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.rf ^Jyju. Ffcil. v. A. A .. Givkard, T. 1982. sd hoipmliuooo: * Dntf ftunuceo&cal in- -c omg comoeaoca o f me Drug Pnce u m Terra R esun* arm. Mai. 1:177- v. P .D .. Brawn, T. taosran law cob* 7Aim . Imrm. M ai. . Mai. U tt. 21:1-2 A M . Mrr Pkam m ni. Taueoi. 1997. 2Z.S7~ i i i t HUMAN HEALTH EFFECTS OF . POLYCHLORINATED BIPHENYLS (PCBs) AND POLYBROMINATED BIPHENYLS (PBBs) 1 | Renaxe D. Kimbrough Center for Environmental Health. Centers for Disease Control. Public Health Service. US Department of Health and Human Services. Atlanta. Georgia 30333 INTRODUCTION ! Polychlorinated biphenyls (PCBs) are chemical compounds with the empirical formula C u Hk^ G , . with n = 1--10. They are a mixture of chlorinated biphenyl congeners. Theoretically. 209 such congeners are possible, but at least 20 congeners have never been identified in commercial products. In addition. PCBs may contain polychlorinated dibenzofurans and chlorinated j quaterphenyls as impurities. PCBs were discovered before the turn of the century, and the useful industrial properties of mixtures obtained by chlorina- | don of biphenyl were recognized early. In 1966 the discovery of PCBs in environmental samples (1) spurred renewed interest in the analysis and toxic ity of these compounds. In recent years many industrial nations have taken steps to control the flow of PCBs into the environment. PCBs and PCB-containing formulations are ' restricted (an exception is sometimes made for mono- and dichloro-PCB) for most uses, except for categories such as closed-system electrical equipment and hydraulic fluids in mining equipment. j Commercial production of PCBs began in thexUoized--Smcs in the late 1920s. In 1971. Monsanto Chemical Company voluntarily stopped open- ended uses of PCBs, and subsequently only the lower chlorinated biphenyls The US Government his the right to retain a nonexclusive, royalry-frce license in snd to any copyright covering this piper. S7 88 KIMHROUCII were produced (Arnclor 1242 and 1016). In 1977 ilic company ceased produc- linn cnliiely (2). Many RCUs manufactured in llic past (3) arc still in use in ulil transformers. (nil even this use is decreasing, 'lire estimated cumulative priMliicliutt and cunsuiiipliun of |*CHs in tlic United Slates in lire period 19)0-1975 (in millions of pounds) was as follows: total production, 140(1; imports, 3; domestic sales, 1253; exports, 150. ITUs arc inert chemicals that are fairly resistant to degradation. Ilccausc of their stability and lipopliilicily, they have accumulated in the environment and in organisms. They have l>een identified in indoor air (4) at concentrations of II. I /ig/m 1(5), in fish (6, 7) and other food products, and in sediments from I lakes and rivers (8, 9). TCIIs have also been identified at varying con centrations in soil (0 (II mg/kg-tOU hig/kg) (10). 'Ihey do not occur naturally. Thus, (heir presence in the environment is linked with human activities, and 4 I concentrations arc higher in urban and heavily industrialized areas Ilian In rural and remote areas. However, trace amounts are also found in remote areas, since the air may Iranspoil such chemicals over large distances. Although ITUs aie rut longer used commercially In the United States because of their persistence? they arc still present in our environment. A I number of traitsrunners and capacitors that contain ITUs. however, arc still | in use. Results of lalwralury experiment* showed that pyrolysis of ITUs at temperatures of 2(X)-60(rC could result in the fnnnalion of significant I amounts of the more toxic polychlorinated dibenzofurans (PCUFs) (II). I In February 1981. an electrical Hie occurred in a New York Stale office t building in tlinghamlun. N.Y. 'lire fire, which originated in a switch gear in JI the basement. caused the bushings !o crack on a nearby transformer. About IRO gallons of ITU dielectric fluid Fyralon (65% Aruclur 1254, 35% chlorin ated benzenes and trace additives) were Inst. A fine layer of oily soot covered many of lire internal surfaces of the 18 floors of the building. Analysis of a soot sample showed that it contained various isomers of chlorinated di- henzufurans, 2,3,7,R-lclraclilorodibenzodioxin, oilier chlorinated di- benzodioxins, and chlorinated bipltcnylcnes. Some of these chemicals are much mure toxic than the Pt'lls. Because of these findings the Dinghamtun stale office building was closed, and workers wearing respirators and pro tective clothing began an extensive cleanup of the building. The cleanup operations lasted four years, and the cost has been enormous (12). Since (lien several other transformer fires have occurred. These fires have not resulted in as much contamination as the one in Dinghamlon, partly because the transformers in the other fires were usually located in a separate vault (13). The problems with polybrommated biphenyls (PUUs), which are also a mixluie of clrcmicals, have been quite different. In 1970 a chemical company in Michigan manufactured polybruminated biphenyls as flame retardants. The same company also produced magnesium oxide, a cltctnical commonly mixed HUMAN Jll-ALTII liM JiCIS OP 1`CUs A PUIls 69 Into icctl inf livestock. The flame retardant was called Piremaster and the magnesium oxide. Null master. In 1973 some hags of Piremaster were accidentally sold as Nulrimaslcr and mixed into animal feed. Thai resulted in widespread contamination in the state-of'Michigan (M). Since 1974 PHUs have not Iteen produced in the United Stales. At the lime of the exposure little was known alroul the toxic effects of Hills. Ten years after the Michigan residents were exposed, no clinical illness has Itccn causally linked to PUD exposure in this group, although cliluracne was apparently noted in some workers who manufactured PIID. HUMAN EXPOSURE Because PCIls are ubiquitous and very persistent in the environment, humans have liecu and will continue to he exposed to them, particularly in in dustrialized countries. PCUs may be inhaled in small amounts through the air or ingested through food. In the United Stales lt>day, people are primarily exposed to PCUs by consuming fish front contaminated waters 19). In the past, some farm families were exposed to PCUs from dairy products; these l*Clls originated from coaling material used in the inside of silos (15). In addition, workers who repair transformers and workers who handle toxic wastes tuny also be exposed (16). The PCU products that were manufactured by Monsanto in the United Stales bad the trade name "Aroclor." Hie particular kind of Aroclur is identified by a four-digit number. Hie firsf two digits refer to the 12 carbon alums, and the second two refer to the percent, by weight, of chlorine in the mixture. Thus, Aroclur 1254 contains about 54% chlorine, and Aroclur 1260, about 60% cltlorinc. The composition of lids mixture uf chemicals, with different properties, changes once it gels into the environment and into organisms. Some com ponents nf the mixture arc more easily degraded in the environment than others. As a result the PCUs Identified in the environment resemble Aroclor 1254 but are not identical to 1. Similarly, the PCU mixtures found in humans usually resemble Aroclor 1254 if exposure occurred primarily through the environment. A different composition of the PCUs may he found in serum or adi|Kise tissue samples from occupationally excised workers. I:ur instance, if the workers arc primarily exposed to Aroclor 1016 or Aroclor 1242, which contain much less rtf the more highly chlorinated Itomologs, then their gas-cliromalogiaphic patterns resemble a combination of Aroclor 1016 or 1242 and Aroclor 1254. Pur this reason Smith cl al (17), in evaluating occupational exposure, divided l*CUs into high and low chlorinated biphenyls. The gas-chromalugraphic patient of the rCII mixture present in humans can be used to determine whether the exposure occuired primarily ______ _____ _______ _____ 90 KIMI1ROUUI1 tluougli occupation nr lluough llic environment, or, in the case of occupation al situations, whether most ol the exposure was recent or occuued many years ago. Although 9.1% of the US population eats fish, the average annual per capita consumption is small: 15 lbs. per year (6, 7). If PCD* are to he quantitated in fish, tire edible portion rather than the whole fish must be examined. Uecausc of their lipophilicily, PCOs arc preferentially stored in the hepalopancreas nf lire fish, giving erroneously high levels if lire whole fish is analyzed. Sim ilarly, levels in cooked fish arc lower (6). Generally. PIlBs are nol found In the environment because they have had less commercial use than PCUs. POD contamination Is essentially restricted to Michigan's lower peninsula. Most persons who lived In Michigan during the 1973-1974 (Krriod have low-level POO body burdens (IB). Hie greatest degree of cuntamination' occurred mainly in areas with contaminated farms; litis segment of the population still has appreciable body burdens (19). Since PUUs and PCUs are lipophilic, they are preferentially stored In adipose tissue. They ere also present, to a smaller extent, hi serum and other organs and in human milk. Hie concentration of these materials in different organs depends upon the lipid content of such organs, with the exception of the brain where lire concentration is lower than the lipid content would indicate. PCBs and PDUs pass (lie placenta and arc primarily excreted through bile and milk. In addition to lipid content, the ratios between adipose tissue, blood, and vital organs are Influenced by exposure level, sex, age, length of exposure, and also by whether exposure is current. At very low con centrations an analytical imprecision influences the ratios much more than at higlter concentrations (19). Since human milk is relatively easy to obtain, it has been used to monitor human exposure. Jensen (20) recently summarized results of such monitoring studied Average levels of PCUs below 2 ppm (mg/kg) in milk fat have normally been found, although women living In heavily Industrialized urban areas may have higher levels. The fit concentra tion in human milk averages 2.6-4.3% (21). At 2% fat, I liter (I) or milk would contain 0.04 mg or 40 fig if the PCUs were present in milk fat at a concentration of I ppm. If an infant weighed 3 kg and Imbibed 730 ml of milk per day. It would lake in about 6 fig/kg, a dose that exceeds the 1.3 fig/kg dose calculated as acceptable by Curdle cl at (6). At 1% milk fat this dose would be reduced to 3 fig/kg. As the Infant gains weight, the dose on a kilogram body weight basis will be reduced to some exieiil, however; milk is the sole food source for only about six months. After the first week, the daily milk intake Is estimated to be 130 ml/kg body weight per day. Ibis consump tion gradually falls after two months and declines to 120 nd/kg body wciglil at four-to-six months. Finally, the amount of PCOs and other halogcnalcd organic chemicals declines with lime. However, at low cuncenlraliuns this .C . HUMAN HUAI. III I I I liClS OI: K'Us & I'Ulb 91 m:iy mil lie obvious because of continued cx|k>siiic of die mother and the variability of (lie analytical results. In addilion lu PCUs, human milk contains trace anmunis of many oilier persistent chemicals. Whether the infant's consumption of such chemicals has any adverse health effects is not known. Most persons, particularly in industrialized countries, have had some expo sure Iti |x>lychlorina(cd biphenyls even if they do not cal fish. Tire con centrations at which such exposure presents a risk are not dear. Recently, Curdle cl al (6, 71calculated the dose of PCUs to people consuming fish from Lake Michigan. They concluded that persons eating Lake Michigan fish ingested an average of 46.3 mg of PCUs per year; this amount ranged from 14.17 to 114.31 ing/ycar/penon. The calculated mean daily dose received by lire exposed group was 1.7 fig/kg/day and ranged front 0.09 to 3.94 pg/kg/ day. Thus, the average sports fisherman consuming contaminated fish would receive a total I*CI1 dose equal to 200 mg in about 4.3 years. No advene health effects or groups uf symptoms dearly related to PCH exposure could be identified in this exposed group. lire presence of PCUs in the exposed penons has not caused any observable adverse health effects similar to those observed in the Yuslio population (see below). However, this finding does not exclude the possibility that the effects tie too subtle for detection or that they require long-ICTiii observation. Similarly, in Michigan an analysis of 1,073 human milk samples showed that all cunlaincd PCI) residues and that the residues ranged from trace amounts lu 5 ppm fmg/kg) based on lat level. The public health significance uf PCI) residues in human breast milk and their effects on brcasl-fed infants ate unclear. Since there are no human data on which to base public health policy, risk predictions for PCUs have been based on results from animal studies, pailicularly Ihc positive bioassay studies. Reviewing these data. Curdle el al (6, 7) concluded that a 2-ppm (mg/kg) tolerance for PCD in fish be established, since a I-ppm (mg/kg) tolerance docs not greatly reduce lire estimated risk. As previously menltnncd, some of the isomers of the PCUs and PUDs arc much more easily degraded or metabolized, because they can be metabolized, they are more easily eacrelcd. Others may be retained in the body for tong periods; in general, the PUUs appear to be more persistent in human tissues Ilian (lie 1`Clls (19, 22). POLYCHLORINATED DIPHENYLS Dticigrom uf When PCU.s were first used industrially some workers developed chloricne. Results of early animal studies seemed to suggest that PCUs might have some toxic effects on the liver. Pcyuiid that observa,fon no information was avail- J T* V MHurww^miffwpnwjjjxr wm w t ppawn f t w s r . s 92 KIMUHOIKII able. Because PCBs were so inert chemically, iliey were nut considered fo cause a gteal deal o toxicity. In I96B a poisoning oullircak occurred in Japan (2J) dial affected over 1.000 persons. These individuals had purchased rice oil. in large drums, from a single source and had used litis rice oil for cooking. Cliloiaciic was one of die leading signs in litse who liccaiiie ill. It was soon discovered that PCBs had been used as a heat-exchange fluid in die factory where the rice oil originated. I*CUs had leaked out of die columns in which they were contained into tire rice oil when the rice oil was heated. Since Ihc disease was caused by ingesting contaminated rice oil, it was called Yusho (rice-oil disease). When the outbreak first occurred, its association with exposure lo PCBs was no) clear. Al that lime the capabilities fur measuring these lypes of clremicals in tissues and body fluids were limited, particularly in Japan. Therefore, early in the investigation lolal chlorine, rather than l*CHs, was