Document np4X9xa199O1RQ6L1aZzgOm52

Environmental Institute for Waste Management Studies Polychlorinated Biphenyls a Toxicological Analysis Open Pile Report No. 17 MONS Escalation of research efforts regsrding hazardous wastes and their manage ment will ba an essential prerequisite toward the attainment of regulations founded upon sound technical date. To help meet the need for data, members and staff of The University of Alabama Environmental Institute for Waste Management Studies have prepared e series of open file reports related to the treatment and disposal of advents. The authors gratefully acknowledge support of this work by the Environmental Institute for Waste Management Studies, The University of Alabama, Dr. P. E. LaMoraaux, Director. Any opinions, findings, and conclusions or recommendations expressed In this open file report are those of the Environmental Institute for Waste Management Studies. This open file report Is currently under technical review end subject to change prior to final publication. The Environmental Institute for Waste Management Studies is a division of The University of Alabama, a state-supported institution of higher education, The Inatitute it committed to the advancement of knowledge related to the safe manage ment of hazardous waste. Institute Members Philip E. LaMoraaux, D.Sc. University of Alabama Charles J. Mankin, Ph.D. Oklahoma Geological Survey Arthur C. Banks, Ph.D. University of Alabama James K. Mitchell, Sc.D, University of California, Berkeley Gary F. Bennett, Ph.D. University of Toledo Carl A. Silver, Ph.D. Drexel University William J. George, Ph.D. Tulene University James V. Walters, Ph.D. University of Alabama Robert A. Griffin, Ph.D. Illinois State Geological Survey Rae Zimmerman, Ph.D. New York University Institute Staff I. Atla Jefcoet, Ph.D. Travis H. Hughes, Ph.D. Robert L. Wells, Ph.D. Tola B. Moffett, Ph.D. James W. LaMoraaux, Ph.D. Bernadette N. Roche Susan I. Rutledge The University of Alabama P.O. Box 2486 Tuscaloosa, Alabama 35486 MONS 027495 POLYCHLORINATED BIPHENYLS A TOXICOLOCI CAL ANALYSIS Open File Report Prepared For The Environmental Institute far Waste Management Studies The University of Alebema BY Camille J. George1, Gary F. Bennett, Ph.O.2'3 Denise Simoneaux1 and William J. George, Ph.D,1'3 3Tulane Unlverslty School of Medicine Department of Pharmacology New Or Ieans, LA 70112 ^Depertment of Chemical Engineering The University of Toledo Toledo, OH 43601 ^Member of the Board Environmental Institute for Waste Management Studies The University of Alabama Tuscaloosa, AL 35487 Accepted For Publication, February 1987 HONS 027496 TABLE OF CONTENTS I II III IV V VI VII VIII IX X XI Xtl XIII Summary Introduction History Commercial Production and Application Regulation Physical and Chemical Properties Environmental Exposure Bloaccumulatlon/Dlstrlbutlon In Animal Tissues Excretlon/Hetabollsm Mechanism of Metabolism Toxicity and Effects of PC8s PCDFs ATPase Enzyme Activity Chloracne Animal Experiments Vapor Exposure Reproductive Effects Human Exposure Physiological Effects Neurological Effects Carcinogenicity Case Studies of Accidental Exposures Regulations of PCBs Elimination of PC8s from the Environment Permissible Human Exposure Blbllography 1 2 2 3 7 8 a li 12 14 16 17 18 18 19 21 22 23 24 25 26 29 32 33 3S 37 MONS 02749? I. SUMMARY Polychlorinated biphenyls (PCS$) are * class of compounds which have, for marly 60 yatrs, baan usad as Insulating fluids, hydraulic and lubricating fluids, heat exchanger fluids and as additives In adhesive Inks and paints. The very properties that made PCBs attractive to Industry, such as resistance to fire and persistence In the environment, are the same properties that have resulted (n their perceived toxicological problems. Mixtures of these compounds which have great environmental persistence and are contaminated with other agents, have been shown to produce adverse organ and system effects on a variety of animals. However, aside from occurrences of a chloracne, no significant chronic adverse health effects have been found In humans In a number of reported studies. Nonetheless, since the mid 1970's, production and use of PCB's have been curtailed based on chronic animal toxicity data and concern about the environmental parslstanca of these highly lipophilic compounds which tend to bloaccumulate In living tissues and the food chain. This report discusses the chesMcal and physical propertlas of PCBs, their biological disposition, and their reported toxicologic effects Including carcinogenic potential. Specific comparisons are made between toxicity of PCBs In animals with effects observed In humans following exposure. Other areas covered Include governmental regulation and permissible levels of exposure. Indeed, as a result of passage of the Toxic Substances Control Act In 1976, Congress singled out PCBs for regulation as required by law and the U.S. EPA banned further production (n 1979. HONS 027496 2 It Is concluded that there ara significant adverse affects of PCSs whan administered to animals under laboratory conditions. However, with the exception of the development of chloracne, there is little evidence suggesting toxicity to man from the chronic exposure to PCBs Including carcinogenic effects In the workplace or environment. II. INTRODUCTION History Polychlorinated biphenyls, PCBs, are chlorinated aromatic hydrocarbons which were discovered In 1881. Effects of PC8$ on the environment were noted more than 75 years later whan accumulations of PCSs were found In aquatic life of the Baltic Sea (34). The cormerclal production of PCBs began In 1929, and during the following decade, cases of poisoning were reported among workers Involved In the manufacturing of PC8s (77). Ensuing safety precautions prevented further PCB poisoning until 1953 when cases were reported In Japanese factories. Widespread distribution of PCBs In the environment was not recognized until 1984 when S. Jensen began to search for an explanation for appearance of mysterious elution peaks during gas-liquid chromatographic separation of organochlorlne pesticides from environmental samples (50). He later attributed these peaks to the presence of PCBs In the samples which resulted In worldwide studies that revealed the widespread distribution of PCBs In the environment. More recent outbreeks of poisoning In men and domestic animals from accidental food contamination with PCBs stimulated an Interest In the toxic effects of PCBs and have resulted In the cessation of the commercial production of PCBs and a regulation of their residues In food. MONS 027499 III. COMMERCIAL PRODUCTION AND APPLICATIONS Tht basic structura of PCBs Is as follows: 3 danotas position occupied by olthor a hydrogon or chlorlno atom. PCBs havo tha gonoral formula whara tho numbar of chlorfnas substltutad on tha btphanyls can ranga from ona to tan rasultlng In tan forms of polychlorlnatad btphanyls. Two-hundred nlna PCB tsomars ara thaoratically posslbla (Tabla 1). Tha numbar of chlorlnas In aach Isomar datarmlnas Its dasslftcatton and nomanclatura (Tabla 2). HONS 027500 4 Table 1 Isomers of PC8s Empirical Formula PS c12h5c15 cilUjc!) Clfciio Molecular Height 154 188 222 256 290 324 358 392 426 460 494 Per cent Chlorine 0 18 31 41 48 54 58 62 65 68 79 Total . . 