, ecTtOa.,iMl aenCdd.o nK6ta2um(r1ai)nt:sa1ut1end7e , , WM1i9t.h:71C. "hAl oSr ou br vi epyh eonfy lsP r aengdn a n t 57. BRK"EiiucpprehiadetOsenumiynlliesoC,.l"ooMgnit.cE,amnSYvitnoiurasdotheynidm. ouWHfraliY,tthhu.Tsah.Po, C,eMorasmaptmP.suoezric1saio:ka1nal1,in9Bg,Jra. ,n1Cd9aa7uno2sde.fd YPboaymlyaIcgnhuglcoehsri,itnioAant.e:dof GENP 005477 39 774123 58. Okumura, M. , and Katsuki, S.: "Clinical Observation on Yusho (Chlorobiphenyl Poiscxiing) .11 Fukuoka Acta Med. 60(6) : 440/ 1969. 59 Goto, M, and Higuehi, K . : '"The Symptomatology of Yusho (Chlorobiphenyls Poisoning)in Dermatology." Fukuoka Acta Med. 60(6) :409, 1969. 60 Stalling, D. L., and Mayer, F. L.: "Toxicities of PCBs to Fish and Environmental Residues." Environ. Hlth. Persp. 1:159, 1972. 61. Berland, T.: Rating the Diets. Skokie, 111., p. 286, 1974. 62. Berglund, F . : "Levels of Polychlorinated Biphenyls in Food in Sweden." Environ. Hlth. Persp. 1:67, 1972. 63. Federal Register 38(129):18096, July 6, 1973. 64. Stanovick, R. P., Shahied, 'S. I., and Missaghi, E.: "Determination of Polychlorinated Biphenyl (Aroclor 1242) Migration into Food Types." Bull. Environ. Contain. Toxicol. 10:101, 1973. 65. Yobs, A. R.: "Levels of Polychlorinated Biphenyls in Adipose Tissue of the General Population of the Nation. " Environ. Hlth. Persp. 1:79, 1972. 66. Gillette, J. R.: "Individually Different Responses to Drugs According to Age, Sex, and Functional or Pathological State." In: Drug Responses in Man. Wolstehholme, G. and Porter, R. (eds.) Churchill, London, p. 28, 1967. 67. Nyhan, W. L.: "Toxicity of Drugs in the Neonatal Period." J. Pediat. 59(1):1, 1961. 68. Smith, R. L., and Williams, R. T.: "Implication of the Conjugation of Drugs and Other Exogenous Compounds." In: Glucuronic Acid, Dutton, G. J. (ed.), Acadmic Press, N.Y1, p. 457, 1966. 69. Gartner, L. M., and Arias, I. M . : "Studies of Prolonged Neonatal Jaundice in the Breast-Fed Infant." J. Pediat. 68(1):54, 1966. 70. Sutherland, J. M., and Keller, W. H.: "Novobiocin and Neonatal Hyperbilirubinemia." Am. J. Pis. Qiild. 101:447, 1961. 71. Lokietz, H., Dowben, R. M., and Hsia, D. Y . : "Studies on the Effect of Novobiocin and Glucuronyl Transferase." Pediatrics 32:47, 1963. 72. Lester, R., And Schmid, R . : "Bilirubin Metabolism." New Eng. J. 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