measured. Retrospectively determining the piecise dose these patients received is dillicult. Whether the consumed oil was uniformly con taminated is also not clear. However, a relationship between the amount of rice oil ingested and some symptoms could be established (24). Because or this poisoning outbreak and oilier environmental problems, animal sludies were started in Japan, in the United Stales, and In other countries to elucidate the toxic cl (eels of PCBs. lliesc data are summarized in several detailed reviews (16, 25, 26). Animal Studies Tliis article addresses primarily the human health effects of PCBs and PUUs. Therefore we highlight only recent results from animal studies that might give belter understanding of implemented public health policies and potential human health effects. One of the difficulties in using animal data lo predict human health effects for PCBs and related compounds is that animal species vary greatly in their responses. Further, many of the animal sludies use relatively high doses. Ilicrcfore. determining how suclt animal sludies relate to the human situation is difficult. Some animal specks, such as the subhu man primates, the guinea pig, and the mink, are much more sensitive ip the toxic effects of PCBs than Ihc rat or the mouse; also the ty|>cs of toxic effects and morphological changes in the organs of different species vary. Most animal sludies conducted during the 1970s used mixtures of PCBs. In general, PCBs were found to affect icpioductiRn'and the immune response, and lo cause liver tumors in rodents (16). When different mixtures of PCBs were studied, however, the results were inconsistent. For instance, lire mix ture Aroclor 1254 alfccis reproduction in rats al much lower doses than does Aroclor 1260 (27). More recently some of the isomers of the l*CB mixture were found lo be much more toxic Ilian others (28-32). The more toxic isomers constitute only HUMAN III1AI.1H LITliC IS OF PCDi & PDUs 93 a very small portion of (lie mixture, particularly those with less chlorine by weight, sutli as Aroclor 1242 or Aroclur 1016. Rcccnlly, Schaeffer el al (33) found dial a German f*CU mixture--Cloplicn A-JO, with in average composi tion (if 1% monochloiobiphenyl, 20.7% drchlurohiphcnyl, 57.4% trichlornbiplienyl, 17.3% lelrachlurobipheiiyl, 1.8% pciuachlorobiplienyl, 1.0% hexachlurobiphenyl, 0.6% heptachlotobiphenyl, and 0.1% ociichlorobiphcnyl--produced a 3% Incidence of hepatocellular carcinoma, whereas Cloplicn A-60 produced 61% incidence of hepatocellular carcinoma in Wistar rats, Hie incidence of the disease in the controls was 2%. The Cloplicn A-60 had an average composition of 0.2% monochlorobiphenyl, 1.1% dichlorobiphenyl, 2.2% trichlorubiphcnyl, 3.1% lelrachlorubiplienyl. 19.8% pcnlachlofbiphenyl, 43.2% hcxachlorobiphcnyl, 25.3% heptaclilorbiphenyl, 4.7% octachlorobiplienyl, and 0.3% nonachlorobiphenyl. Sim ilarly, Nuiback A Wellman (34) and Kimbrough el al (35) were able to produce hepatocellular carcinomas in rats with Aroclur 1260, the more highly chlorinated Monsanto product. When Aroclur 1254 was fed to rats, fewer liver tumors developed in exposed rati (36); however, the incidence of gastric intestinal metaplasia and adenocarcinoma of the stomach increased (37, 38). Whether PCD fraction without hcxaclilorobiphenyls, heplachlorobiplienyls, and oclichlorobiphenyls produce hepatocellular carcinomas in rodents should be explored. Particularly in the United Stales, mixtures such as Aroclur 1242,1254, and 1016 were used more than Aroclur 1260. Because of these differences in potency, the PCOs in heavily conlamirialcd areas of our environment should be characterized according to their isomeric composition. For instance, whether lire PCIIs in Lake Michigan are of the same composition as those found in New Bedford Harbor, Massachusetts, is not clear. Aside from tumor formation, PCOs cause a variety of oilier biological effects, such as the induction of enzymes (39). In some species they may cause atrophy of the thymus, Inlrahcpitic bile duct hyperplasia, hyperplasia of the epithelial lining of the urinary bladder, atrophy of the sebaceous glands, and liypcikeratosis of the ducts (40). Some Isomer* arc fetotoxic, and some produce metaplasia of the sebaceous glands, nailbeds, aineloblasls. thymus coqiuscles, and gastric mucosa (28, 4 1). Subhuman primates, mink, and guinea pigs are particularly sensitive to the toxic effects of PCHs; other species, such as the rat, (he mouse, and the dog, can tolerate much higher doses. From empirical.observations, humans also appear to be less sensitive to the'toxic effects of PCBs. The ability to stoic these chemicals In adipose tissue may he protective. Generally, the subhuman primates and mink have less adipose tissue Ilian humans. Animals with greater ability to store vitamin A on a quantitative basis, such as the hamster and the rat, arc somewhat less susceptible to the toxic effects of these types of compounds (42). Hie 94 KIM U KO U lill mechanism by which iticse types of chemicals affect hepatic retinoids is not clear. Apparently, lite duration uf the reduction of hepatic iclitiuids docs not correlate with the induced aryl hydrocarbon hydroxylase (Alfil) activity (43). Body Burdens Many investigators have reported rCOs In human tissues (44, 45). In the United Stales, according to data from the Centers for Disease Control (CDC), mean I t 'l l serum levels arc aboul 5-7 ng/inl (pbb), although some patients may have higher scrum levels without any documented unusual exposure. These data were also summarized by Krciss (46). Levels in adipose tissue and in human milk fat arc 11X3-200 times as high, since It'D s arc highly lipid soluble (20). Mes et al (47) reported Ilia! PCI! levels in adipose tissue of accident victims ranged from 0.9-9.4 mg/kg. Said cl al (4R) surveyed PCD blood levels in 738 pre-employed and 1,058 currently employed woikcrs of a utility company. The median blood level before employment was 4 mg/l and the range, 1-37 mg/l. These levels were quite similar to those in the currently employed group. Patients wlm died of cancer In Denmark had somewhat higher levels of PCDs in their adipolc tissue (49). Since terminal cancer patients have usually lost a great deal of weight, bioconcentralion inay have occurred. Similarly, in patients with highly impaired liver function, tissue concentrations of xcnoblotics may be slightly higher Mtan tirse in healthy persons. However, levels remained higher if parameters such as weight, height, occupation, and resi dence were considered (50). wirereas levels of PCDs in breast fat tissue from patients with breast cancer were similar to tirase of controls (51). Furthermore, Lawton el al (52) demonstrated Ural random errors and inlcrlaboralory variations in procedure and methods of data reporting can Influence serum and adipose PCD levels. Unless an inlcrlaboralory qualitycontrol system is set up, measured levels between laboratories are not neces sarily comparable. For Instance, l,awlon el al (52) found that the results of repealed analyses on serum samples of known composition showed the 95% prediction interval for an individual measurement to be aboul 42%. This interval depends on the method of extraction, the procedure used, and the means of quantitation. Summary o f Human Epidemiology Studies Recently, investigators studied the predominantly black population of Triana, a mall rural town in the southern United Stales (53). This population was excessively exposed to DDT residues by consuming contaminated fish. The residents also had PCD body burdens. Fish consumption correlated positively with PCD blood levels; no other source o PCD cx|rasurc could be established. These researchers noted Ihal PCD scrum levels Increased with age and that HUMAN II1IA I.Ill lim -C IS OF PCDs & PUIIs levels were lower in females of each age group. Similar findings were m. for 1)1)1' residues. Hie sennit cholesterol level was positively associated w the log rCII level, independent of" age, sex, fish consumption, body-in index, and alcohol consumption. Rales or borderline and definile hypert sion for study participants were 30% higher thin lliosc expected on the bi of national rates (34), Log 1*08 serum values contributed significantly explaining (lie variability of log systolic and diastolic blood pressure multiple regression analysis (S3). Median total cholesterol levels of dividuals in the United Slates increase with age from about 150 to 160 mg at age 2(1 to over 200 mg/dl at age 50. PCBs in blood n e influenced by sen lipid content, and populations with inhciently lower total scrum cholcstc levels appear to have a different PCB serum to adipose tissue ratio. *1 agc-associatcd increase In blood PCB levels could be related to lire ]o half life of some PCI) isomers that are preferentially retained in iiiainm (29); as long as exposure continues, a true steady slate between intake s exaction is never reached. Ollier variables affecting body burdens may differences in metabolism with age. In the Triana studies, the blood levels total 1)1)1 residues also increased with age, and otlicn have made simi observations (56, 57). Lawton el at (58) studied workers who had be exposed lo electrical-grade Arocfor 1016, 1242, and/or 1254; llw slu covered the period from before the workers were exposed to two years af PCI) exposure ceased. Scrum levels for (tic lower chlorinated PCBs in 19 ranged from 57-2270 ppb and in 1979, from 12-392 ppb; for the higl chlorinated PCBs serum levels ranged from 6-142 ppb in 1977 and fit 4-108 ppb in 1979. These findings again illustrate the preferential cxcrctf of lower chlorinated PCB. Lawton ct at (58) also found that cholesterol lev correlated with log serum PCBs. Similar associations wiih tug scrum PCI were found for log gamma glutamyl lianspeplidase IGOIP) and, in son cases, for log alanine aminotransferase. When the PCB concentrations we expressed as levels In scrum lipids, all the associations between scrum lipi or en*ymes and log serum PCDs disappeared except for those between h UUll* and log PCBs. Similarly, Chase el al (59) found no signifies correlation between either icruin triglycerides or aminotransferases and il PCI) levels in adipose tissue. How age and length of exposure affect the: parameters is not adequately explained in the article. Finally, Akagj Okumura (60) were not able to conrmii a positive association between PC IiIihkI levels and elevated blood pressure in Yuslio patients. I bus. as Brown (61) has suggested, lire positive association between PC seiuni levels and elevated triglycerides and scrum cholesterol can be c plained by the increased solubility of 1*01 in seiuni with higher lipid conleni In scvcial crnss-scclinrti! studies of exposed workers, only mirw abnormalities not necessarily related to l*CH cxposuie have been dcleclc . 96 KIMllKOUGfl ! (62-66). In cross-sectional studies, however, llie ability to evaluate chrmiic | health effects is limited. In several studies, a posilive association between results rtf one liver function lest--the lest for y-glutainyllranspcplidase--and ! PCB blood levels has been found. Kimhrougli (67) has summarized earlier I I studies on the health effects of PCUs observed in workers. | In 1930 and 1940. chloracne. a disfiguring skin disease, was reported among workers exposed to l*Cf)s. One of the clinical features of chluiacne is lire chloracne cyst, which is skin colored and measures from I-10 min in diameter, with a central opening. The other dominant lesion is the comedo. 'lire skin lesions may only involve the face, hut tinny also extend to oilier parts of the body. Microscopic examination of human skin biopsies from chloracne cases shows markedly dilated hair follicles filled with keratin, llie sebaceous glands involute partially or completely, llie epithelial cells lining the hair follicles and the adjacent surface epithelium proliferate, and acantho sis is pttsctil. In old lesions, lire epithelial lining of the greatly dilated hair follicles becomes atrophic. fones & Alden (6B) examined 17 of 23 workers engaged in the production of I'CB*. *lhe workers had chloracne Involving the face, genitalia, trunk, and extremities, ttcforc the outbreak of chloracne In the plant, the electrical properly of the PCHs had fallen below specifications, and the color had deepened. In the repoil, symptoms of illness were extensively described for the first worker who was diagnosed as having chloracne. TTiia worker com plained of lassitude, loss of appetite, and fuss of libido. Over the years, oilier cases of cliluracnc following exposure lu PCBs have been reported. Most of these Involved exposure to vapors that developed when I'C lij were heated (69). At limes, llie skin rashes that developed in workers were accompanied by pruritus. Some workers also complained of burning of the eyes, nose, and throat; dry throat; nausea; and dizziness. Meigs cl a) (70) reported chloracne In workers who had been exposed to PCB vapors for 5-14 months. The concentration of PCDs in the workers* breathing zone was 0.1 mg/m'. Evidence of slight liver Injury was alsu present. Ouw ct al (71) (ound air levels in a capacitor plant that ranged from 0.32-1.44 mg/m' Aroclor 1242 (l*CB). Here workers complained of burning eyes, face, and skin in general, and persistent body odor. One worker suffered from chloracne, five com plained of eczematous rashes, and a few had abnormal liver function tests, lliese workers had a mean PCB blood level of about 400 ppb (fig/kg). In mnsl studies of workers witli chloracne, evidence of liver injury was also found; in one study, wuikeis who did not have chloracne were found lo have abnormal liver function (69). PCtls also affect the liver by inducing nuxedfunefton oxidases. Alvares et HUMAN HEALTH EITI-CIS OP PCDi & PllDi 97 al (72) determined that in five wmkers occupationally exposed lo Aroclor I1H6--a ITT) mixture primarily composed of dichlorobiplicnyls, trichlorohiphcnyls, lelrachlmohiphcnyls, and pcntachlorobiplicnyls--plasma antipyrinc half-life was signincautly lower Ilian that in matched controls, suggest ing the induction of mixed-function oxidases in the liver. 