209 not a PCS: not added In total Table Source; Durfee at al. (1976). No. of Isomers 1 3 12 24 42 46 42 24 12 3 1 Th* commercial production of PC8s Is carrlod out by tha chlorin ation of blphtnyls with anhydrous chlorlna In tha prasanca of a catalyst, usually Iron filings or ferric chloride. This reaction occurs at extremely high temperatures resulting In a crude product that must subsequently be refined by an alkali wash or sometimes be distilled (47). The final commercial products are PCS mixtures that vary In chlorine concentration, PC8 Isomers as well as Impurities. Table 2 Chlorine Content of Selected PC8$ Arochlor # 1221 1016 1242 1254 1260 Per Cent Chlorine 21 42 42 54 60 Kanechlor # 300 400 500 Per Cent Chlorine 43 48 53 MONS 027501 5 In addition, ralated chemicals, polychlorinated dlbenzofurans (PCDF) and polychlorinated quaterphenyls (PCQ) are also formed (Figure 2) and are present In some mixtures (35). These different PC8 mixtures are marketed throughout the world under a variety of trade names: Arochlor, Chloretol, DyKanol, Inerteen, and Pyranol (United States); Phenochlor (France); Clophen (West Germany); Kaneclor and Satatherm (Japan); Fendor (Italy); and Soval (Soviet Union). The varied compositions of Isomers In the different PCS mixtures can be Illustrated by two of the Kanechlor products. Kanechlor 500 is composed of 55X pentachloroblphenyl, 26.5* tetrachloroblphenyl, 12.8* hexachloroblphenyl, and S.O* trlchloroblphenyl while kanechlor 400 contains 43.8* tetrachloroblphenyl, 32.8* trlchloroblphenyl, 15.8* pentachloroblphenyl, 4.6* heptachlorobiphenyl, and 3.0* dlchloroblphenyl (32). Figure 2 Byproducts Found In PCS Mixtures Polychlorinated dlbenzofuran (PCDF) Polychlorinated quaterphenyl ______ _ (PCQ) Cl Cl HONS 027502 s Sine* the Monsanto Company began production of PCBs In 1929, they had been used In Increasingly different capacities until the regulation of their use in 1971 (70). There were three categories of PCS usage: closed uses, nominally closed uses, and open-ended uses. The closed uses of PCBs Include Insulation for electrical wire, cables, and condensors as well as coolant/dlelectrlc In transformers and capacitors. These applications Isolate PCBs from the environment. The nominally closed uses of PCBs Include hydraulic fluids, heat transfer fluids, and high pressure lubricants. These uses do not totally Isolate PCBs from the environment, but for the most part do not allow direct contact. Open-ended uses of PCBs Include additives to paints, Ink dyes, platlclzars, protective coatings for woods when low flammability Is necessary, dedusting agents, adhesives, pesticide extenders. Ink and dye carriers, and for microencapsulation of dyes for carbonless duplicating paper (34). These applications exposed PCBs directly to the environment. from 1971 until 1976, Monsanto produced an average of 27,000,000 lb/year of PCBs with sales to fewer than 40 customers. PCB production ceased In 1977, nearly 2 years before the Toxic Substances Control Act (TSCA) required It. Of the documented production of approximately 1.4 billion lb of PCBs In the United States (as of 1981), estimates are that SO million 1b have been destroyed, 300 million 1b are In landfills, 156 million lb are in the environment, ISO million lb were exported, and 7S0 million 1b are still In use (122). In 1971, U.S. producers voluntarily limited the sale of PC8s to those applications that minimized Introduction of the chemicals Into the environment. Table 3 Illustrates that applications of PCBs have been limited to closed systems since 1971 (34). HONS 027503 7 Table 3 Typt of Systems In Which PCBs Have 8tn Employad Applications of PCBs Closed electrical systems Nominally dosed systems Open and applications Prior to 1971 SIX 13* 26* After 1971 100* 0* OX Tht major productr of PCBs In tha U.S. was tha Monsanto Industrial Chamlcal Co. which had two plants, ona at Anniston, Alabama (closed^ In 1970) and tha stcond at Sangat, Illinois. Tha Sangat plant producad 99* of tha PCBs (trada nama, Aroelor) usad In U.S. industry. Sevanty parcant of thasa PCBs wara usad In capacitors whlla tha ramalntng 30* wara utlllzad In transformars (48). Raoul atIon Oasplta uncartalnty about tha haalth affacts of PCBs, Congrass singled them out for regulation under tha Toxic Substances Control Act (TSCA) of 1978. In 1979, tha U.S. EPA banned further production of these compounds. However, utllltlnjwere allowed to continue to use existing transformers and capacitors containing PCBs for tha duration of their normal service life,, although certain uses have been banned. Under new rules Issued by the U.S. EPA In July, 198$, utilities must phase out the use of PCB transformers In or near buildings by 1990. Ultimately, they must destroy all PCBs In equipment and clean up or contain any PCBcontaminated sites that are environmental hazards. Disposal regulations for PCB's are quite restrictive. In the SO to SOO ppm range, the U.S. EPA allows landfilling. However, whan PCB levels are greater than SOO ppm, materials must be Incinerated. Below tha SO ppm level disposal Is unregulated by the U.S. EPA, but, States' rules may mandate otherwise. MONS 02750h s Ironically, PCBs are still manufactured by Germany, France, Spain, and Italy and certain Eastern European countries and they continue to be used throughout the world (122). IV. PHYSICAL AND CHEMICAL PROPERTIES PCBs have physical and chemical properties that make them valuable In the previously mentioned applications of electrical Insulations, l.e. stability and fire resistance. Pure PCBs are solids at room temperature (2SC), and their melting points range from 54C for 2-chloroblphenyl to 310C for 2,3,4,S,S,2',3',4',5',6' deeachloroblphenyl Generally, PCB melting points Increase with the complexity of the compound. The chemical mixtures of PCBs used In Industry are usually colorless to lightly tinted oils. Oensltles of such mixtures as Arochlors an Kanechlors are approximately 1.2 to 1.5 g/cm3 and have refractive Indices of approximately 1.62 (32). PCBs are fat>so1uble, water-insoluble, and very stable. They are very resistant to degradation, oxidation, and other chemical agents such as acids and bases. They can withstand extreme temperatures up to 1S00F (870C) and are fire resistant (32). PCBs may dimerize and when they do they form polychlorinated guaterphenyls (PCQs) (Figure 2) (120). Another property of PCBs that make them attractive to Industry Is their low vapor pressures. This property also reduces the probability of exposure even with concentrations of several thousand parts per million (37). V. ENVIRONMENTAL EXPOSURE There Is no evidence that PCBs occur naturally In the environment. Apparently, all PCBs present In nature can be attributed to dissemination by humans. The majority of PCBs In the environment Is found In surface marine waters, mainly of the North Atlantic Ocean (34). However, since restrictions HONS 027505 9 of PCB us* and production, th* North Atlantic surfaca water has shown a 40-fold dacraas* In PC8 concentration since 1972. Tests In September, 1973 tndlcat* a disappearance of 20,000 tons of PCBs In the upper 200 meters of water during that on* year time span (34). In 1972, th* rivers of th* United States were tasted for presence of PC8s. Th* concentrations of PCBs found ranged from less than 0.01 to 0.45 ug/T (107). These are low concentrations compared to that found In Japanese drinking water ' and North Atlantic surface water which contained 10-100 ug/1 and 1- 35 ug/l, / respectively (70,104). Th* Hudson River Is a prim* example of PCS pollution / as a result of unregulated discharge. Between 1942 and 1970, two General Electric plants (Fort Edward and Hudson Falls) discharged an average of 14 kg of PCBs per day Into th* river. Sediment samples from th* river bed have been found to contain concentrations of S40 to 2,980 ug/kg. Fish taken from the river demonstrated PC8 concentrations of 82 to 13$ mg/kg (6$). These concentrations have greatly decreased since th* cessation of PCB discharge Into th* river. Sedimentation testing during th* early 1970's In Lake Erl* (1971), Lake St. Clair (1970 and 1974), and th* Oetrolt River (1974) revealed residues of PCBs which were 3 times higher than those of all organochlorln* Insecticides. These levels have also decreased since th* restrictions of PCBs (16). An Important environmental concern about PCBs Is their Incorporation Into th* food chain. Benthic Invertebrates feeding on th* lake bottom consume PCBs and later pass them on In th* food chain to fish, birds, man, and other creatures. As PCBs pass through th* food chain, concentrations accumulate and are transferred from on* organism to another. As a result, th* upper trophic levels are most prone to PCB accumulation (34), and freshwater fish are th* major source of PCBs in th* diet of humans (47). It has been MONS 027506 10 Indicated that adults consuming ISO g per week of Coho salmon from Lake Michigan also are Ingesting 15 mg/kg of PCBs whereas In Japan, 30 g of fish contains the same quantity of PCBs (70). Studies of 70-79 year old Japanese men revealed S.1 mg/kg of PCBs In fat tissue. Japanese women of the same age bracket had 2.4 mg/kg PCBs In fat tissue (49,70). A 1972 survey by Yobs of 637 Americans from 18 states Indicated that 2SR had 1-2 mg/kg PCBs In fat tissue (98). In the same year, a report by the U.S. Department of Agriculture listed PCB presence In many common foods such as cheese (0.25 mg/kg), milk (2.27 mg/kg), and eggs (0.55 mg/kg) (32). There are four major routes by which PCBs enter the environment: Industrial accidents or discharges, Imcomplete destruction of PCB containing products, natural weathering of PCB containing products, and leaking from land-fills (32). Most PCB leaks result from pump leaks Into the cooling water used In capacitor and transformer production resulting In the Introduction of the PCBs Into municipal sawers (48). Once In the environment, PCBs can be transported by leaking, diffusion, rain, snow, and dust (32). Domestic sources of PCBs In the U.S. are: 1) industrial and municipal sewage disposal, 2) paper recycling plants, 3) PCBs In the soil, 4) Incineration, and 5) municipal (solid waste) landfills. The PCBs put In carbonless copy paper from 1957 to 1971 contaminated the paper products which have subsequently been recycled and put back Into the environment. PCBs have found their way Into soil from disposal sites and equipment servicing as well as oils used In dust control which may have been contaminated with PCBs. Incineration Is probably the best method for destruction of PCBs, but If not properly executed, Incineration can release PCBs and their by-products back Into the environment. Incineration can be accomplished In a number of HONS 027507 11 thermal devices Including Industrial hollars, cement kilns, and hazardous waste Incinerators. All appear, If properly operated, to satisfactorily destroy the chemical (1). U.S. EPA regulations governing Incinerators require 99.99% destruction, thus allowing a maximum of 0.01% to escape. Chemical landfills are presently effectively used to Isolate PC8s from the environment, but the danger of erosion and leaking Is present (47). PC8s are also Introduced Into the U.S. by atmospheric currents from other parts of the world, but the amounts are nominal compared to domestic sources (34), VI. BIOACCUMULATION/DISTM8UTIQN IN ANIMAL TISSUES Environmentally, the bloaccumulatlon of PC8s Is very Important. Out to their low solubility In water and high accumulation coefficients, PCBs display high bioaccumulatlorr values In animal tissue. Aquatic organisms, such as fish, experience the greatest amount of PCS accumulation. For Instance, the concentration of PCBs In Lake Michigan averages approximately 0.008 ug/kg while PCB concentrations found In the lake trout are approximately 28 mg/kg (108). This concentration Is over 3 million times that of the external environment. Different species of fish collected from the same environment In Lake Michigan contained different amounts of PCBs. Lake trout and carp both have approximately 10% body fat and contained more than five times as much PC8 as yellow perch with only 4% body fat. It appears that species of fish with higher amounts of body fat (such as carp or catfish) contain more PCBs than other species of fish having less body fat (such as yellow perch or northern pike) (96). This difference In the bloaccumulatlon of PCBs Is mainly dependent upon adipose tissue and under stress this may present a release HONS 027508 u mechanism is PCB-contalnlng lipids are mobilized (34). PCBs also may accumulate In skin and muscle tissue. After PCBs reach the bloodstream, they become located within the liver and muscle. From these locations they are redistributed and become Incorporated within other tissues such as adipose tissue and skin which, although they have lower blood perfusion rates (137), also have higher affinities for PC8s. This distribution of PCBs primarily In adipose tissue is displayed in feeding experiments with Sherman rats ($9). These rats were fed a diet of 500 ppm of Arochlor 1254 for S months. After 10 months, the rats were sacrificed and PCB concentrations were determined. Adipose tissue contained 1200 ppm of PCBs while liver tissue contained only 22 ppm (69). In another such feeding experiment, rats were fed diets of 1000 ppm Arochlor 1254 for 98 days. The adipose tissue contained 11,278 ppm while other tissues had less than 200 ppm (36). Experiments with pheasants Indicate that as much as 82* of the PCBs are absorbed via the gastroenteric tract (112). Additional absorption, though reduced In amount, Is by way of the respiratory tract (123). Excretlon/Metabol1 am Although adipose tissue accumulates more PCBs than other tissue types, the liver still must be considered an Important target organ because of Its Importance In the excretion of such toxins In the body. Furthermore, liver tissues still can accumulate concentrations of PCBs at levels twice that seen In the rest of the body (128). Hlcrosomes of the human liver transform certain PCBs Into less lipophilic compounds to facilitate excretion (139). However, the nature of the PCBs In question dictates the fate of these toxins because their excretion Is associated not only with the rate of metabolism, but also with their llpophlllcity. HONS 027509 13 In vitro experimentation involving the metabolism of PC8s by human Hvar microtomes 1ndicts that PCBs must hav two adjacent unsubstitutad carbons to ba matabolizad. Any unmetabolized PCBs appaar to aeeumulata In adiposa tissua (139). Chlorlna atoms on tha blphanyl compound also affaet tha rata of matabolism in both numbar and position on tha blphanyl group. In mica, tha rata of metabolism and alteration dacraasa as chlorination incraasas in orally administarad PCBs (137). Similarly, studios by Bunyan and Paga dealing with quail suggest that absorption, matabolism and excretion become increasingly impaired as chlorination Increases on the biphenyl compounds (1S1). However, the amounts of chlorination alone are not the only thing to affect metabolism. Different isomers seem to affect hepatic enzymes differently. Tha hexaehloro- biphenyls seem to have yielded the-strongest results. This study indicates that activity of PCB Isomers differs sufficiently to warrant individual studies on each Isomer to determine metabolism and excretion. Testing with rhesus monkeys demonstrated that the majority of PCBs from a diet of Aroclor 1248 accumulate within liver and adipose tissue and decrease slowly following discontinued exposure. In fact, the PCBs appeared to have a half-life of at least 3 to 4 months. ________ Beagles were used in an experiment in which both 2,3,g-heptachlorobiphenyt. (HCB) and(l ,4.j^haptabromobiphtnyT. (HB8) ware given in 0.6 mg/kg doses. Tha results Indicated that 70% of the Z,3,6-HCS was excreted in 3 days while only 14% of the 2,3,3-HCB was excreted in 20 days. The 2,4,5-HCB was 66% excreted in IS days while only 8% of the 2.4.S-HBB was excreted in 25 days (142). Thus, the rate of elimination was determined by chlorine position, probably by MONS 027510 14 controlling the rate of metabolism. The amount of metabolism and rate of excretion It also determined by the specific halogen. Another experiment Involved beagles treated with an Intravenous dose of 0.6 mg/kg of C * labelled ,4'-PC8. Excreta, bile and tissues were collected from IS minutes to 28 days following treatment. These specimens oxidized and was quantitated by scintillation counting. The results Indicated that SOX of the dose of 4,4'-PC8 was excreted as metabolites within the first 24 hours. Urine contained 7% of these metabolites, while feces contained the remaining 43X. Any remaining 14C In the dogs was present mostly In fat, muscle and skin. By S days after the termination of exposure, more than 90S of the original dose of