1 lese workers had (teen exposed hi Aroclor f1116 (or al least Iwu years and had no obvious symptoms of l*CII poisoning. Other health effects arc eye and upper respiratory irritation. Warshaw cl al (65) studied a group uf 326 workers in a capacitor plant with a mean empluyincnl of mure than 15 years and mean employee ages uf 41,1 years fur males and 47.3 years for females. Work-related eye or upper respiratory irritation was rc|Hirlcd by 48% of lire workers, and 10% had experienced lightness in the chest. Spiromclric studies were conducted on 309 workers; 66 of them were drop|>cd from the study because they had been ex|>osed to tile, textile dust, or asbestos. Thus, 24) men were available fur analysis. In males, there were alnml twice as many smokers and exsmukers as nonsmokers. In females, the pro|>otlion of nonsmokers was higher. Thirty-four of the workers (14%) had a reduced vital capacity, and 27 of these demonstrated a restrictive pattern of impairment. Uecause of additional variables such as smoking and asbestos exposure, these findings ate difficult lo interpret. Taylor cl al |73), in an attempt lo determine whether the fetus would be affected in capacitor workers, examined pregnancy outcome andbitih weight, and found that the gestation period was reduced by one week. The infants weighed slightly less Ilian the cnnliols; (his finding could be explained by the reduced gestatiun period. Smoking and alcohol consumption were not con trolled. however; furthermore, whether the socioeconomic status of this group of women was similar lo that uf the control group is not clear. Thus, until other studies confirm these findings, they should be viewed with caution. In several papers Jacobson and his associates reponed behavioral changes and a reduced gestation period In association with higher fish intake or higher intake of rCUs (9, 74-76). Fuilhcrmore, Jacobson el al (74) reported that intrauterine PCI) exposure may have a delayed effect on central nervous system functioning. Since genetic makeup, the mother's lifestyle, and acute illness also alfccl these parameters, these findings are difficult to interpret. Funhermme, many other chemicals are also excreted in human milk (20). Kugait & (laden (77). fur instance, found that mothers with high levels of 1)1)1: |t.l'-l2,2-dichloroclhenylidcne)-bts-4-chlorobeiuenc| in their milk tended to wean their infants earlier, as they did not thrive. Apparently, PCD levels in milk were higher in older women, women who drank alcohol regularly, and primparas (78). Whether high levels of l ) l ) t affect lactation is not clear. In animals, DDT 98 K J M im o iK ill homologs, Iml nul specifically l)l)Ii, have been show to have estrogenic eMetis (79). Define these findings can be clarified, additional studies must Ire dime. No conclusive evidence llius far rc|Nirtcd shows that occupational exposure lo PCUs causes an increased incidence of cancer. Dalin cl al (80) reported results of a preliminary study of a group of 51 research and development employees and 41 refinery plant employees at a New Jersey (Klrochcmlcal facility, lletwccn 1949 and 1957 these workers had heen exposed to Aroclor 1254. 'Iliiec melanomas and two carcinomas of the pancreas were found, lliis incidence was significantly higher than expected. Hxposurc to other chemicals also occulted, however, and the cohort was small. Drown A Jones (81) conducted a retrospective mortality study of 2.567 workers in two capacitor plants, Tlic relatively few deaths (16.1) severely limited the statistical (tower of the study, and the average follow-up was only 15 years, whereas latency |>eriods of 2Q-.1l) years arc not uncommon for cancer. Over 5l)% of lire sample had exposure to PCUs for two years or less. Deaths from liver cancer, cirrhosis of the liver, and rectal cancer were slightly higher than expected* but not significantly for both sites combined. The ohserved increase fur cancer of the rectum was statistically significant among females al one of the plants. In a follow up study (82) no additional cancers of the rectum were noled. and the standardized mortality ratio (5MK) dropped hum 116 to 211. However. two-additional cancers of live liver and biliary liact were observed, bringing the total of these tumors In five as reported on the death certificates. However, a review of the medical records raises questions about at least one of these tumors. Dcrtazzi et al (81) reviewed the mortality of 290 males and 1.020 females wIki had woikcd for six months or more in capacitor production. Males had a statistically significant increased number of deaths from all neoplasms. When deaths were analyzed by organ system, deaths from neoplasms of the di gestive system, the peritoneum, and the lymphatic and hematopoietic tissues were higher. Among females, all causes of deaths were significantly elevated, lire actual numbers in this study, however^ were small. Yusho and Yttcheng Two outbreaks of poisoning have been reported that followed the ingestion of rice oil contaminated with polychlorinated dibcnzufuians, biphenyls, and qualcrphenyls (PCQs). The first outbreak occurred in Japan In the summer of 1968 and the second outbreak, in Taiwan in 1979. Ironically, the outbreak in Taiwan rt|>caled what had occurred 10 years earlier in Japan. Many studies of these two outbreaks have l>een published in Japanese or Chinese. In 1984 some of the information in these reports was published in English in the HUMAN HliAl.TII U I I.CIS OP PCBs & r o d 9V Anu'tit tm Jotmutl o f fm luttriat M a lU in t 5:1-15]; (lie infnrmaliun is also summarized in volumes 59 and 60 ui Environmental Health P tnprtU vei. Iii Japan and Taiwan (lie disease was lirsl recognized because chluracne dcvclti|Krd in (he affected patients (B4). In Japan, members of all of the affected households had purchased rice oil fioin a specific company, and the toxic rice oil produced or shipped on f;cbiuary 5 and 6 of I96B contained large amounts of Kanecldor 400, a brand of J*CII with a chlorine content o f 48%. At the lime of the outbreak, no analytical methods specific for PCBs were available in Japan; the concentration of Kanechlor 400 in the oil was therefore estimated from the organic chlorine content to be 2,000-3,000 ppm. KancchInr 4tX) had been used for healing the rice oil in a metal container at over 200X, at a teduced pressure of 3-44 mill llg, to remove odorous material fiom 1. Kanciiilur |K) must have leaked from the licating pipe into the processed oil, hut the actual mechanism of the contamination has apparently not been determined, lire analysis of the K-rice oil, once the tnclliods were devcli>|>ed, showed that some of the oil samples contained 1,000 ppm (mg/kg) PCD. Iliis concentration was much lower than had originally been estimated, llicrefurc, other chlorine-containing compounds were assumed to be in the oil. and additional samples were analyzed. Ihe oit was found to contain an average of 5-ppm polychlorinated dibenzofurans (85). According to Buser el al (H6|. the Yuslio oil contained more than 40 polychlorinated dibenzofurin Isomers, including the highly toxic 2,3,7,8-lcltachlofudibenzofuian (TCOF) and 2.3,4,7,8-pcnlaclilorodibcnzofuran (pCDF). In addition, the oil con tained l*CQs al a coiicenlralion of B66 ppm (87, 88). According In estimates made by Kuralsunc (89), the total amount of PCD, I'i.'DF, and PCQs consumed by the patients was, on the average, 633 mg of 1*0). 3.4 mg of I'COF, and 596 mg of l*CQ. 'I bis calculates to roughly 157 pg/kg Ixtdy weiglil/d. PCI), 0.9 jig/kg body weighl/d. PCDF, and 148 ftg/kg body weight/d. PCQ. Al this dose the length of the latent period between exposure and onset of clinical illness was roughly 71 days, with a range from 20 to 190 days. Some of the oil llie patients consumed may have contained higher or lower levels because in auch situations contamination is usually not uniform. Furthermore, the patients consumed different amounts of con taminated rice nil. Hie severity of symptoms was positively associated with the amount of contaminated rice oil consumed (24). Fatly in the outbreak the patients had chluracne, dark-brown pigmentation of the nails, itching, pigmentation of the skin, swelling of the lirnbs, pig mented mucous membranes, eye discharge, hypcrcmic conjunclivae, jaun dice. swelling of the upper eyelids, a feeling of weakness, numbness of the limbs, and fever. Over I,(NN) people were affected. Ifntiy-six babies showed fetid PCI) syndrome, which consists primarily of a dark-brown pigmentation MX) KIMIIROUGII or llie skin (Cola babies). The cutaneous pigmentation was caused by an intiease in melanin pigment ill the epidermis (90), i he mucous membranes wete also pigmented. In all cases, the pigmeuiaiion disappeared by the lime Ihe babies were between two and live monlln old. In allccled inianli, llie lace was edematous, and *|Milty calcifications were noticed in llie parietal and iKL'ipilul arcus ol llie skull. In few of the infants, llie teeth had civpled at hiitli. Subsequently, the adult patients with clinical disease complained of having to expectorate a great deal and. on auscultation, wheezing was noted; however, on examination, (here was no evidence of bronchial asthma or pulmonary emphysema. In many of these patients, (lie icspiralory symptoms have persisted, and the patients have chronically infected airways. In the early 1970s. some changes were noted in Ihe patients' serum immunoglobulin levels, but the levels returned to normal. Over lime the severity and Ihe extent of the skin lesions improved considerably In the exposed population. Fifteen years after Ihc accident, only a very few patients had extensive chluracne (91) ' About live years after the outbreak of Yuslio, tissue and body fluids of Yusho patients were analyzed Tor various congeners of FCB and PCDF. At Ibis lime, ihe FCD levels in adipose tissue were 1.9 1.4 ppm (mg/kg). In Ihe liver they were 0.08 0.06 ppm and in blood. 6.7 5.3 ppb (pg/kg); thus, they were not very dilfcicnl from levels in the general population in Japan. On flic oilier hand, llie isomeric distribution for the l*CI)s in the Yuslio patients varied from that in the control population in Ihe same area (92). About 40 I'O JF congeners were identified in the rice oil that llie Yuslio patients ingested. Only some FCI)F congeners were retained in the body for a long lime; they included 2.J.6.8-TCDF, 2,3,7.8-TCDF. 1.2,4.7.8-FCDF, 2.3.4,7,8-PCIJF, and 1,2,3,4,7,6-licxacliloriiialed dibenzufurans. Since these congeners do nol have free adjacent carbon alums, they are not as easily metabolized and excreted. Mure of llie 213,4,7,BI*CDF than the other iso mers was retained in llie patients* tissues. In the five patients studied, llie concent ration of this isomer ranged from 6.9 ppb (pg/kg) in a specimen obtained in 1969 to 0.1 ppb (pg'kg) in a specimen collected in 1977. Measurable conccnlralions of TCDFs were only delected in Ihc earlier years. Although nol the most toxic isumcr. Ihe 2,3,4,7,8-FCDF caused inixcdfuiiction oxidase induction at dose of I pg/kg in rats, and atrophy of Ihe thymus, suggesting toxicity at a very low dosage level, 'thus, the clinical manifestations observed in these patients were primal ily caused by the rCDFs, specifically by the more toxic isomers. In Ihe Yucheng episode. It was never determined with certainty liuw the lice oil was contaminated (93). In 1979 a school for blind |>crsuns informed a local health bureau in Taichung County that a strange disease characterized by an acnclike skill eruption had been occulting frequently among students and human health i-n iicrs o r pcui & roui staff since the end of March. At the same lime, 85 of 15(1 workers in a i plastic shoe factory hod the same symptoms. Later that year, this mi was also reported to a local health bureau. Victims in both outbrcal consumed the same brand of cooking rice oil, which had been manufa by the same company and which had been purchased in the same slot this reason the rice oil was the prime suspect in the outbreak. In add reports of outbreaks In other companies and in the general populalii victims had consumed the same type of C-rice oil. Finally, liecausc the disease resembled the Yusho disease in Japan, sa uf C-rice nil and patients' blood were analyzed in Japan and were fur contain either a KanechloMWJ or a Kaiicehior-500 mixture at ccncenlr as high as 65 and IOB ppm (mg/kg), respectively. Over 2,000 patients finally identified as having been poisoned by contaminated rice ui samples collected from other outbreaks contained PCOs at concentratii .11-300 ppm (mgrieg). Retrospective studies determined that the peri ITU intake ranged from 3 hr 9 months. The average total intake foi person varied from 0.77 lo 1.8 mg of PCD. Within the lirsl year i outbreak, the blood levels of ITU in 11 patients ranged (rum 3 ppb lo ppb. Most of the patients had blood levels between II and 150 ppb (/ij The symptoms observed in these patients wctc quite similar to those al described lor the patients in the 1968 Yusho outbreak in Japan. Ilie rice oil was nut only contaminated with ITUs but also with PCD! polychlorinated quatcrphcnyls. It, contained the same major componei l'CI)|:s observed in the rice oil in Japan--namely, 2.3.4.6.7-PCPI 2.1.4.7.8- IT I)I:. Relatively high concentrations of 2,3,4,5.3',4, -hexj fohiphenyl were found in the blood and adipose tissue of the Yu< patients. 'Ibis particular ITU isomer is biologically quite active, an concentration of 2,3,4,J'4'-pcnlachforubiphenyl was also elevated in patients. l:urihermoie, as In the Yusho patients, the concentration of 2,] TCDF was comparatively low (92). Cltcn el al (94) analyzed addi samples uf the oil, blood, and adipose (issue of the Yucheng patients.' investigators identified several TCDF and PCDF isomers. Appan 2.3.7.8- TCDF was only a minor component in the oil; the major comp was 2.3,4,H-1CI)I:. One of the major furans in the toxic oil was 2,3,4 PCDF. The concentrations of the PCDFs in different oil samples ranged from 10 |.f>8 ppm. Polychlorinated quatcrphcnyls were present in cunccntn ranging hour 25 to 53 ppm (mg/kg). Overall, the concentrations of P( nod ITQs were lower in these oil samples Ilian in the oil samples Ilia caused the Yusho outbreak. Whether these oil samples were rcprcscnlati not ically known. The l/tJM'-leliaLliluroliiphenyl was also identified i 011 (hat caused Yuclicng disease in Taiwan. This isomer s considered- V 102 KIMOROUGII lite most toxic PCII isomer present in connnercial PIT) preparations (93); it was jnesent at a cunccnlraiiun of about 1%. Must liter commercial PCU preparations, such as the Aroclors, in the Unilc Slates have nut been shown to contain this particular isomer. In addition In the epidemiological studies, some disease-specific in vestigations were also conducted. 'Ihe blood pressure of the Yucheng and Yusho patients was not affected (60). Although some of the patients in the Yusho cohort have died of cancer (90), the number lias been small; because tire latency period may be long, tlie population should be followed for a longer period to determine whether the cancer incidence will increase. Although l*CUs and related compounds are known to affect reproduction In animals, and altliougli they affected some fetuses and neonates lit the Yusho and Yucheng episodes, Ihe Information on reproduction and fetal toxicity in general is very limited. In one such study, liara (96) examined women working tn a capacitor plant who also nursed their infants and who themselves had mild chloracnc and erythema of the akin. The human milk of some of \ trese women contained, on a whole milk basis, PCI! levels that ranged from below 50 ppb (jijj/kg) to about 400 ppb (jrg'kg). Forty children of these mothers were followed fur a five-year period. Sume children were found to have "decayed'* nails, gingival pigmentation, mottled enamel, and denial caries. No relationships between these changes or symptoms to PCI) blood levels, however, were observed. Tire general population in Ihe United Stales and other countries also lias body burdens of PClls, l*CI)Fs, and polychlorin ated dibenzodioxins (97, 98). However, these background concentrations-- particularly for the biologically active isomers--ate far lower than they were in the Yusho and Yucheng patients, even, several years after exposure. Chang cl at (99) examined live delayed immune response in 30 Yucheng patients and compared their responses with litse of 30 controls. The mean age of patients in both groups was about 14 years. Ih e authors injected a solution of streptokinase and slreplodomase subcutaneously into the llexor side of lite forearm. Ihe response was read at 24 liouts (hr) and again at 48 hr after injection. lUghty percent of the controls had an induiaiton of 5 mm or more in diameter 24 or 48 hr after they were injected; only 43% of lire exposed group responded similarly. All of the poisoned patients liad dermal lesions, and the percentage of patients with a positive rcs|Ktnse decreased with increasing severity of the skin lesions (chloracne). Furthermore, the degree of Ihe dermal lesions appeared to be associated with the whole blood PCI) concentrations. Patients with minor skin lesions that were classified as grade I appealed lu have a normal skin response. Ih e saute authors found that PCUs caused a decreased concentration of IgA and IgM, but not of lg(j, in scrum. Furthermore, the percentages of total T cells, active T cells, andT mu cells decreased, whereas (he percentage of 0 cells and T gamma cells were not HUMAN lU iA l.IH l.l l liC IS OF PCIH & FBI) 10 affected (100). These (wo reports aic Ihe first in which the effect on th immune response was actually coirelated wiili body burdens of PCHs and ii which only severely poisoned patients showed this effect. This finding i consistent with the findings fioiu animal studies in which relatively high dose of IT'lls affected the immune response and also caused some oilier advers effects. In Ihe Japanese and the Taiwanese Yusho and Yucheng poisoning out breaks, sensory neuropathy was reported in a number of patients for whun nerve conduction velocities were measured (lU t. I(I2|. The blood levels o the various chemicals (PCBs, I'CDFs, PCQs) were negatively correlated will Ihe lowered nerve conduction velocity, suggesting dial these types of dietni cals affect nerve conduction velocity. (It is not quite clear why most in vesligators measure nerve conduction velocity to delect sensory neuropathy Other tests that would measure flic detection or vibration, touch, and tempera lute would lie more useful from a clinical perspective.) Scppalainen cl al (103) examined 16 men working in a cardboard plant win were exposed to fumes that resulted from Ihe explosion of IS capacitor containing Clophcn A*3l). The first IT'U air concentrations, measured S.5 h after the explosion, were B.000 to 16.000 /rg/in* air. PCDFs were alsi formed. The soot samples contained Ictrachlorodibcnzofuran up to 90 pg/g of which 6.5 pg/g was 2,3,7.8-lelrachforodibenzofuran. In addition, mono clihitopytcnes aud dichlorupyrenes were found. Must of the men had i transient sensory neuropathy in their lower extremities. Chang cl al (l(M) repotted increased urinary -aminolevulinic acid uropor pitytin. excretion in 69 Yucheng patients over that of 20 controls. No informs lion on the patients* clinical conditions or on how these findings related it degree of exposure was given. No such observations have been reported iron Japan. POLY I)NOMINATED DIPHENYLS Since Ihe toxicity of PODs both in lal>oraiury animals and livestock wa< recently reviewed (105), we do not review it here in detail. In laboriiuiy animals, PUUs generally cause effects similar to those that the PCDs cause. 'I hey produce morphological changes in the liver, affect reproduction, and promote biochemical changes, such as hepatic porphyria knd induction of mixed-function oxidases. Teratogenic effects have also been noted. In addi tion, atrophy of the thymus has been reported, aud hepatocellular carcinomas have Ikcii produced in troth rats and mice. Ilic overall findings reported in animal studies arc similar to those that have been repotted for PCBs. Although the PCI) contamination of Ihe environment is a more general piohlem, the Pl)t) contamination primarily affects certain areas within the state of Michigan. Most persons living within the lower peninsula of Miclii- . .'04 KIM BROUGH '1 gan have had slight cx|M>sure, since the contamination resulted from daily products and since notmail marketing channels (nr these products involved the mtaing of milk from many |noduccrs in tclalively iew processing facilities. In addition, most cull dairy calile are used for hamburgers ami |>iocessed meat products llial would also receive wide dislrihuliun. I bus, the marketing system diluted llie degree of exposure for the individual; however, il increased the number of those exposed. In 1978. the dislrihuliun of I'UUs was comptclvcnsivcly studied in a probability sample of 1.738 | im)iis. Will levels in scniiu wcie determined, and 844 adipose tissue samples were also analyzed for Wills. Wills were delected In 97.3% of the adipose tissue samples, in 68% of the adult serum samples, and in 72.7% of the scium samples from childicn. 11 mean Pllll concentration in adipose tissue was 400 pph l/ig/kg); in serum it was I..1 pph (igflcg) Tor adults and 1.8 ppb (ji/gkg) for childicn. lire highest atli|iosc tissue concenlralion was 37 ppm (mg/kg) 110). In add!- lirnial studies, when cohorts of WlU-exposcd residents of Michigan were complied with icsidenls of the stale of Wisconsin, a higher prevalence of a variety of symptoms and complaints was noted in llte Michigan residents (106). Similarly, in comparative ncurobehaviorat studies, the Michigan pop ulation was found to lie alfceted more than that in Wisconsin (107). Since the fimjings were not coitelatcd with body burdens of Will in any of these studies, determining whether other factors may be resjmnsible Tor these differences is difficult. In 1976, the Michigan Department nf Public Health established a cohort of fanners who had been exposed to varying con centrations of Wills in llieir products and their environment. A total of 3,R77 persons were emolled. Tliey included farm residents, direct recipients of farm products, chemical workers and their families, and a few |rsons who had been oiiginally studied in a smaller previous study. lire scrum PUI1 levels in Ihis entire group ranged from mi detectable levels to 1,90(1 pph (pg/1), with a mean of 21.2 pph (jig/l) and a median 6f 3 ppb (jig/l). Because of the wide range nf exposure and (cause results could be analyzed by regression analyses with exposure as a variable, a comparison group for acute health effects was not included. Ttiis cohort was found to have various symptoms and conditions; however, these symptoms did not correlate with Will body burdens. Symptom prevalence rates were slightly higher in persons with no delectable I'UUs in serum than in those with measurable quantities. In all groups, including chemical workers and quarantined farm residents, the highest prevalence rales were ill persons with the lowest scrum PUII levels (22). Similarly, in this study and In a previous immunologic study (IUR) no dosc-rclalcd depression of lymphocyte funclinn in persons exposed to Wills could 1 demonstrated. All llsc findings suggest that there may be no causal HUMAN I.IT liC IS OF PCU* & N lllt 10! lelalinnship between llic abnormal lymphocyte functions observed n sonir Itersos or llie prevalence o other symptoms and cx|h>suic lo PUUs. Ibis cohort o Michigan residents is slid being followed by like Michigan Depart ment o Health in collaboration with the Centers for Disease Control. Several studies of subgroups of this population and surveys for chronic health effects have ticen conducted since the cohort was first assembled (109, 19). Wlrcn scmm and adi|Mse (issue concentrations were compared, a significant concia lion was found. The sennu:adipose tissue concentration ratios ranged (rom I to 140 lo I lo 260 for pregnant women and male chemical workers, respec tively. Males from farms had a significantly different ratio of I to 323 to 329. Potential transplacental passage of I'Dl)s was demonstrated, since they could also lie found in the fetus and ncwliom. Curd blood contained one-tenth of the cunccntrolinn found in the maternal serum, which indicated partial placental passuge. Human milk contained I'UHs al 107-119 limes the quantity found in maternal serum. 1*11Its were also delected in bile and feces, which indicates that these materials can be transferred into the intestinal tract. All of these coiicculralinns were measured long after the population had first been exposed to I'ltlls (19). Concentrations of PDUs observed in bile and feces were about one half tu seven-tenths o the serum levels and are probably about 0.3% of the adipose tissue levels. These findings indicate that PlIUs ate very slowly excreted, which is consistent with the findings uf Tuey & Matthews in rats It 10). Hie estimated half-life for Plltl is 6.3 years. . Moic recently, two groups of Michigan residents--those with high PUD sennit levels and those with PUD scrum levels around I ppb--were matclicd lor age, sex, and smoking. Por both groups, various clinical laboratory tests were conducted, blood pressure was measured, and height and weight were determined. In this study, 83 participants had PUD serum levels of 30 ppb f/ig/l) or more. In the middle group, 83 had PUU levels of 3-49 ppb and 96 liad PIIU levels of 0-44 ppb (figfi) in serum. Urinary porphyrins were also measured in all uf (he participants. Thus far, the final results of this study have mil lceit reported. For most of the parameters studied--which included serum glucose, liglycerides, high-density lipoproteins, various liver func tions, creatinine, uric acid, thyroid function, proteins, calcium and phospliotus in serum, and also measurement of various porphyrins--no differences of clinical significance were found among different groups (M. Uarone, personal communication). (Note: Even though significantly more women in the high Pill) group used birth-cunltol pills than women in lire low PUU group, loo few were using them to affect urine |H>tphyiiii levels.) In none of a variety of other studies conducted on this population as well as oilier groups in Michigan did any findings indicate that exposure to PUU had impaired lire health of the ex|N)scd group. All of these studies have been reviewed by Fries (11)3). 106 KIMimOLKll Although this population wax exposed during a 9-innnlh period in 1973 and 197-1. wliellicr ii will have chronic heiltli effects is unknown. This particular cohort needs to be followed for 30 to 40 years Ik:fore the question of chronic health effects can he intelligently addressed. Two problems with assessing chronic liealih effects are that the cohort, in spile of its size, is still relatively small and that ihc amount of exposure it has received varied widely. Although some members of lire group exposed In PDIls have relatively high body burdens, tltcsc burdens arc Mill appreciably lower Ilian those of rats in which liver cancer developed. In the study by Kimbrough ct al f111), liver cancer developed in the rats (hat received a dose of 1.00(1 mg/kg body weight. Ibis dose for humans would roughly translate into a dose of 70 grains per person. Ihese amounts are much greater Ilian Ihc estimated mean Inlal exjKisure per person. 'Ihc highcsl exposure was about 11.7 grams, and lire mean was 170 mg per person. In rats given 200 mg/kg, a dose that for humans would be between 12 xand H grams, only neoplastic nodules developed in their livers; there was no evidence of hepatocellular carcinomas. Of course, whether humans would Ire mure or less susctytihle to the toxic effects of HI Us and whether their icsjtonse would he similar In that of rats is not known. In conclusion. various toxic effects uf Plllls and PCIls have been described in laboratory animals. In humans, acute poisoning outbreaks have only occurred following exposure lu a combination of PCIls and PCDFs. When humans were exposed only In PCIls or Plllls, (lie only observed acute effects have generally been minor. So far. no significant chronic health clfecls have been causally associated with exposure to PCUs or PUIls. Use of trade names is hjr identification only and docs not conslilule endorsement by Ihc Public Health Service or the US Department of Health and Human Services. Literaturr C lin t 1. Jrn un. 5 l% 6 Repml of anew clienti* c il hazard N rw Stt. .If 612 2. 19K2. bi)d*nyWllVDst: inam ilwtuiinf. pintessinf. ditliibulion in riHfimcirr. and u u pfnhihilinn*: u in r l t t l m i l equipment f t d . J trjiir. 47:17 342 Ml 3 D M . Pnlychlivtnaicd M|tan)ih t t f l l ' l : niamjlauutiny, |>UHeiriy. (lifiiilw tl in ctm tnKirr. and u u niohihiiinns: u u in dined and cunliullcd wadt man- ulaciutinf pruecsset. t t d . Rtgitt. 47 41,m 96 4 M il.rod. K I: I1BI hilyrhldtinainl biplienyl* in mJdof air. tn\iron. Jri. Tnfinol JX y Kun. r W. Yanf. II. S. C. 1976. A nule un ptilyildm m O td biphcnylt in air. In f w . Noti ( V ii/ , F id ti htot inairii Biphf* d i, ( hit ano. 1971. FI'A3M V6- 75 004, p (M W ailitn(lim . IJC; lm vitnti l'idi Afenry 6 Ondlr, F . I.ihIi<, R .. Sprinter. I. 19X2. Dcicimioalion ut human tini in rcfulaiinf |Hilyildniinalcd bjiilienyls (K.'llsl~-a c au sludy. CMC roihiif. S u l A u ro . 2 211-25 7. ( `indie, F,. I.mkc. R., Sprinter, I. 19X2. Ridi su Miteni in a federai regulalnry ite m i: an iiicm iikpI a l li.tfc iMU'iaicu in lite human ctKiuitnpliiKi ni mine iikici nf fisti cnnlaminaied with pdlyshliwinated hiphcnyls | K | ! i | . tiu n m Hrahh /'rr.i/*nl. 45.171-12 V _ ,' HUMAN IlHAt.lll EFFECTS OF PCDi PBOi B. Sullivan. J B ,, Dclfino, J. I., Bueluw, C R . Shelly. f 0 IV I) polychlori nated biphenyls {n the Fish and sediment nf the l^ iw tr F iu River, W iK uniin. Pull Environ. Conrans. Totlrol M 9. S th w u li, P. M , Jacobson, S. W ,. Fein, C*. t i. , Jacobson. J, I... Price. It A. 1981. t a i t M ichi|an liih consump tion bi i source of polychlorinated biphenyls in human cimu serum, meter* nal scrum, ami m ilk. Cm. i . PuMic Health 1,1:29.1-94 Id. T ii i u i i w i , R. 197ft. PCD polluting of tlvc Japanese environincni. In PCB Pon oning and Pollution, ed, K. Ilig u th i. |ip 147-79 Tokyo: Kodaniha I I . M oiita. M , Nakagawa. |. , Rappc. C. IV7K. Polychlorinated dil<nrtt|utan t l `CUF| formation ftom I t 'D m iilu it by heal and oaygen Buff, fa w ra n . Con tain Touted. 