the 4,4'-PC8 was excreted. Cynomolgus monkeys were exposed to PCBs In an identical experiment. However, only 15X of the dose was excreted within the first 24 hours. At 24 hours, the blood and bile contained 7SX and 100X, respectively, of their original values.The remaining PC8s were located mainly In the adipose tissue (33X) as the parent compound. Skin and muscle contained lesser amounts. After 28 days, only S9X of the dose was excreted. Hence, with 4,4'PCB, the beagles appear to be capable of eliminating highly chlorinated PCBs more quickly than the monkeys due to metabolic differences In the organisms (136). Mechanism of Metabolism Biphenyls are hydroxylated then conjugated before Incorporation In rat bile for excretion. After doses of 2,2'-{2,4-;2,3-;3.4-; 3,3'-; and 4,4'dlehloroblphenyls, the primary metabolites were dlchlorodlhydroxy biphenyls (69). PCBs have been Indicated In some cases as the toxins responsible for mutagenicity and liver damage In animals and humans. It seems that these advene effects result from electrophilic Intermediates produced during the HONS 027511 IS metabolism of PCBs (139). Hydroxylatlon, the major pathway of metabolism for PCBs, may sometimes Involve arene oxides as Intermediates. Arene oxides may lead to carcinogenic, cytotoxic, or mutagenic effects. Increased arene oxide production may be due to the activity of both PCBs and PB8s working addltlvely together (75). Furthermore, hydroxylted chioroblphenyls are more hazardous than the starting PCBs (34). It also has been Indicated that rats exposed first to PCBs or PBBs have an Increased likelihood of toxicity from other chemicals such as carbon tetrachloride, chloroform, and bromobenzene. Certain Insecticides are also more toxic when given with PCBs (72,74,99). Since degree and position of chlorination dictate the rate of PCS metabo lism, It may suggest that the limiting factor Is the rate at which arene oxide Intermediates are produced (4). The production of these highly reactive, elec trophilic arene oxides may be due to the activity of hepatic and extrahepatic aryl hydrocarbon hydroxylase (AHH). The metabolism of 4-dlchloroblphenyl often yields 4,4'd1chloro-3-b1pheny1o1. This Is probably due to a rearrange ment of a 2,3-epoxide or a 3,4 epoxide using an arena oxide as an Intermediate. If a 2,3 epoxide Is rearranged, the metabolite Is 4,4'-d1chloro-2-b1phenylol. However, If a 3,4 epoxide Is rearranged then a 3,4' dlchloro-4-blphenylol Is the metabolite (16). A mixture of the two Is most probable. A major concern with PCB metabolism Is the effect resulting metabolites may have on the young of exposed pregnant adults. Arochlor 1254, In doses of 10 or 50 mg/kg, was administered to rats from the 7th to the 15th day of pregnancy (36). These doses resulted In average PCB concentrations In fetuses excised on the 20th day of 0.63 and 1.38 mg/kg for the above doses, respectively (36). These values, although low, Indicate a definite transfer occurring from parent to fetus. Laboratory studies Indicate that greater quantities of PCBs HONS 027512 16 are transferred by breast feeding after birth thin prenatally through the placenta. This may b due to the fict that PC8s accumulate mora readily and In graitar quintlty In tha fit of maternal milk nthtr thin In mitarml serum (82). Tests of blood, milk, ind idlpose tissue of Infants md mothers yielded data which demonstrate that tha leading maternal source of PCBs for Infants (s, In fact, maternal milk fat (Table 4). Additionally, tha fetus accumulates the majority of PC8s In adipose tissue. Table 4 Maternal Sources of PC8s and Distribution Found In Infants Source Maternal milk Maternal milk fat Maternal blood Infant blood Fat only Total adipose tissue liver Adrenal Concentration of PCBs foobl 350 1.4 2.5 470 ISO 7.3 26 VII. TOXICITY ANO EFFECTS OF PCBs Toxicity of PCBs is a valuable consideration when dealing with living organisms. The lethal doses of PCBs such as Arochlor 1242 and Arochlor 1260 administered orally are 4.2S g/kg and 9.S g/kg, respectively '(158), In laboratory rats, oral toxicity decreases with Increased chlorination; however, there Is no similar correlation with rabbits and toxicity (40,41). The exact effects of PCBs are difficult to ascertain because the mixtures often contain Impurities. PCB mixtures have also been demonstrated to contain several other types of chlorinated compounds such as polychlorinated naphthalenes and polychlorinated dlbenzofurans (PCOFs) (140). The presence of these PCOFs In PCB mixtures may arise from the dlstlllatton process during purification (Figure 3) (34). HONS 027613 Figure 3 Conversion of PC8s to PCOFs During Purification Process 17 PCOFs | PCOFs The effects of PCOFs have baan widely studied because of their possible connection with PC8 toxicity. Rats on diets of PCOFs displayed Inhibition of food consumption. PCBs also caused reduced food consumption but the decrease was far less than that demonstrated by PCOFs. In addition, ehloraene-llke lesions appeared on the ears of these rats. Low levels of PCOFs cause the hemoglobin hematocrit and mean corpuscular volume to decrease. At higher concentrations, 10 ppm or more, PCOFs cause additional erythrocyte count decreases (1$9). PCOFs have also been demonstrated to decrease serum glutamic- pyruvic transaminase activity as well as testosterone concentrations within the testes. Concurrently, an increase In serum glutamic-oxaloacetic acid transaminase activity Is typical for these PCOF treatments. Mixtures of PCBs and PCOFs cause a variety of symptoms In treated animals Including Increased MONS 027514 13 strum cholastarol levels, elevated cholinesterase activity, and decreased triglyceride and amtnopeptldase activity (154). ATPase Enzyme Activity PCS* are also capable of altering ATPase enzyme activity In organisms. It appears that the lipophilic properties of PCBs are the dominating factor In PC8 Inhibition of ATPases. The Inhibitory activity of PC8 decreases as Its aqueous solubility Increases. It seems that the lipid portion of the ATPase enzyme readily associates with PC8s. An allosteric change probably occurs in the ATPase enzyme by the lipophilic separation and results in decreased activity of this ATPase (130). In fact, studies by laRocca and Carlson Indicate Arochlors and other chlorinated hydrocarbons are equally capable of Inhibitory activity on both Mg** -and Na*/K*- adenosine trlphophatases (ATPases). More specifically, It was determined with In vitro experimentation that a concentration of 30 ppm of PCBs Inhibits the MgATPase activity of brain and heart tissue (8,46,64,121,126). The activity of each of the 209 Isomers of PC8 as ATPase inhibitors varies according to each compound and Its corresponding association with a given ATPase (130). Chloracne Chloracne, a common symptom of human PCB poisoning. Is a skin disorder associated with poisoning by any chlorine-containing compound. It occurs as severe acne but does not disappear as quickly as It appears and can be severs enough to leave facial scarring. The effect of PCBs on skin Is manifested as typical chloracne In addition to hyperpigmentation, loss of hair, and gprphyn+t(90). The acnelform eruptions of chloracne form both closed comedomes (cysts) and open comedomes. The cause of these acnelform eruptions appears to be the HONS 027515 19 follicular excretion of PCBs with the sebum. These excretions continually Stimulate the skin and result In the acnelform characteristic of PCB poisoned patients (149). Anlmel Experiments On the Acute Toxicity Chart, PCBs are only ranked slightly toxic to non-toxic (37). Recent studies Indicate that short-term exposure to PCBs does not teem to be particularly toxic (134). The short-term toxic effects seen In laboratory animals would appear to require dosages In terms of pints or quarts to cause corresponding effects In humans (26). Experiments with rhesus monkeys on a diet of 300 ppm of Arochlor 1248 resulted In chloracne, loss of eyelashes, and subcutaneous edema (119). Longer terms of exposure In male monkeys resulted In slight