19.665-70 12 O'Keefe, P. W . Silk worth. I D . Gier- lliy . I. F , Smith, R. M . DcCaprio. A . P . cl el I9H5. Cot m itai and biological investigations o f a transformes accident at llinghaintun. New York. Environ. Health Pgrtprt I. 441101-9 I I . Ilu u in g ct, O ., (ihulam, O. C .. Drucb, ( i Johnston, !.. E. IV8.V Formation of |mlychlorinated dihcnridutans ami dioioi during combustion, electrical equipment fires and PCB incinetalion. Hmtrun. Health f ' r r w i t . M l.) 9 14, Caiicr, L. 197ft. Michigan r t l l l in cipient. Chemical mia-vp leads to disas ter .irin tiY 192:240*45 15. W illett. !.. u :, Liu. T. T. Y .. Durst. II. I , Cardwell. B I) . Renkie. E. 17. I9H.V Quantification and distribution of JN ilyihlm tnitrd biplKnyls in farm silos, luff, tnviion. Contant. Toticol. 15:51441 Ift. Kimbrough. 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( M in i naletl biphenyl induction of ary111) diu rni hon hydiosylasc k livtly; study uf itm cfuic activity telilio n ih ip . Mot. Phoimarot. U.9J I -31 31. S c h K iln , E., freim . ll..,fio e stnct. W. 1984. patholoay of t h n n k polvclduiinattd b i|iio i l |P ( ) fre d in i in tali. T arin if Appi fhaem aiot. 71:271 HR 31. Ninback, D II . Wcfcmao. R. I l 1983. M jf t h lw t n iit f biphenyl induction of hepatocellular carcinoma In (he SpragueDawlcy tal tn r e a . Health f r r i j i r r i . Ml 97 III) 73 KitnbnMi|h. R 1).. Squire. R. A . U n der, R l!., StianJbcrg, I. 13., Montali, R I . Burse, V. W. 1973. Induction of liver liim m in Sherman alrain rats by ^ chRomaicd biphenyl Aruclot 1260. ail. C a n ti fru. 33.1451-39 36. National Carnet Institute. 1977. Biosssay ol Arncli* (iratkmark) 1239 for possible carcinogenicity. Spiingficld. VA : Nall. Itc h Inf. Sere, at PI) 279 6I4r|(iA, N C lt.'O IRON. Chcm. Abut. Sri*. Nu. 27721-II I. b llE W PuM,, N ili 711111 37. Ward. I. M . 7983. 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Time and dose tarpons of the reduction in retinoid concen trations in r i7 B I/R jj and I7BA/2 mice induced by J,4,7'4'tctrcMoohi- pbcnyl Totuol. Appi, i 'harmattil. 78: IHI) R9 44 Kulr, F W., Slramnan. S. C 1976, Recidaci ni polydilnrinslcd hijdirnyls in he generai pojHiUtion f llic United Sialo Stc Rei. 3, w . 139-48 43. Iiiilie w c r, T .. Nicwiadnwika, A , Radooiamkl, T. 1977. Polycldorinatti bphcnyl rciiduei in htnnan adipose lis ine r a t Psjc. l e i 72:177-173 46. K it in . K 1983. Siudiea m populalinni espuseti lo |M>|ychl(Mnsted tnphcnyll. l a t i rati llta llh Pertprrt. 60:197-199 47. Mcs. I-, Osvici, I). I . Tunon, b 1982. Polychloiinaitd hpiwnyl and othei chlminaird hydtncailion icsidues in adi pose linuc of Canadiani. flati. C niioiit, Contatti Tatuai. 28 97-104 48. SsM. I. Ih . Cmckcr. ? .. tbmlon, R J , Faedcr. li. J. 1983. Polychlorineted liipltenyls in lite blood sii pcrsonncl II ohi n eleeliic utility, i . th ru p . Med. 27:619 41 49. Unger. M . Otscn. 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Wnng. O .. Ihm m v. t) , S u l. II W . Bciney. 0. W . Simon. R. K. I9H2 Clinical and mciaUilic uhnnimalilic* a*ot:ialcd with oceupaliitn il eipiuuic in n iljc h lm in iltJ bi phenyl*. / . O n up. Aled. 24.109-M Ml A l a g i . K , (H um or*. M, 19X1 A**nctalinn of Mmid picn u ic and It'H level in Yutlm n ilic n li iLmirmt. Health I'ettpetl. 19 M llin n , I. F |i. 1904 Polychlorinated liiplicnyl IPCB) pailiimning between itdi|i*c liu a c and *eium. Bull, In*iron. Cimiitm lo n i'd f .VI J)7-W I h i lim m rtl. I: A 1981, I'olycldoiinitcd biphenyl e ip titu ic and c l l n l t in Hintfunner itpan m u lc t*. Em turn, Henfih Pe i/i I Ml |0 V 92 h i Humphrey, II. E. B.. Price, II. A ., Iludd. M. I. 1976. Evaluation nf change* nf the level nf p o lyih lo tim lrd biphenyl* If V B l in human liu u e / im il Rep UtA ( 'iiiiiiiu i Afn. W M J -J IlW . Wathinglnn, IK !. U llfiW , ID A M lla kci, E L. It.. Laming in . P I , G lu e d , C. I . 7 .td . M M l i . I.id.llr. I A . el at |9MI. 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(1 ( I Iniiaulciinc capumre of human h u n t to IT U i: m eaiuiri of n p iiu i p C fll; Human and Enettartm, 7/ntnrdi. rd. F. M. DTtri. M Kan Kp l l l - O . Boilon: Bulieiwmih ogin. W ., (laden. B. 1901. Dun of bicat|.feeding and cnvtronn* conn m inim i in m ill. Am. / . EpiJe* 116361A 70. Rugan, W. I . . Gladen, B. C.. Mt ncy. I. f> . Carterai. H ,, llaidy. I1 al. 1906. PulychliHinated biplie iP C IItl and dichlotodiphenyl chlorocthenc (DDE) in human n effect! of maternal facto am! prrvi lactation. Am. / . Public Health 76 1 77 79. Gcllert, R J., Ilcin tich i. W. I... Sm lo ll. R. S. 1972. DDT hmmihtgi tin fcn like effect* on the vagina, ulc and pituitary of the rat. EmittertnoI 91 1(791 100 00. Bihn. A. K -. Rmenwaike. I . I f ntann, N . Grover, P.. Slcllman, OT^eiry, K 1976. Melanoma after potuic to PCB. ft. En$f. / . hi 291:410 no KIMUIKHKitl 81 Brown, I) P.. l i m i , M 1981 Mortal ity ind industrial hygiene Uudy u l work er caposed lo polychlorinated hi Arth Environ. Ilratih 36: 120 29 81. Blown. I) P 1986 Mortality o f wink en tip o K d In' polychlorinated biphe* D fli'- in U |k iili An h Environ. HcoUh In preti 11. Br Harri, P. A , Zucchetti, C . Ciuci- cilena, S , Puglia, M II.. P enim i, A , Ribaldi. !.. IV8I- Mortality aludjr of nialt and female wmkcia capuaed Io K "B i. Presented at Int. iim p Peer. O ttiyi to m rr. Hrhinii 84. Kutaliune, M , M o rii awa. Y .. I lim iti- la, T ., N iihirunti, M . Kofichi, S , cl al. 1969 An epiJcmiologic study r ti Yuihn m rhh itohiphenyls Pul nulo Ada Mtd. 60:311-32 (In lapancscl 83. M irala, I l . Kailiiutofo. T ., Kunita N. 19/1. Detection and delciminaliori of puljrchlixinalcd dihenrofmant in ih k iiu I nuotati tissuei and Kanemt tie r oil caused Kanemi Yusbu. / . fo o d Hv$. 3m 18 26(1 63 86 Buses. I l R.. Rappe. C., Gaia, A. 1918. Polychlorinated dibentofutana 81*9.01*1 Inumi in Yusho o il and in used lapancsc P i' ll Chrmmphnt 3 439-49 11. Miyata. I I . KashimtXti. T 1978 Stud i o on the coni|Mtunds trialed In l*CB |IV |. Investigation on polychlmudl- bcnroluian (minaiion ). food II\r . , Soc. 19 18-14 tin lapaneae) 88 Kamps. I., V, R , Tiottcr. W. !.. Young. S. 1 . Carson. I I , Roach, f. A. G , cl il. 1911 Polychlorinated quater- ptienyli identified in rice o il associated with lapaneae ` Yusho' poisoning Bull. Environ Contom Tosirnf. 20389-91 19. K latitine. M 1980. Yuitio. Sec Ref. 26. pp 7 -3 0 2 90. Kikuchi. M 1984, Autopsy of patient! with Yusho Am. J Ind Sir<3 3:19- 30 91. Utabe, I I , Aaahi. M 1983. Pail and cu iirn t dermatological ilatua of Yusho 5alienti t/n iro n . Health Penned. 9 11-13 92. Masudii. Y. 1983 Health statua of lapancse and Taiwancac after capusute lu contaminated lice oil. Environ. Ilratih P trip n l. 60 321-23 93. llsu. S. T . Mac. I . Ilsu 5 . K l l . Wu. S S. llsu . HU M . Ych. C C. Wu. S B. 1983. Discovery and epidemiology of PCB poisoning in Taiwan: a fourycai follow up, t netton. liratih Prriprct. 30 3-10 94 Cltcn. P. II , W ont. C. K-. Rappe. C.. Mylie n . M . 1983 Polychlorinated bijdicnyti, dibcnrofuians aijd qualcr- rhenyts in Im ic rice-bran oil and In the blood and (issues ol pallenti siiti It'D poisoning (Yu Cheng) in Taiwan, En viron. Ittaltli Prnpert. 39:39-63 93. Abdel llamid, F. M , Monte, I. A ., M anlio* t. I l II. 1981. Contoaialive atudy of 3 .4,3',4' Icltadilorobipliefiylin male and Iemale tata and female mon keya. / fo t If of. Environ, Health 7:181-91 96. lin a . T. 1983 llra llh ilatua and K 'O i In blond of uoikcia eapo.ved to ICBs and of (heir childicn. Environ, litalih Pertpetl. 39 83*9(1 97. Bappe. C . Ilcig q vi't, p. A ., Ilantaon, M . l.a iiO w e . K .. I indiubnt, G ., cl al. 1984. (Ttcotisliv and analytic of poly* chlorinated diosina and dilienrofutana In biological saiuplea. Ifanbury Report fA; Riiilocical mechanism* of diocin action. 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C \. el al. 1983, Folyihlnrinilcd biphenyl poison|ng: correlation of reniorv and motor nerve conduction, neurologic lyinptoms. and hlood Icvclr of polychlorina ted biphenyl*, ipiailcqihcfiyli. and dibcnxdurani Environ. Met.- 37, 340-48 102. Murai, Y.. fiu m i wa. Y. 1971. Periplictal ncmoniihy in clilornbiohcnyla poisoning. n n irn fiiyv 21:1173-76 103. Scppalaincn. A. M ., Vuojolahll, P., Flo. O. 198) Revci tibie nerve lesion* allei accidental polychlorinated biphenyl capotine, l i and J. Work Environ. IIeahh 11.91 93 104. Chang, K. I . l u . F !. . Tung. T C , le e . T, P 1980. Studici on palicnla with polyc him tnalcd biphenyl poiio n Ing. 2. licleimnaiion o f uiinaty ci^ru- Cupiiyrin, utuptuphyrin, dclla-atiunavolink acid and porphobilinogen. T' human iM:Aim i-m-cis or rcu* & ruui 11 A n . Corwnun ('Arm. Pathol. Pharma- tot. J(K3)347-34 IU.V l i i t i , ( i. 1983. The PBB cpixulc in Michigan: an overall anmaiial. CRC CVri. Arv. Toticot. 16:1(13-36 11)6 AiHlcnun, II. A .. l. it lii. R., S tli(liu((, I J , Rirtcntnan. K. I)., V i k i u l u , I. A ., cl al. 19)8. Unanticipated p itv t- Icmc ml symptom* niHing dairy lu iix n in Michigan and W iiconiln. tm u o n . lltalth Ptt\prt l 2 1 2 17-26 KIT. Valciukai. I A . I ill . R . W olff. M. S .A n d c ia o n .il A. 1978. Outiparenve ncuiobchavimal ttudy p i a pnlybnnm- ncd b iplitnvl t>p<>wil population in Michigan and m m ti|M w l ginup in W nriinnn, Environ. llrahh P rttpn l. JVIV9-2IU KIR. Ilekcsi, ) ( i , Holland. J. F., Anderson, II. A ., lischbein. A. .V, Rum, W ,. cl at (9 7 8 . Lymphocyte (unction i Michigan dairy farmers eipored i pul) (nominated biphenyls Trim. m . 1107-9 109 K it its, K ., Roberti. C., Humphrey, II E. B 1981. Serial PUB levels. I \ I levels, anJ clinical cbcmintiei in M iJn Ian'a FDD cohort. Arch. Enviroo tratih )7 |3 ).1 4 M 7 NO Tuey. 13. B., Matlhcwi, 11. B IVBu Distribution and tacieiinn u 1 .2 ',4 .4 ',3 .3 ' heaahronwbiphenyl t< rati and man: pharmacokinetic nn*k icdklioo*. Toriroi. Appt. Pharmatoi 10)42001 I I I . Kimbrough. R. D., Groce, D F . Knt ver. M P . Burse. V. W. 1981 Indue lion of liver lumori In female Shcimin sliain tala by polybrominaicd bijdtcnyli J . Natl, firm e r tan. 66:3.13-42 Health & Environment \ publication o f the Freshwater Foundation ftitiirifi inform ation jm m its himitb & Hnrinnnwnt .W'inori.' Feature A rticle Polyclilorinated Biphenyls: How Do They Affect Human Health? Until 1971, polychlorinated biphenyls (PCBs) were used commercially in the U.S. in capacitors and trans formers, carbonless copying paper, paints, and hydraulic fluid. While many countries have since restricted PCB use, the compounds are still found in old transformers, capacitors, and other products. PCBs are a group of 209 stable, fat-soluble chemicals. Not easily broken down, they have accumulated in fish from polluted waterways, in wildlife, and in human organs, fatty tissue, blood, and milk. In the late 1960s and early '70s, PCBs were also detected in meat, eggs, milk, and cereal. Today, however, because of regulatory* restrictions and other measures, polluted fish are the primary food source of PCBs for humans. Because they are fat soluble, PCBs tend to concen trate in fatty tissue, and to a great extent, PCB levels in different organs depend on the organs' fat content. Thus, in humans, fatty tissues contain the highest PCB concen trations. In fish, the highest levels are found in body fat snd the hepato-pancreas, not the edible portion. Aroclor is the commercial name for the American product of PCB mixtures. Different mixtures are further identified by codes, such as 1242. 1016, 1254, that designate the percent of chlorination of the mixture. Because the time necessary for different components of PCB mixtures to break down in the environment varies, PCB mixtures found in soils, sediments, and biota have a different composition from commercial products. Most are similar, but not identical to Aroclor 1254. Studies in laboratory animals To learn how PCBs might affect health, investigators have studied PCB exposure experimentally in animals and in humans occupationally or accidentally exposed to the compounds. Except for feeding studies in mink, which used PCBpolluted fish, most animal studies have tested commer cial products. Results show that the toxicity of commer cial mixtures varies. Mixtures like Aroclor 1260. with a high degree of chlorination, produce liver cancer in rats. Mixtures with much less chlorination, on the other hand, yield a much lower cancer incidence, with a tumor incidence similar to that in unexposed rats. Most tests have not demonstrated any mutagenic properties for PCBs. Other adverse effects observed in different animal species vary. While all mixtures and congeners' tested induce mixed-function oxidases in the liver, the type of enzymes induced varies. PCB isomers that appear more toxic and that are retained longer in the body seem to induce aryl hydrocarbon hydroxylase. Liver enlargement seems to accompany enzyme induction. In some species fed high doses of PCBsl investigators have observed liver cell necrosis and fat accumulation in liver cells. Editorial Board Richard H. Adamaon. Pn 0 0 ec (of Oiv'I kvi ot Cancar E loogy National inanim ai of Maaiin National Cancar mantuta Hanry K Anderaon, M 0 Dfuet Environmental and Chrome O ise a it Ecemioiogy Wisconsin Q m iion o f Meaitn John O ouil, U D .P H 0 0 osaiImani of Pharmacology University of Kansas M ettcai Cantar Vernon N. Houh, u 0 Onactor Cantar tor Environmental fra aim Camara for Oim im Control Barbara 3. H u lla . U D M P H Chur D e p a r t o t Eo<enooi?y Scnooi or Puoiic Meaitn University of Norm Carotina 5 ^ u < * Klmbraugti, UO Dwactor M iann and Ris* C apacities O ffice o l tna Adm inistrator Envtionmamal Protection Agency Robert W. Leader, D VM Department of Pamoiogy Uicnigan S ta ll University Richard J. Lartne. M 0 . M P H Director Department ai Eoroermoiogy Chemuai industry institua Of Toiicoiogy Jack S. Mandai. Pn D Environmental and Occupationat Meaitn Scnooi of f\to iic Htatm University ol Minnesota Raymond R N eutra. M D . Or PH Cruet E ffcem oogien Sluotes Suiveianca Secten California Deoirtm em of Haaitn V icto r W. Sidei. M 0 Professor ol Social M e ao n t M ontature Medical Center AJtfen Einslem College of Metterne Arthur C. Upton, M 0 Director institute Of Environmental Mettane Ne ton University Medicai Cante* Bardara Scott M utdock Editor Pauta J. Ripley Gmarai Managir ONE by Renate D. Kimbrough, M.D. l\S. Environmenoi Protection Agency, O ffice o f Regional Opera tions, D irector; Health A Usk Capabilities Rhesus monkeys exposed to technical PCBs have developed hyperplasia, or over growth, of the epithelium of the gastric mucosa. In rats, investigators have observed cell transformation, noting that hepatic cells transformed into pancreatic cells. This effect on cell differentiation, apparently modified by the epithelial growth factor, is more pro nounced in rats exposed to Arodor 1254. Because the mixtures tested may have been contaminated with chlorinated dibenzofurans, such contamination may have contributed to the toxic effects and be partly responsible for the variation in effects seen between mixtures and between animal species. In experimental animals, some mixtures affect reproduction more than others, but all effects have been fetotoxic. In minks and monkeys, investigators have noted sponta neous abortions; in rodents, they have seen resorptions. Exposure to lower doses may reduce the weight of the offspring. No one has reported malformations after exposure to PCBs. Finally, some species, such as monkey and mink, are much more susceptible to the toxic effects of these chemicals than rats or mice.1-*--* Effects on human health Thus far, no conclusive advene effects have been demonstrated in people who carry O 'o*r*ear .v Guboo . . /Achlorinated dlbenzofuran C Hydiofui 1. .. r'-Vf.