periorbital edema and erythema (9). Oral administration of a 6SX chlorinated biphenyl to laboratory animals resulted in atrophy and lesions of the liver (1$6). More specifically, male dogs on a diet of 100 ug/g of PCBs have experienced observable reductions In growth rates while displaying an enlargement of the liver. Serum levels of alkaline phosphates are also elevated (84). Studies on the effects of PCBs on microorganisms such as the Eugltnt and the Scenedesaws also demonstrate reduced growth rates. Other microorganisms that contain chlorophyll, the cyclosterlum and thalosslosioa, also display suppressed growth (14,42,43,127). Guinea pigs, rats, and rabbits that were topically treated on a dally basis with 0.02S ml (34.S mg) of undiluted chlorinated biphenyl all demonstrated fatty degeneration and central atrophy of the liver. In addition, the epidermis thickened at the site of application (123). Testing with Ulster rats fed 1000 ppm of Kanechlor 300, 400 or 500 resulted In MONS 027516 20 the development of cholangloflbrosls. lower doses did not display such symptoms. In addition, Increasingly larger concentrations of PC8s with greater chlorination caused higher occurrences of medullar hyperplasia (68). Sherman rats fed high doses of Arochlor 1254 exhibited adenoflbrotlc lesions. Mice also demonstrated liver changes when given highly chlorinated com pounds In concentrations of 300*500 ug/g (34). A 300 ppm dosage of Arochlor 12S4 was administered to two groups of mice. Group one was exposed for 11 months while group two was exposed for 6 months. Histological examinations of these mice Indicated that one of the 24 mice In group two developed hematomas. Furthermore, of the 22 mice In the first group, all displayed adenoflbrosts (85). Birds also suffer adverse effects from long-term exposure to PC8s. For example, chickens dtsplay reduced egg production and fertility over long-term exposure to PCBs (12$). Chickens have also displayed slight morphological deformities and a decline In reproductivity which Is accompanied by subcutaneous edema when doses of 20-50 ug/g of PCBs were administered (34). Chickens treated orally with 100 ppm of Arochlors 1242 and 1254 display decreased rates of hatching eggs (54). Qualls exposed for 2 months to Arochlor 1242 showed discontinued production of eggs and displayed decreased levels of Vitamin A In the liver with as much as $0% of the original level of Vitamin A being decreased (20). Wild fowl, In general, display reproductive changes when exposed to PC8 concentrations of 50-200 u9/g (34). American kostlels exposed to PCBs demonstrated nominal Increases In the thickness of egg shells. Higher doses 80 mg/kg were necessary to cause decreased egg production and a 12% decrease In eggshell thickness. Ring doves fed 10 ppm MONS 02 751? 21 of Arochlor 1254 displayed lower hatching rates. Cytogenetical testing on the embryos of these PC8 fed doves yielded higher than normal chromosomal rearrangements and aberrations when Irradiated with X-rays (131). Of all bird species studied, ring doves appear to be the most susceptible to PCBs. A 10 mg/kg dose of PCBs has been reported to greatly Increase embryonic mortality rates In the second generation as well as cause chromo somal aberrations. In addition, behavioral changes have been observed In the parent birds (117). It Is apparent that different species of birds have varying tolerance and reactions to PCBs. Birds also demonstrate many symptoms experienced by laboratory mammals. Chickens as well as other species show enlarged kidneys, splenic atrophy, and congestion and Infiltration of fat In the liver (11,143). Pelicans have been shown to experience some hepatocellular alterations when exposed to PCB doses of 100 wg/g (34). Vapor Exposure Vapor exposure to PCBs seem to result In an Increase In the occurrence of adverse effects on animals. Vapor exposure of mice demonstrates that chlorinated diphenyls could cause Injury when used In small concentrations. PCB exposure, In this fashion, may be more dangerous than exposure to chlorinated napthalenes (42,43). However, guinea pigs that underwent vapor exposure to PCB concentrations of BIS ug/1 of air for the 7 hr/day over 14 days showed no toxic effects. This concentration was near saturation and did cause poor growth, but nothing so profound as Indicated by the experiment with mice (42,43). Skin exposure, as mentioned previously, can causa chloracne. In addition, high doses of PCBs may cause systemic effects. These effects Increase In MONS 027518 II severity with the amount of chlorination of the biphenyl (140). Systemic tfftcts were observed In rats given five skin applications of Arochlor (1 ml of 20% solution mixed In olive oil). These rats displayed general malaise, rough fur, loss of body weight, death with and without convulsions and coma (10). Reproductive Effects One of the leading concerns regarding PCBs today is the effect on mammal reproduction and the reproductive system. With regard to the endocrine system, PCBs can cause Irregularity In the menstrual cycle (90). In monkeys, small doses of 2.S-S.0 vg/g will cause an erratic menstrual cycle as well as an Increase In abortion rates (78). Reproductivity tests (n female rhesus monkeys with PCB doses of 2.5-S.O ppm were carried out over a 8 month period. The monkeys on the 8.0 ppm dosage demonstrated Irregularities In the menstrual cycle. Six of the eight females tested were capable of conceiving. Of the six animals that conceived, five had abortions or experienced early fetal resorption. The eight females receiving dosages of 2.8 ppm were all capable of conceiving. However, three did not carry to full term and the surviving Infants showed reduced size and dark skin pigmentation (119). Studies by Klhlstrom et al. determined that a decrease In Implantation capability occurred In mice when both the mother and father were nursed from PCB or DOT-treated mothers. When the mothers alone were treated with PCBs, Implantations dropped to 7$% from a control rate of 94%. The control rata dropped to 79% when the mothers were treated with ODT. However when only one parent was nursed from a treated mother, there was no noticeable decrease In the Implantation rate. It seems that the milk on which the mice nursed, contained PCBs and was capable of Increasing standard catabolism. The end result was an alteration of normal sexual development of these mice (124). HONS 027519 23 A similar experiment was carried out by Burke end Fttzhugh with rite. The ret* were fed diets of Arochlors 1242, 1254, end 1260. Concentrations of 1, 10 and 100 ppm were administered. At lower concentrations of 1 and 10 ppm there were no noticeable effects. However, when dosages of 100 ppm of Arschlor 1242 were used, the animals displayed decreased mating indices In the second generation. Oosages using Arochlor 1264 caused the number of pups born to be reduced and also decreased the survival rate of second and third pregnancies (91). An Increased rate of stillbirths was only apparent when the dosages were of Arochlor 1260 (116). A decrease In fetal weight and presence of neoplastic nodules In the liver were apparent (21). Additional experiments with minks were performed with PCP doses of 10 ug/g. At this concentration, the minks display decreased growth and reproduction (14). Studies by Tombergs Indicate that PCBs can affect the reproductive and adrenal hormones of animals by stimulating microsomal enzymes responsible for metabolizing the adrenal hormones (165).VIII. VIII. HUHAN EXPOSURE The lack of sufficient data concerning PCS exposure Is the limiting factor In determining toxicity as well as affects In humans. Rare accidental PCB exposures have become the major source of nearly all of the acute health data. The first of these Is an accident which took place in 1968 when thousands of people were orally exposed to PCBs In Fukuoka, Japan. This exposure was caused by PCB contamination of rice oil which was subsequently used for cooking. The disease described by these symptoms was called Yusho rice oil disease. The