-V- >t # Q kvtw .-- 7 V / `;" L ' . ' .v / V :* :'1 ` ^ ** , ,r' r . * - /( Chlorinated dibenzofurans m3y be responsi ble fo r the health effects attributed fo PCBs. body burdens of PCBs from environmental exposure to trace amounts of PCBs. Such exposure is much less than that received by workers who made transformers or capacitors from the 1940s through the 1970s. Even workers with exposures two orders of magnitude greater than environmental exposures seem to show no convincing chronic health effects. In a number of capaci tor plants, workers developed chlorucne. a persistent skin disease that primarily affects hair follicles. Whether the chlorucne resulted from PCB exposure or from exposure to chlorinated dibenzofurans, a known cause of chlorucne and a possible contaminant of the PCBs, is unclear. There is reason to believe that chlorucne and other health effects popu larly associated with PCBs are really caused by chlorinated dibenzofurans. In 1968 in Japan and in 1978-79 in Taiwan, two poisoning outbreaks took place in people who accidentally ate rice oil con taminated with a mixture of PCBs and poly chlorinated dibenzofurans. The poisoning, called Yusho disease in Japan and Yu-cheng disease in Taiwan, led to chlorucne and dark discolored skin among most of those exposed. Children were bom with erupted teeth, and dentition of the permanent teeth was affected. Further, these people-had many other acute health effects, such as abnormal liver and nerve function tests, abnormal menses, and persistent bronchitis. Babies were bom with dark skin discoloration and low birch weight for term infants. In both episodes. later inves tigation established chlorinated dibenzofurans as the cause of poisoning. One reason for this conclusion is that L'.S. workers exposed to much higher PCB doses than patients with Yusho and Yu-cheng dis ease do not show the same health effects. Some workers complained of burning eyes, nose, and throat. Some studies reported abnormal liver function tests. One study, in a capacitor plant, noted abnormal lung function tests among the workers. However, these workers had also had other exposures that could have resulted in abnormal lung function tests.' Attempts to conclusively demonstrate health effects in populations that cat fish from polluted waterways have generally failed. Occasional repons have noted behavioral changes and shorter pregnancies with higher fish consumption or higher intake of PCBs. `' However, because these studies couldn't rule TWO l util other causes, the significance of their findings is unclear. Several occupational studies have pre* *nted no conclusive scientific evidence that pCBs have caused cancer in humans.' While one study found a positive association tjetween PCB blood levels and high blood pressure/' the association appears spurious. The levels of PCBs in serum are primarily a function of the amount of fat present in scrum. Serum PCB levels arc, for instance, positively correlated with blood cholesterol levels/'" The associations disappear when PCB levels are expressed as a funaion of fat in scrum rather than as whole serum. In popula tions on Western diets, both serum fat levels and whole serum PCB levels increase with age. They are usually higher in males than in females, which corresponds with population survey findings that females usually have lower cholesterol levels than males in the same age group. Finally, the prevalence of elevated blood pressure also increases with age. In essence, all the associations go in tandem and appear to be spurious. Thus, despite positive laboratory animal data and except for chloracne, exposure to PCBs has led to no convincing, clinically demonstrable, chronic health effects in humans. '.V ttn b c n o f the same chemical fam ily; each member diners in ihc number o r location o f substituents. R rferrncri: /. KimbmuRb r t at,. Environ Health l*ersp. 2 4 ./"+ 84. /y -tf; J. Kimbruufib r t at,. Environ Health hrrvp, J9- 99* /M i. 198%; J. K im tm iuit r t at., Ann. Hev PhamuKol. Toxicol. 2T / r - / ; / . m * /. Jacobian r t at,, Oiv Psychol. 20.-2J-JJZ 984: J. f t i n r t ai., J. Pediatr. 10 2.JIJ-JJ0. 1984; <1 K r r iit r t at.. ). Am. Med. Assoc. 1981. ", Lawton r t at,. Envi ron. Health Pcrsp. 60.165-84. 98%. C om m entanr Harnessing Natural Processes To Degrade PCBs. by Michael A. Kanuin, Ph.D., Professor, Center fo r Environmen tal Toxicology, Michigan State U niversity As numerous analyses of air, water, sediments, wildlife, and other environmental samples have shown. PCBs are extremely persistent com pounds found in all parts of the environment. In ambient air and water, PCB levels are quite low. Even if one assumes a lifetime exposure to the highest measured levels all day every day, air and water offer a low risk of human exposure. Fish, however, appear to be a more significant source of PCBs. Why? First, PCBs bioaccumulate and biomagnify in the aquatic food chain. Further, as many people become more health conscious, they tend to eat more fish. For people whe subsist almost entirely on fish they catch themselves, high environmental PCBs in fish are the sediments in levels plus high consumption can lead contaminated rivers, takes, streams, to significant exposure. and estuaries. About one-third of all Because fish are such an impor PCBs in the global environment are tant source of PCBs, government contained in fresh and saltwater agencies have taken steps to minimize sediments. this exposure. On the federal level, Most remaining environmental the Food and Drug Administration has PCBs seem to be stored in open set maximum tolerance levels for waters around the world, largely as a PCBs in fish sold in interstate com result of atmospheric transport and merce. To address intrastate consump deposition. Despite worldwide disper tion, some states publish fish sal. however, studies of oceanic life advisories that recommend limited or suggest that PCBs are not evenly dis no consumption of fish from bodies tributed: the highest levels are in the of water significantly contaminated northern hemisphere, especially at lat with PCBs and other chemicals of itudes that encompass the industrial concern. A number of states border nations. ing Lake Michigan have collaborated In addition to the large quantity on a common advisory for Lake Mich of PCBs in the environment, an igan fish. v approximately equal amount is still in use, mainly in dielectric fluids in PCB reservoirs sealed electrical equipment. The most Limiting exposure by regulation important step for limiting future or recommendation docs not address exposure emails exercising great care the fundamental reservoirs of expo in disposing of all PCB-concaining sure--where PCBs are stored in the materials still in service. In most environment. Available data clearly .cases, users of electrical equipment indicate that the main sources of arc taking care: continued vigilance THREE jtiould spare the environment further in sediments are degraded naturally, PCB degrading organisms to contain ^ult from this source of PCBs. probably through the action of micro the genes responsible for the degrada organisms. The degradation seems to tion capacity. Introduced into the Treating PCBs in the environment work by dechlorinating PCBs to form environment under the right condi PCBs already released, however, less chlorinated, and generally less tions, these organisms could multiply jrc more difficult to control. For toxic, congeners. Because natural on their own and dechlorinate PCBs example, PCBs are dispersed in con dechlorination seems to be quite rapidly. sumer and commercial products in slow, researchers at Michigan State If successful, these methods many sanitary landfills and private University have been looking into would provide a means of in situ dumps* Because of careless disposal, ways of improving on nature by destruction that could avoid the nega PCBs from some sites have vaporized enhancing degradation rates. A logical tive aspects of other disposal meth 2nd contaminated the atmosphere. first step will be to determine if the ods, such as air pollution from' Locating and properly sealing disposal degradation is caused by microorga incineration or possible spillage dur sites can help reduce the environmen nisms and, if so, to isolate the organ ing transport to a secure site. Regard- tal burden. isms responsible. Jess of the efficiency of new Still, because sediments appear to If such organisms can be cultured techniques, the volume of PCBs be the most important reservoirs of and studied in the laboratory, it might already in the environment is so large human PCB exposure, this is clearly be possible to increase the environ and so dispersed that, they will be not enough. Because they are persist mental degradation rate in a number with us for a long time to come. The ent, PCBs become less available of ways. One would be to enrich the hope is that their levels can be signifi mainly through burial, becoming cov soil or sediment with nutrients in cantly reduced in critical locations to ered by organic debris over time. The such a way that the desired bacteria minimize the chance of human or process is slow. While it takes place, can increase greatly in abundance. In animal PCB exposure. Though we disturbances of bottom sediments can a related approach, investigators can't put the genie back in the bottle, resuspend PCB-Iaden particles to con- might seed an area with a large quan- . it's important that we tame it is much laminate the food chain for years to ticy of the organisms or, to maximize as possible. come. Therefore, some environmental researchers advocate actively attempt ing to reduce environmental PCB lev els, instead of waiting for nature to take its course. the effect, use a combination of enrichment and seeding. A third pos sibility is to genetically engineer non- Readers Rirunr Suggested e roding : Tanabr, JL "PCB Problems in the Future: Foresight /m m C urrent Knowledge. " Envimnmcntal Ptillutiun 30. f-JH. i'JHH: D i m . F .If. an d St.A. K a m rin . etls.. PCI): Human and Rm irufuncntal H lc m K A nn A rb o r Science / 'JMJ. . One approach has been to dredge PCB-contaminated sediments for bur M inam ata Disease gait. In May, the hospital's director ial in secure landfills. This approach has not proven successful. Incinera tion, used to some degree to treat contaminated soils, is both time-con suming and costly, and would be As the Update reportfrom NewJer sey points out, a tack o f integrated response from government agencies, lim ited implementation o f regulations, and poor communication can create envi ronmental problems and hamstring their reported the outbreak of unknown dis ease of the central nervous system (CN'S) to the Minamata Dept, of Public Health. By December 1974. 798 patients with "Minamata Disease" had been officially recognized; IIP had died; 280U others even more expensive as a treatment for sediments. Capitalizing on natural processes More recently, a new effort has begun, based on the finding that PCBs management. The history below reviews a case in which such conditions had disastrous effects. In April 1956. (he Chisso Corpora tion's factory hospital in Minamata. Japan, began to admit a number of patients with delirium, disturbed speech, and abnormal had applied for recognition. Forty cases resulted from exposure in utero. Symptoms included sensory loss: ataxia; impaired speech, hearing, and gait: difficulty in chewing and swallowing; involuntary movements*, and bilateral Continued on page 8 The H ea rt* M n m m M P<| i ^ (ISSN 08034347) K a monthly publication of the FrM hwatar Foundation, a public nonprofit io u w a tta i n o w m illio n M to Im p keep . w alar uaabto lot human conaunpuen, in o ra n * and n erva tio n . Tha ta rn a tio n u oe o rta a w ia ty of rnaaren and aducaiionaJ programa oaaimo wttn frw ftw a ta f nacum a. 2) .contact tha ta rn a tio n , w rit to: Fraaftwetar tam danon. 2900 Shadywood F a Boa 90. Navarra, UN 55383-0080: (013) 471440?. Tha O pacf draw on m * nw rttae of a natwom of repraeaniadvee m 22 aohoota o f pMdo M ann. SO data naajtn department, and ovar 73 r w ir r n M M u d p ru ci-"*'i.