second major accident leading to human exposure HONS 027520 24 occurred in 1978 in Taiwan. Not unlike tha Yusho cast, PCBs wtrt ingested by humans through ust of contaminatad rice oil. From thasa two specific Incidents and other lass noted PCS exposure situations, tha affects of PC8s on humans hive baen pieced together. Physiological Effects Gross morphological or pathological affects arc rarely related to PCS exposure In humans. Instead, only minor Impairments result (34). The general symptoms of PCB Ingestion are weakness, nausea, headache, Impotence, insomnia, loss of appetite, loss of weight and abdominal pains. Muscle spasms and muscular pain also may be related to PCB poisoning. Ocularly, PCBs are capable of causing inflanssatton and burning, edema of the eyelids, cysts of the tarsal glands and eonjuctlva (90). The sebaceous gland of the eyelids, the Meibomian gland, may also become hypertrophic and result In cheese-like discharges from the eyes (149), Autopsies of humans exposed to PCBs in the Yusho rice oil poisoning revealed typical chloracne and pigmentation of cutaneous tissue. In addition, follicular hyperkeratosis, dilation of hair follicles, and melanin Increases In the epidermis were observed in histological preparations of skin (89). Other PCB effects on the skin Include xerosis, nail deformity, hair loss, and hyperldlosis. In survivors of the Yusho accident, the acnelform, follicular cysts, pigmentation, and nail change all Improved dramatically or returned to normal within 2-S years (149). It is possible that PCBs stimulate the melanocyte in soon fashion, but the pathogenesis of pigmentation is unclear and any relation with PCB Is merely theory (149). Within the blood, serum triglycerides have been noted to Increase due to PCB Influence. A decrease in serum bilirubin is also noted. Organ system HONS 027521 25 Impairment such as fibrosis, hepatocellular necrosis, enlargement of tha llvar, and riductlon of air capacity In tha lungs has been observed (90). It appears that prolonged exposure to PCBs can cause liver damage. However, the severity of such hepatic damage Is not certain (140). In addition, hypertrophle, hyperplastic gastritis, and ulcer formation have been observed In the gastrointestinal tract (76). A group of women occupationally exposed to PC8s was studied to note effects In pregnancy. The mean birth weight of Infants born to these women was 53 grams lighter than the weight of infants born to women In a control group. The gestation period was reduced by 6.6 days In the exposed women and this decrease in the gestation period may account for the decrease In blrthwelght (145). Neurological Effects The extent of the effects of PCS exposure on the nervous system are, at most, vague. Some studies Indicate that both a 30% decrease In motor and a 50% decrease in sensory nerve conduction velocity occurs In PC8 exposed patients (30). In addition to nerve conduction velocity decreases In the central and peripheral nervous systems, other sensory disturbances may also occur. The senses of taste, hearing, smelling, and sight may be distorted as well (90). Studies Indicate thet there Is no correlation between neurological manifestations and PCB concentration In the blood. That Is, high PCB concentrations In the blood do not always give rise to neurological effects (30). Speculations are that these neurological symptoms are caused by some other chemical substance or that genetic factors may make certain Individuals more susceptible to PCB related neurological dysfunctions. WONS 027522 26 In 1980, i neurological study was performed with 35 of the 2000 people exposed to PCBs In the 1978 accident In Taiwan (30). Neurological symptoms of some type were observed In 31 patients (89%). Thirteen patients (37%) suffered from a dull, non-pulsating headache. Dizziness or 1Ight-headedness was experienced by 12 patients (34%). Nausea and vomiting sometimes accompanied these symptoms, but no vertigo or tlnnltls was observed. 8oth paresthesia and hypoesthesla were experienced, and some patients demonstrated sluggish or absent deep tendon reflexes. Blood testing revealed no correlation between these effects and PCS concentrations in blood. Carcinogenicity It has been determined that large doses of highly chlorinated compounds have the ability to Induce tumor growth In both rats and mice, but the specific role of reasonable levels of PCBs In promotion of tumor growth Is unclear (34). In mice, PCS Induced the development of liver tumors (78) and mice exposed to high levels of PCBs (500 vg/g) for prolonged time spans have displayed hepatocellular carcinomas and nodular hyperplasia (81,111). Although few PCBs have been tested for carcinogenic effects, Arochlor 1254 and 5001 have been determined to produce both benign and malignant tumors In the livers of mice (80). In a study of Kanechlor 500, 7 of 12 mice fed 500 ppm PCBs over a 32 week period developed liver nodules. Five of the mice had hepatocellular carcinomas whereas other organs displayed no trace of metastases or tumors (29). There have been extensive data collected on the carcinogenic effects of PCBs In laboratory animals, but few concerning humans (58). Limited accidental and prolonged occupational exposures are the only,source of such data. Of the thousands of Individuals exposed In the Yusho, Japan Incident of MONS 027523 27 1968, four deaths were examined to determine the absence or presence of PC8 related effects. The four autopsies which were conducted, Included three adults and one stillborn Infant (88). All four Individuals displayed skin lesions that we now know are characteristic of PCB exposure. Additionally, mesenteric fatty tissue and skin contained high levels of PCBs. This again Is to be expected since PCBs tend to bloaccumulate (n adipose tissue (86,87). The stillborn was heavily pigmented, being In a state referred to as "Brown Baby". This pigmentation Indicated transported passage of PCBs to the developing fetus (86). Only one of the four autopsies revealed any hepatic damage. This victim, a 48 year old Japanese woman, was diagnosed as having liver cirrhosis with multilobular cirrhotic changes being accompanied by many hepatic-cell carcinoma nodules (88). Although the dermatitis of these four Individuals has been associated with PCB exposure, the stillbirth and liver damage Is not conclusive enough to establish a causal relationship between PCB exposure and these given effects. Furthermore, reevaluation of mixtures of the contaminated rice oil from Yusho Indicate that other compounds, such as hazardous polychlorinated dlbenzofurans (PCOFi) (62) and polychlorinated quaterphenyls (PCQs) were present In the PCB mixture (120). The major PCB-related effects In humans are subtle even when the PCBs are present In large concentrations. Although, acute exposure Is rare for humans and wild life (34), an exception to this Is the direct and cumulative occupational exposure to PCBs. Some workers In capacitor plants have been exposed for decades to PCBs (27). Lower levels of PCBs may be linked to minor transient effects such as headaches, abnormal fatigue, and possible Joint soreness. Higher levels may result In dermatological effects such as hyperpigmentation and chloracne (146,147). HONS 027524 29 On* occupational exposure study usid 14 capacitor plant workers who w*r breathing 0.1 mg/m* of PCBs. S*v*n of th* 14 workers acquired chloracn* which disappeared aftar txposur* to PC8s was dlscontlnutd. Of th*s* 7, 6 poss*ssd normal 11v*r function. Th* remaining Individual with chloracn*, had only borderline 11v*r abnormal1t1*s. Within 13 months aft*r Urmlnatlon of xposur*, 11v*r function r*turn*d to normal. Although chloracn* appars to b rtlatid to PCS txposur*, th* data suggast that It Is unllktly that th* Hvtr probltms war* caustd by PCBs. Lack of controls and only a slngl* iiv*r abnormality mak* Its occurrence not significant (106). Th* South Carolina Department of Health conducted a study with 32 capacitor plant worktrs (138). Tan of th*s* individuals war* rtgularly xpos*d to