^> V government aganoaa. atata puaio M atm asaocutlon, and m eaieil aociatiaa. S la rite funda ware provkjad by a grant tram tna Quail ta rn a tio n . Subacnptptu to tM Qtgmt ara STS per yar. Special ratea ara aval tar ornara of two or mora. Application tom an at aacono-claia portage ratva la p a rt-in e rt i*, ` * '* " . M lnnaacpia, u n . POSTMASTER: Sand addrtaa change to: Tha Haaiin A Environment D ig **i. u o i BtooWyn Bivd.. S u it ICS, Minnaapdta, UN 42?; 5334182. . - C oorngm O io ta F r a r f m i i f t a r t M o n - v : V* C' ,, - hafcl'** --y,|* FOUR .I n HUMAN HEALTH EFFECTS OF ELECTRICAL-GRADE PCB's J .F . Brown, J r ., Ph.D. Manager - Life Sciences Branch Corporate Research and Development Center Schenectady, N .Y . J .T . Coe Staff Executive Environmental Quality & Safety Corporate Health & Safety Operation Fairfield, Conn. H .D . Pocock, J r . , M .D . Associate Company Medical Director (re tire d ) Corporate Health & Safety Operation Fairfield, Conn. Corporate Health & Safety Operation General Electric Company 3135 Easton Turnpike Fairfield, Conn. 06431 August, 1981 \ i Section Section Section Section Section Section Section INDEX Page I Introduction II PCB Composition and Terminology III History of PCB Use IV Health Effects of PCB and PCDF Mixtures 2 4 7 9 A. Observations on Test Animals 1. General Bioeffects 2. Impurity Effects 3. S tru ctu re-A ctivity Relationships 4. Toxicity and Carcinogenicity Test Results B. Human Health Effects Observations 1. Early Occupational Chloracne 2. Yusho Episode 3. Effects of Eating Fish Containing PCB's 4. Clinical Studies of Capacitor Workers 5. NIOSH Mortality Study 11 C. Health Effects Summary 18 V U. S. PCB Regulations VI On-going Research Programs V II References Cited 20 22 23 Abbreviations which may be unfamiliar to some readers include; ppm parts per million ppb parts per billion kg ' kilogram; 1000 grams gm gram (s ) mg milligram (s); one thousandth of a gram pg/m3 micrograms (millionths of a gram) per cubic meter pg/L micrograms per liter (approx. = ppb) LDc0 an acute toxicity measurement meaning dose lethal for 50% of the test animals EPA Environmental Protection Agency FDA Food and Drug Administration GGTP Liver serum enzyme gamma glutamyl transpeptidase HEW Health, Education and Welfare Department (now called Health and Human Resources Department) NIOSH National Institute for Occupational Safety and Health OSHA Occupational Safety and Health Administration p,p '-D D E Metabolite 'of DDT present as background in blood analyses SGOT Liver serum enzyme glutamic oxaloacetic transa minase TLV Threshold Limit Value: an exposure concentration representing conditions under which it is be lieved that nearly all workers may be repeatedly exposed day after day without adverse effect. Human Health Effects of Electrical-Grade PCB's* Section I Introduction Although the production of polychlorinated biphenyls (PC B 's) in the U .S . has been banned, definition of the human health risks they may pose continues to be an important issue. The PCB's were widely used for nearly 50 years, chiefly as dielectric fluids and plasticizers, and large amounts are still present in electrical equipment that will require servicing and disposal. PCB's are also present in numerous environments that may, or may not, merit containment or restorative actions. Small, but measureable levels are found in some edible fish. Thus, the potential for human exposure to PCB's remains. A t present, Company managers, employees, physicians and public officials concerned with appropriate handling of these exposure situations face a contradictory array of information on the possible health hazards. On the one hand, the U. S. press and environmental literature ( e .g ., ref. 1) increasingly portray PCB's as very toxic materials, and situations resulting in human exposure at any level as hazardous and alarming. The Toxic Substances Control Act of 1975 (T S C A ) and attendant regulations generally ban PCB manufacture, processing and distribution; severely limit use; and impose strict requirements for PCB labeling, disposal and storage for disposal. On the other hand, many European countries have made a quite different risk/b en efit assessment of PCB's since they continue to permit PCB manufacture and use in closed electrical equipment. More importantly, 40 years of U .S . occupational exposure in capacitor manufacturing has proven relatively uneventful, as judged by documented adverse health effects. Many medical studies or observations of human populations th at were heavily exposed to PCB's have been reported (2 ,3 ,4 ,5 ,6 ,7 ,8 ,9 ,1 0 ,1 1 ,1 2 ,1 3 , 1 4 ,1 5 ,16,1 7,1 8,1 9,20 ,33 ,47,4 9,5 0,-5 1,5 2,55 ,56 ,59,60,6 1,6 3). Some of these investigations are very recent and have only become available since the public image of PCB's was formed. Not all are yet reported in the pub lished literature. The authors have undertaken this paper to provide perspective for- General Electric managers and physicians, and to help identify situations of human exposure to PCB's that might present cause for concern. It draws on extensive GE experience in plants manufacturing PCB-filled capacitors, as well as on review of the scientific literature. The paper reflects today's knowledge and may be extended if significant new information becomes available. The concluding section describes on-going research that may provide additional information relevant to some present uncertainties. * This paper presents many quantitative observations because these are critically important to any health effects perspective. The fact that PCB's are persistent and readily detectable at low concentrations does not neces sarily mean that they are toxicologically significant. \4s u s e d t h r o u g h o u t th is p a p e r " e ie c t n c a l- g r a d e P C B 's " d e s c r ib e s v a r io u s P C B 's u s e d in G E c a p a c ito rs a n d tra n s fo rm e rs . 2- Section I Introduction The PCB bioeffects literature is voluminous, comprising several hun dred original articles. The present paper will not attempt to survey all aspects of this information, but will focus on those portions the authors judge most relevant to human health effects evaluation. In addition to literature citations the bibliography lists health-related conference reports (2 1 ,2 2 ,2 3 ,2 4 ,2 5 ) and several review books and documents (2 6 ,2 7 ,2 8 ,2 9 ,3 0 ). \ V 3- Section II PCB Composition and Terminology In chemical terminology "phenyl" denotes a ring structure of six carbon atoms attached to something else; "biphenyl" results when two such rings are attached to each other; and a "polychlorinated biphenyl" (PCB) is any molecule having multiple chlorine atoms attached to the carbon atoms of a biphenyl nucleus. Biphenyl and a representative trichlorobiphenyl (PC B ) are illustrated below: / 2 ,4 ,4'-Trichlorobiphenyl-(a PCB) There are 209 theoretically possible chlorinated biphenyl molecules, differing in the numbers (homologs) and positions (isomers) of the attached chlorines; of these 209 species, about half have been identified as being present among the complex mixtures that constitute commercial PCB pro ducts. These products range from light oily fluids ( d i- , tri'-, and te tra chlorobiphenyls) to heavy, honey-like oils (penta-chlorobiphenyls) to greases and waxes .(more highly chlorinated). The manufacturers of PCB's sold them under trade names; e .g ., "Aroclor" (Monsanto, U S A ), "Phenoclor" and "Pyralene" (Prodelec S .A ., France), "Clophen" (Farbenfabriken Bayer AG, Germany), or "Kanechlor" (Kanegafuchi Chemical Industrial Co. L td ., Japan). They also assigned product numbers that usually reflected either the-average degree of chlor ination o r, what is equivalent, the weight-percent chlorine in the mixture. Thus, the American Aroclor 1242, its French equivalent, Phenoclor DP3, and its Japanese equivalent, Kanechlor 300, all contained 42% chlorine, or 3 chlorine- atoms per biphenyl on the average. Likewise, Aroclor 1254 and its German equivalent, Clophen A50, contained 54% chlorine, or 5 chlorine atoms per biphenyl on the average. Aroclor 1016 designated a Monsanto PCB product similar to Aroclor 1242 with enhanced biodegradability, which was accomplished by removal of higher chlorinated homologs. Electrical equipment manufacturers fu rth er purified these commercial PCB products to insure electrical performance; blended them with stabi lizers and diluents; and then put the resultant PCB mixtures into capaci tors and transformers under their own trade names and product numbers. \ GE's trade name for its PCB mixtures was "Pyranol." "Askarel" is a gen eric, industry-w ide term fo r a PCB or other fire-resistant dielectric flu id. -4- Section II PCB Composition and Terminology In short, the materials now collectively referred to as "PCB's" are d ifferen t complex mixtures of chlorinated biphenyls used under a variety of product names. These mixtures always contained several dozen individ ual PCB isomers and homologs clustered around some average degree of chlorination, frequently some trichlorobenzenes as diluents; often about 0.5% of an aliphatic epoxide as a stabilizer; and parts-per-m illion levels of trace impurities such as the polychlorinated derivatives of methylbiphenyls, terphenyls, naphthalene or dibenzofuran. * Returning to chemical terminology, "furan" denotes a ring structure of fo ur carbon atoms and one oxygen atom; and "dibenzofuran" a tricyclic arrangement of two benzene rings and one furan ring fused together. This structure can result if an oxygen atom is added to a biphenyi-system. If multiple chlorine atoms are attached to this nucleus, then a "polychlor inated dibenzofuran", or PCDF, results as illustrated below. There are 135 theoretically possible chlorinated dibenzofurans. Cl o 1,3,7-Trichlorodibenzofuran (a PCDF) Trace levels of PCDF's have been detected in laboratory samples of U. S. PCB's, including specimens of both individually synthesized isomers and commercial mixtures (3 2 ,3 7 ). * There are two plausible explanations for the presence of PCDF's in commercial PCB's: F irst, contamination may have occurred during manufacture, possibly as a result of oxygen in the benzene used to make the original biphenyl. Such contamination may have existed in French and Japanese PCB's, but apparently was not significant ly present in American-made PCB's after one episode in 1333. Second, PCDF's may have been formed during usage as a result of high tempera tu re oxidation. Oxidation experiments (31) report maximum conversion of Aroclor 1254 to total PCDF's as 2-3% at 550-600C. Conditions suitable for significant conversion of PCB's to PCDF's did not exist in the normal manufacture of, and are not expected in the normal use of, capacitors and transform ers, but may occur in high-tem perature heat exchangers. 5- Section II PCB Composition and Terminology A related group of molecular species mentioned in this paper are the polychlorinated quaterphenyls (P C Q 's), which contain four phenyl units and a variable number of chlorine atoms as illustrated below: 6" Section III History of PCB Use The Swann Chemical Co. began commercial U .S . production of PCB's in 1929. In 1935 Monsanto Industrial Chemicals Co. (Monsanto) purchased Swann and continued the manufacture of PCB's, initially at Anniston, Ala. and later at S a u g e t,III. PCB's are excellent non-flammable, high-boiling, thermally and chemi cally stable dielectrics and solvents, and these properties led to .a wide range of industrial applications. In addition to serving as dielectric fluids in capacitors and transformers, PCB's were used as plasticizers, hydraulic and heat exchange fluids, and were incorporated into such products as dust-settling agents, die-casting lubricants, inks, dyes, paints, pesticides and adhesives. PCB's were widely used in carbonless reproduction paper and entered paperboard production. PCB's from such sources have entered into the. environment. Slow biodegradability and bioaccumulation account for the presence of PCB's in sediments under rivers and lakes and in fish. Trace quantities have been found in some other food as well. As a result, PCB's are found in trace quantities in the blood and fa tty tissue of the human populations of all industrial nations. Concern over such accumulations in the environment led Monsanto in 1970 to begin voluntarily restricting PCB sales to manufacturers of sealed electrical equipment (3 3 ). In 1976 Congress enacted TSCA, which man dated a phaseout of PCB production and use. Although similar PCB phase outs were instituted in Japan, Canada and Sweden, many other industrial nations ( e . g . , U .K ., Germany, France, Spain and others) continue to permit PCB production and the manufacture of PCB-filled capacitors and tran sfo rm ers. Estimates (34) _for the cumulative total of U .S . industrial uses of PCB's from 1930 to 1975 and th eir service status in 1976 are noted in Table 1 below: Table I Use Capacitors Transformers Plasticizers Hydraulics and Lubricants Carbonless copy paper Misc. industrial Heat transfer r Total Millions of Pounds In d u s tr iaal PCBB's C urrently PCB Purchases in Service 630 450 335 300 ns 80 45 8 28 20 1253 758 -7- Section III History of PCB Use vI y Estimates (34) of the status of these PCB's are shown in Table II below: Table II Disposition Environmentally biodegraded Incinerated Landfills and dumps In soil, w ater, air and sediment C urrently in electrical service In use other than electrical service Total Millions of Pounds 30 25 290 150 750 8 1253 -8- Section IV Health Effects of PCB and PCDF Mixtures A. Observations on Test Animals 1. General Bioeffects PCB's resemble other fat-soluble chlorinated organic chemicals in biological uptake and internal transport. An animal can readily absorb PCB's through the lungs upon inhalation or through the intestines following ingestion, or less readily through the skin after phys ical contact. Fish can absorb PCB's through the food chain or through th e ir gills, and the bioconcentration factors* can range between 103 and 106. Once inside the body PCB's gradually distribute themselves equally among all fa tty deposits present. Elimination processes are generally slow, especially for the more highly chlorinated homologs. When increasing doses of PCB's are administered to animals the firs t observable effect is the induction, prim arily in the liv e r, of the cellular enzymes variously, known as "drug metabolizing" or "detoxification" en zymes, or as "mixed function" ( i . e . , chemically non-specific) oxidases. These enzymes catalyze chemical processes by which the animal's body seeks to convert lipid-soluble foreign chemicals into water-soluble sub stances excretable in the urine. Such effects are also produced by many other substances, and are generally regarded as physiological rather than pathological processes. At high enough doses in animals, PCB's can induce many types of toxic effects and eventually death. The reported toxic effects with chronic exposure include chick edema disease and teratogenesis in chickens; liver hypertrophy, fibrosis, neoplasia and cancer in rodents; gastric and d e r matological lesions in monkeys; and reproductive dysfunction in several species. An extensive literature on this subject is referenced in the bibliography (21-30). There can be differences in toxicity between different PCB products, with the higher homologs generally being reported more toxic in chronic tests and the lower homologs more toxic in acute tests. There can also be large toxicity differences observed between different specimens of the same type of PCB, apparently caused by im purity-level variations. 2. Impurity Effects In 1970 a Dutch scientist, J .G . Vos, served striking differences in chick embryotoxicity among three commercial PCB's that all contained 60% chlorine: Aroclor 1260 (which had virtu ally no e ffe c t), Clophen A60, and Phenoclor nDP6. He then demonstrated that the variable toxic agent in the system was an im purity, polychlorinated dibenzofuran (PCDF) (3 5 ). He also showed that this impurity was responsible' fo r chloracne in PCB dermal tests with rabbits (3 6 ). ob It is not possible to determine if the toxic response variabilities ob served in other PCB animal tests should be ascribed to variations in PCDF levels because, unfortunately, few of the investigators reported impurity levels in the PCB specimens they tested. Chemical analyses have sub- 'A b i o c o n c e n t r a t i o n f a c t o r i s d e f i n e d a s t h e r a t i o o f t h e P C B c o n c e n t r a t i o n i n a f i s h to that in i t s a m b i e n t w a t e r -Q - 1\ Section IV Health Effects of PCB and PCDF Mixtures sequently reported that European and Japanese PCB's contained 5-20 ppm PCDF as manufactured, while the U.S.