PCBs. Th* findings r*v*al*d that th*r* was "no tvldanc* of physical harm resulting from working with PCBs* (S9). Th* carclnogtnlclty of PC8s was tstad In thr** additional *p1d*m1olog1cal /**' studlts. Th* first on* used 92 refinery worktrs. Of th*s* 92 p*opl, thrtt had mlanomat. How*v*r, this* employees may hav* b**n exposed pravtously and slmultanaously to other known carcinogens (6,7). Th* second study covered a tlm* span from 1946 to 1965. In this study, 89 Monsanto workers with at least 6 months txposur* war* monitored. Neither llvar cirrhosis nor liver dysfunction was nottd In any of th* *mp1oyt*s. four rtsplratory cancer cases occurred, but w*r* not statistically significant from controls. Furthermore, there were additional exposures to known carcinogens, particularly through cigarette smoking (160). The last study used 2,587 capacitor plant employees In whom there appears to b* an Increased rat* of death due to liver eancar (18). However, th* Incidence of cancer was 'Inversely related to duration and latency of HONS 027525 29 txposurt" ($9), which dots not suggest occupational txposurt to PC8s as tht causatlvt mtchanlsm. Additionally, thtra was an Incrtastd rata of rtctal canctr. Tht plant was, howtvtr, locatad In an arta whtrt thtrt Is a higher than avtragt rtctal canctr mortality ratt for all Inhabitants (103). From thtst occupational studlas, high ltvtls of txposurt to PCBs hava damonstratad tht ability to caust dtrmatltls, but othtr clinical afftcts, Including canctr, havt not bttn obstrvtd. Studlts of Individuals who wart tnvlronmtntally txpostd to PCBs, not occupationally, damonstratad no clinical afftcts, including dtrmatltls (63,59). Tht small samplt sitt and simultantous txposurt to additional toxic compounds makts tht canctr avaluation in thtst studlts difficult. Thtst studlts dtmonstratt an txcassivt mortality ratt pattam that is Inconsistent with tht probablt carcinoganic afftcts of PCBs (SB,$9). IX. CASE STUOIES Of ACCIDENTAL EXPOSURES Tht bast insight into tht afftcts of PCB txposurt has coma from cast studlts of accidtntal and occupational txposurts. In 1983 In Slmcot County, Ontario, a material dripping from a fluortsctnt light fixture in a school room was found to contain 200,000 ppm of PCBs (20% PCB by weight) which was latar identified as Arochlor 1254. Tht ballast of tht light had originally contained 1 1/2 ouncts of PCBs and 1/3 of an ounct was lost in tht Itak. Among all the students and teachers txpostd to thtst PCBs, thara wart no nottd symptoms txctpt several headaches which ware attributed to the pungent odor that was prtstnt. Tht Yusho txposurt of 19(8 was caused by a Itak In a htat-txehangtr used In rict oil manufacturing. Kanachlor 400 was tha PC8 prtstnt and tha contam ination ltvtl was dtttrmlnad to be bttwttn 1500 to 2000 ppm of PCBs. Of 12 HONS 027526 30 Yusho patients studied, 10 subsequently died. Four of these patients (ages 13, 25, 4$, and 73) died from heart failure. It was never determined If my of these four victims had a family history of heart disease. Three other patients died from respiratory failure. Rupture of liver carcinomas resulted In the deaths of two patients and a tenth patient died as a result of aspiration pneumonia. Analytical methods for the determination of PCBs were not developed until 5 years after the Yusho Incident. In 1973, gas chromatography was used to determine PC8 concentration In whole blood. By this time, the Yusho patients had a mean PCB level In blood of only 7 ppb (120). Later testing verified that the rice oil was also contaminated with PCOFs (52). Almost all Yusho patients displayed PCQ blood levels greater than 0.02 ppb (120). Elevated concentrations of PCQs and PCOFs In the rice oil Indicated that the oil was heated first (28). Recent data concerning the Yusho Incident seem to Indicate that adverse health effects originally blamed on PC8s were really due to exposure to these toxic contaminants of the PCB mixture (37). The source of PCB In the 1978 Taiwan Incident has not been determined. However, Just as In the Yusho case there was more than one chemical In the contaminated rice oil. In addition to a PCB concentration of S3 to 99 ppm In rice oil samples, there were also PCOFs and PCQs present In concentrations of 0.18 to 0.40 ppm and 2S to S3 ppm, respectively. One of the most hazardous PCBs, 3,4,3',4'-tetra-ch1orob1phenyl, was present In rice oil samples as well as adipose tissue of patients. Furthermore, a highly toxic PCOF.2,3,4,7,8* pentachlorodlbenzofuran, was also present In the oil sample and In liver tissue of a patient who had died (28). HONS 027527 31 Most extended exposures to PCBs have been associated with Industrial accidents with workers who manufactured PCS-contalnlng goods. In 1975, approximately 12,000 people were occupationally exposed to PCBs. The majority of these exposures occurred In the production of capacitors (152). In Industry, most of these exposures were dermal, not oral, so the common effect was chloracne. There are reports of several deaths Involving dermal exposure to very high concentrations of PCBs, but evidence suggests the presence of chlorinated naphthalenes In these substances (32). The General Electric Corporation conducted studies on almost 200 workers at their capacitor plant In Hudson Falls, New York. These workers had direct contact with PCB mixtures and vapors for several decades. The results of these studies revealed that no confirmed cases of chloracne or other PCB-related effects were present In workers exposed to ordinary, unpyrolyzed American-made PCBs (27). Another study Involving occupational exposures divided exposed workers Into two main groups. The first group Included silk workers from Kyoto exposed to PCBs by the oil used on the machines. Levels of SO ppb were found In some members of this group but no clinical symptoms were displayed as In the Yusho case. The PCBs present were Identified as Kanechlor 500. Furthermore, PCQ levels were lower than 0.02 ppb In blood. The second group In the study Included paint manufacturers who were exposed to paints containing PCBs. As In the first group, concentrations were found to be higher than In the Yusho patients, but no ellnelal symptoms were observed. The PCB present In these workers was Identified as Kanechlor 600. Again, PCQ concentrations In blood were less than 0.02 ppb (144). MONS 027528 32 X. REGULATION OF PCBs I it. 1978. th* manufacturing process and us* of PCBs In th* United States were banned by th* U.S. EPA In spite of dear evidence Indicating that long term exposure to PCBs by numerous electrical equipment workers was not a serious adverse health problem (102). Th* stringent regulations placed upon PCB us* were based upon th* assumption that any level of exposure to PCBs Is hazardous. Th* ban regulations which were Instituted In 1976 were based upon only on* human exposure Incident (9) out of approximately 2500 scientific articles published prior to that date. However, recent research shows that, In fact, lower-level exposures to PCBs are not hazardous to man (37). In th* 5 years following th* Issue of these ban regulations, over 5000 additional scientific publications detailing PC8 toxicity have been published Indicating that PCBs have not been shown to be significantly hazardous to man (139). It seems apparent that all scientific resources and studies were not used In establishing regulatory bans on PCBs. The last several years hay* provided many additional human exposure cases which need to be considered In updating th* alleged toxicity of PCBs (37). A committee established by th* National Research Council of th* National Academy of Sciences to reevaluate PCBs In 1979 concluded: 'An analysis of PC8 data compiled following th* criteria of FIFRA and TSCA proposed guidelines, leads to th* conclusion that PCBs are persistant, and are likely to accumulate. PCBs do not appear particularly toxic for short-term exposure, but results are subject to Interpretation.* (37). A revaluation of PCB toxicity, especially In humans, revealed that human health Is generally not seriously Jeopardized by PCB exposure. PCBs do not appear to be carcinogenic In humans, and there Is no proof that leads us to believe that PCBs are mutagenic, teratogenic, Indicative of birth defects, or MONS 027529 33 deterlmental to human reproduction. Only dermatitis and chloracne have been conclusively proven to be caused by PCS exposure. Both of these adverse effects are completely reversible and disappear If PC8 exposure (s terminated. Oata compiled In the last decade have Introduced additional human exposure cases upon which to base these conclusions (37). [n Hay of 1982, the U.S. EPA sponsored a symposium on the effects of PCBs. It was concluded that PCBs themselves do not promote unreasonable risks to the environment or human health. XI. ELIMINATION OF PCBs FROM THE ENVIRONHENT There are several means by which PCBs can be eliminated from the environ ment. Hydrolysis can be usad under extreme conditions although PCBs are usually Inert to this reaction (71,118). Chemical degradation Is another method that can be used to eliminate PCBs (17). The stability of PCBs Is so great that environmental conditions are not likely to promote chemical reactions with them. However, under controlled conditions, oxidation, reduction, nitration, Isomerization, and nucleophilic reactions can occur with PCBs (71). For example, PCBs have recently been shown to be degraded to polyphenylene and sodium chloride by treatment with metallic sodium (140). Photodegradation Is another method for destruction of PCBs. Dechlorina tion of PCBs as well as the production of polymerized materials occurs In hexane when exposed to Irradiation In sunlight (100). Chlorine can be re placed by hydrogen or hydroxyl groups, a condensation or rearrangement may occur, or even the production of polar products can result from such a reaction. Specifically, Arochlor 12S4 can be degraded to hydroxylated and carboxylated species by irradiating It In the presence of hydroxyl 1c solvent it pH 9 (100). HONS 027530 34 Very little photodegradation of PC8s occurs naturally because they are usually sub-terrestrlally stored and not readily accessible to sunlight. Another natural process that can eliminate PCBs from the environment Is biodegradation. A recent report Indicates that natural soil processes will degrade PCBs (19). In this process, both position and degree of chlorination of PCBs play crucial roles In determining whether or not microbial degradation will occur. Bacteria can transform biphenyls of lower chlorination, but encounter difficulty with more highly chlorinated biphenyls (122). Many PCBs are oxidized to their corresponding chlorobenzolc acids, but other mixtures of dihydroxy compounds, meta-cleavage compounds and other unknown products are possible based upon the degree of chlorine substitution (SO). Conversion of PCBs to chlorobenzolc acids Is the main process of biodegradation (figure 4). Figure 4 Most Probable Reaction In Biodegradation of PCBs Meta-cleavage Compounds Chlorobenzolc acid MONS 027531 35 Not only do Aclnetobacter bacteria follow this pathway, but so do other genera of bacteria such as Aletlllgtnts, Arthrobtettr, Aehromabtetir, Noctrdit, and Psiudomonts (58). All pathways and products must be considered in biodegra dation because It Is possible that metabolites generated during this process are even more toxic than are the PCBs (58). The final method for the destruction of PC8s, as previously mentioned, Is Incineration. As PCBs are Incinerated, hexachlorobenzene Is formed. 8oth PCBs and hexachlorobenzene can be destroyed thermally at a temperature of 950C with a residue of 100 mg of hexachlorobenzene per kg remaining (101). Heating may cause PCBs to form different polymeric compounds Incorporating oxygen (161). Heating PCBs to 500-600C will cause formation of degradatlve products such as chlorinated dlbenzofurans (22). Despite these methods for eliminating them, PCBs remain a persistent problem 111 the environment. Of the 570x10 kg of PCBs produced In the U.S. since 1930, more than half (60%) are still In service and Twelve percent Is mobile In the environment. Twenty-eight percent of these PCBs have been eliminated, 5% by Incineration or chemical degradation and 23% by being placed In landfills (34). XII. PERMISSIBLE HUMAN EXPOSURE It Is difficult to assertaln the quantity of PCBs, If any, that would be a permissible exposure limit for humans. Generally, the concentration of 200 ug/kg of body weight per day has been determined to be the mlntmum oral Intake of PCBs shown to produce toxicity In humans (101). Signs and symptoms of toxicity occur In humans after an oral intake of 0.5 g (114). HONS 02 7532 35 This quantity represents a fairly large dosage and would Indicate that thara has batn an over-reaction to tha percalved toxicity of PCBs. The affects of PCBs on human health still have not been conclusively determined. Problems arise concerning this determination because accidental exposures to PC8s cannot be clearly Identified as pure PCB exposures or as exposures to mixtures of several hydrocarbons. Additionally, Interactions between chemicals can occur within the body following Ingestion of food, breathing air contaminants, as wall as simultaneous or later exposures to other chemicals. Such Interactions can produce additive effects making the study of PCB effects very difficult. HONS 027533 37 XIII. BIBLIOGRAPHY 1. Ackerman, O.G., ScInto.L.L., Bakshl, P.S..Oelumyea, R.G., Johnson, R.J., Richard, G., Takata.A.M. and Swortym, E.M.: Dastruetlon and Disposal of PCBs by Thermal and Non-Tharmal Methods, Noyes Data Corp., Park Ridge, NJ 2. Ahmed, M. and D.O. Focht: Degradation of polychlorinated biphenyls by two species of Aehronobtcttr. Can. 0. Microbiol. 19:47-52, 1973. 3. Ambrose, A.M.: Pharmacological Observation of Chloracne. American Society for Pharmacology and Experimental Therapeutics (43rd Annual Meeting). Fed. Proc. 12:298, 1953. 4. Anderson, M. and Mathews, H.B.: PCS chlorination versus PCS distribution and excretion. Presentation at the U.S. Environmental Protection Agency Sponsored National Conference on Polychlorinated Biphenyls. Chicago, Illinois, Nov. 19-21, 1975. 5. Aulerlch, R.J. and R.K. Ringer; Current status of PCB toxicity to mink, and effect on their reproduction. Arch. Environ. Contain. Toxicol. 6:279-29Z, 1977. 6. Bahn, A.K., Rosenwalke, I., Herman, N., Grover, P., Stallman, J. and O'Leary, K.: Melanoma after exposure to PCBs. N. Engl. D. Med. 295:450, 1976. 7. Bahn, A.K., Grover, P., Rosenwalke, I., O'Leary, K. and Stallman, J.: PCB? and Melanoma. N. Engl. J. Med. 296:108, 1977. 8. Baiba, H.M. and Saha, J.G.: Studies on distribution, excretion, and metabolism of Alpha-Isomers and Gasmw-lsomers of [C-14] chlordane In rabbits. Environ. Scl. Health 13(3):211-233, 1978. 9. Barsottl, O.A., Marlar, R.J. and Allen, J.R.: Reproductive dysfunction in rhesus monkeys exposed to low levels of polychlorinated biphenyls (Arochlor 1248). Food Cosmet. Toxicol. 14:99-103, 1976. 10. 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Bovard, K.P., Fontenot, J.P. and Prlode, 8.W.: Accumulation and dissipation of heptachlor residues In fattening steers. J. Anlm. Scl. 33(1):127, 1971. 16. Brooks, G.T.: The metabolism of Dlene-organochlorlne (Cyclodlene) Insecticides. Residue Rev. 27:81, 1969. 17. Brooks, R.E.: Chemical and biological destruction of PCBs. Presentation it the Summer National AIChE Meeting, Cleveland, Ohio, August, 1982. 18. Brown, O.P. and Jones, M.: Mortality and Industrial Hygiene Study of Workers Exposed to Polychlorinated Biphenyls. Arch. Environ. Health. 36:120-129, 1981. 19. 8rown, J.F., R.E. Wagner, 0.1. Dedard.M.J. Brennan, J.C. Camaban, R.J. May and T.J. Tofflemlre: PCB dechlorination In upper Hudson sediments. Proceedings of the American Chemclal Society, Miami Beach, Ft, April 24, 1986, ENVR-0012 (1986). 20. Buck, W.B., Osweller, D.G. and Van Colder, C.A.: Clinictl tnd Oitgnostic Votorlnory Toxicology. Iowa State University, Ames, Iowa. Farm Chen., 138(13):36, 1975; Rep. 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