-m ade Aroclors had 0-2 ppm (3 7 ). 3. S tru ctu re-A ctivity Relationships Many recent animal studies have aimed, at relating the molecular structures of individual PCB, PCDF or similar molecules to th eir biological activities. These studies have shown that chloracnegenic activity is specifically associated with molecules shaped like flat rectangles with chlorines at the corners (3 2 ). All such chloracne genic species are also capable of inducing one specific type of mixed function oxidase/ designated cytochrome P448 because of its spectral ab sorption band position. Most lower homolog PCB molecules do not induce P448; however, some higher chlorinated PCB homologs, which constitute a few percent of the higher Aroclors and which are virtu ally absent from the lower Aroclors, do exhibit moderate P448-inducing activity. By comparison, 2 ,3 ,7 ,8 -te tra chlorodibenzofuran is 700 times as potent a P448 inducer in rats as the active PCB isomers and is many orders of magnitude more biologically potent than most other PCB and PCDF molecules (26 chap. 6 ). 4. Toxicity and Carcinogenicity Test Results Toxicity testing of PCB's in experimental animals has produced a large body of experimental observations. Repeated short-term feeding tests have shown the acute toxicities of PCB's in animals to be low, with LD5Q values reported from 1,300 to 11,300 mg per kg of body weight (2 9 ). Concerns over chronic human health effects of chlorinated aromatic hydrocarbons (including PCB's) led to a series of 3-4 month inhalation tests in animals at the Harvard School of Public Health in the 1930's (38) and confirmatory tests at the University of Cincinnati's Kettering Labora tory in the 1950's (3 9 ). From the observations in both test series the investigators recommended threshold limit values (T L V 's ) of 1000 pg/m3 for PCB's with 42% chlorine or less, and 500 pg/m3 for the more highly chlor inated PCB mixtures. These T L V 's, used by industry during the remain ing period of PCB use, were accepted as standards by the American Con ference of Governmental Industrial Hygienists (A C G IH ) in 1956, and by OSHA in. 1971, and were adopted by many other countries as well. When PCB's are chronically administered to rats in increasing doses, there is apparently a dose-related progression from "no-effect", to mild, reversible effects (4 0 ) to serious irreversible liver disease. The observed progression of effects on rodent \Iivers includes cellular enzyme induction, microsomal proliferation, cellular hypertrophy, focal necrosis, fibrosis and eventually the development of increasingly abnormal types of tissue (41,42, 43). In some of these tests in rodents, PCB's have been judged to show carcinogenic activity, while in other tests the same materials (Aroclor 1254 and 1260) were judged not to have shown carcinogenic activity (33, 42,43, 44 ) . -1 0 - Section- IV Health Effects of PCB and PCDF Mixtures Reports of positive carcinogenic findings in long-term tests of sub stances in rodents at high dosage levels, while prompting caution with respect to human exposure, are not an uncommon observation. General Electric has noted that in HEW's "Survey of Compounds Which Have Been Tested for Carcinogenic A c tiv ity ", PHS Document 149, Vols, 4 ,5 ,6 , & 7, 70% to 80% of all substances tested from 1960 to 1973 were reported to produce excess tumors in animals (4 5 ,4 6 ). B . Human Health Effects Observations 1. Early Occupational Chloracne Reports During the firs t years th at PCB's were in industrial use, three American medical reports described unambiguous episodes of PCB-Iinked occupational illness.* Two involved PCB vapors from high-tem perature equipment, and the other was ascribed to an unidentified im purity. 35 The firs t episode occurred in 1933 at the Swann Chemical Co. when 23 of 24 men working on the manufacture of PCB's almost simultaneously developed skin eruptions, diagnosed as "chloracne." The eruptions were similar to adolescent acne, i . e . , a progression of blackheads and pustules th at persisted several months before disappearing. Some of the men also complained of lassitude but showed no clinical signs of ill health other than the skin condition. In th eir report on this PCB episode, the investigators concluded that the toxic agent was probably an unidentified impurity that appeared in the PCB when a new source of crude benzene was used for making the biphenyl (4 7 ). When purchase from this benzene source was discontinued and the process equipment better enclosed, the problem disappeared. Chloracne was known by this time to be induced by chlorinated coal ta r products and by chlorinated naphthalenes (Halowaxes). Later, occupa tional chloracne was frequently observed among electrical workers who handled "cable wax" containing the latter materials. Chloracne was found to clear up some time after the contact was removed and improved hygiene instituted. Concerns about long-term effects of chloracne have been ad dressed by a recent study, in which a group of 121 male chemical workers who had experienced a chloracne attack in 1949 (unrelated to PCB's) showed no excess in total mortality nor in cancer mortality after 29 years (4 8 ). A background incidence of chloracne in children in Northern ItaKy has been reported as 0.1 -0.5% (26, p .3 3 1 ). ! i The second episode involving PCB's occurred in 1950 and 1951, when 7 of 14 people exposed to vapors (reported at 100 pg/m3 ) from a leaky PCB-containing heat exchanger developed chloracne (4 9 ). A th ird epi sode was noted in the early 1960's when 13 of 16 people exposed to vapors from an oven in which PCB-plasticized enamels were being baked were similarly affected (50). Q>o/ne o t h e r e a r l y p a p e r s c o n f u s i n g l y a s s o c i a t e d P C B ' s w i t h t h e h e a l t h effects o f certain o th e r c h lo rin a te d hydrocarbons. -11- ( ' Section IV Health Effects of PCB and PCDF Mixtures 2. Vusho Episode Despite the long and relatively uneventful PCB occupational exposure experience the Japanese "Yusho" (oil-disease) incident in 1968 created a wave of concern. In that episode some 1300 people in southwestern Japan developed a very severe and persistent form of chloracne after eating rice oil found to have been contaminated by fluid leakage from a heat exchanger originally filled with Kanechlor 400, a Japanese PCB ( 5 1 ) .* In addition to the acne-like eruptions and feelings of lassitude p re viously observed in chloracne outbreaks, the Yusho victims commonly ex hibited swelling of the upper eyelids, increased eye discharge, hyper pigmentation of the nails and skin, sweating of the palms and a variety of other individual effects. Signs of the disease were also transmitted in some cases to newborn children. The brown dermal pigmentation of these children is reported to have diminished with time. (26 chap. 9B 1). In the same period a chick edema epidemic that killed 400,000 chickens was traced to consumption of feed containing the same rice oil. The firs t contaminant to be identified in the rice oil was Kanechlor, and a widespread demand for controls or elimination of all PCB's resulted. A fter the Vos identification of PCDF impurities as the active toxic agent in two PCB animal test sytems, Japanese scientists reanalyzed some of the rice oil specimens that had caused Yusho illness (5 2 ). From 1975 to 1978 it became known that these rice oil samples contained about 1000 ppm PCB's, 5 ppm PCDF's and 1000 ppm of another chlorinated material, later identified as polychlorinated quaterphenyl (5 2 ,5 3 ,5 4 ). The PCDF's and PCQ's presumably were formed from PCB's by thermal oxidation and con densation in the heat exchanger at high temperature. The apparent PCDF content of the leaking heat exchanger flu id , calculated from the above analysis of rice oil contaminants, is 2500 ppm (0.25%), a very high level compared to PCDF levels in U .S . electrical-grade PCB's as manufactured (0-2 ppm). As the Yusho victims were estimated to have ingested an average of 2.0 gm of the heat exchanger fluid (5 1 ), this amount would have included about 1.0 gm each of PCB and PCQ, along with approximately 5 mg of PCDF. As will be noted later, 1.0 gm of PCB is less than the average body burden of heavily exposed capacitor workers; however, the Yusho victims apparently eliminated their PCB burdens more rapidly than capaci tor workers, exhibiting nearly normal background levels of PCB's after 5 years. Nonetheless, many Yusho patients remained sick, and such autopsy liver samples as became available showed concentration of penta- and hexa-chlorinated PCDF's in that organ (5 2 ). "A s e c o n d e p is o d e , in v o lv in g e ss e n tia lly id e n tic a l c irc u m s ta n c e s a n d con sequences, has ju s t b e e n re p o rte d fro m T a iw a n (59). -1 2 - ~ - - - r-- " ^ " r^ e c lio n .lV , Health Effects of PCB - and PCDF Mixtures These later Japanese investigations linked the disease to the PCDF content of the rice oil. This conclusion is consistent with PCDF activity in animal tests and with the observation that body burdens of electrical-grade PCB's (from inhalation and skin contact) larger than the PCB doses in gested by Yusho victims have not induced Yusho illness in capacitor workers. The Japanese Yusho investigators also reported th at the minimum dose fo r induction of the disease was about 0.5 gm of the thermally decomposed heat exchange fluid (the PCB-PCQ-PCDF m ixture) (5 1 ). Using a range of reported PCDF analyses (5 2 ), the PCDF toxicity threshold dose might therefore be estimated at 1.0 - 1.5 m g .* A similar threshold dose (1.26 mg) has been estimated from data on the amount of PCDF consumed by pa tients before the onset of the symptoms in the recent episode in Taiwan (60). 3. Effects of Eating Fish Containing PCB's The Michigan partment of Public Health, under the sponsorship of FDA, conducted a study of 182 adults, 105 of whom consumed over 26 pounds of Great Lakes fish per year. A significant correlation between blood PCB levels and quantity of fish eaten was observed. The mean blood PCB value for the exposed group was 73 ppb, while that of the comparison group was 20 ppb. Individual blood PCB levels ranged from 7 ppb for a person who ate no fish to 366 ppb for one who ate 132 pounds per year (1 1 ,1 2 ). De Evaluation of health histories and current medical problems of the study subjects failed to identify a significant difference between the ex posed and comparison groups. Symptoms characteristic of reported PCB toxicity (Yusho symptoms) were not found nor did those with the highest PCB levels have a consistent pattern of complaints or conditions. Although the data demonstrate an association between fish consumption and PCB levels in humans, no toxic manifestations from this exposure have been identified to date (1 2 ). The question of PCB accumulation over time and the effects of long-term exposure' are being evaluated in a continuation of this study. A recent study (6 1) of 458 persons who had significant exposure to DDT from eating fish also reported PCB blood levels (arithmetic mean, 22 p g /L ; range 3.2- to 158 p g /L ). The authors report that the following significant correlates of log diastolic blood pressure might account fo r 24.1% of its variation in this cohort: body mass index, 6.8%; sex, 8.3%; log PCB level, 6.3%; age, 1.5%; Hollingshead index, 1.1%. 4. Clinical Studies of Capacitor Workers The most extensive long term exposure of humans to PCB's has probably occurred in capacitor plants around the world. (There were 17 capacitor plants using PCB's in mA r e c e n t r e a n a l y s i s o f Y U S H O p a t i e n t d a t a p u t s t h i s f i g u r e a t 0 . 6 m g . ( 2 6 p . 2 9 1 ) -13- ..Section IV Health Effects of PCB . and PCDF Mixtures th U .S .) 'M any employees in"these plants had daily PCB skin contact for several years and inhaled PCB's at levels in the 100 to 1000 pg/m3 range. General Electric's major capacitor fluid usage was originally Aroclor 1254, then changed to Aroclor 1242 around 1954, and subsequently to Aroclor 1016 (and some 1221) in 1971. This usage pattern was probably typical of the industry. PCB blood tests of 174 heavily exposed GE capacitor workers have indicated a geometric mean* around 300 ppb and an arithmetic mean of about 500 ppb. Ten percent of the individuals' analyses were above 1000 ppb. A blood PCB value of 300 ppb roughly corresponds to a 100 ppm level in fatty tissue of the same individual, or a body content of about 1.5 gm (1 6 ). By comparison, mean serum PCB background levels fo r various groups of industrially unexposed persons in the U .S . range from 2-24 ppb (26 p.269); In capacitor plants the most frequent PCB-related health effect ob served was transient skin rashes affecting a small percentage of exposed employees. For example, analysis of GE medical records of the Ft.-E dw ard and Hudson Falls, N .Y . plants for the 1960-1975 period showed a cumula tiv e total of 49 contact and allergic dermatitis cases attributed .to PCB's among an exposed employee group totalling about 1300 individuals (5 ) . This condition responded to simple topical treatment and employee reassign ment to other work areas. The medical records of this worker population have shown no obvious incidence of systemic disease attributable to PCB's. Additional studies (described below) are continuing. Observations of high PCB blood levels, some dermal conditions and isolated cases of chloracne have been reported in the industrial hygiene literature of Japan, Finland, Australia and Italy ( 2 ,3 ,4 ,6 ,7 ,8 ) . The re ported biochemical examinations ( 2 ,3 ,4 ,6 ,7 ) identified scattered individual abnormalities in serum enzymes; however, on a group basis the various liver function tests were considered normal. The Italian chloracne cases of re f. 7 were observed in men who had worked whore the level of Aroclor 1254 was measured at 5200-6800 pg/m3 (10-14 times the U .S . T L V ). Ref. 4 states that the Finnish capacitor workers are in good health and th a t, in spite of approximately 50 times larger PCB concentration in their blood compared with a control group, the researchers were unable to detect any biological- effect caused by PCB in them. In a 1977 U .S . study 32 capacitor workers were examined in a pro gram sponsored by the South Carolina State Department of Health *and Environmental Control (D H EC ). Newspaper reports (January 1978) quote D r. D .H . Robinson of the DHEC\as saying that the study "clearly shows th at at present there is no evidence of physical harm resulting from work ing with PCB's." D r. Ira Rosenblum of Albany Medical College, who directed the study, is also quoted as stating, " It is exceedingly difficult * T h e g e o m e t r i c m e a n o f n num bers e q u a ls the n t h r o o t o f t h e i r p r o d u c t . F or a lo g n o rm a lly d is trib u te d p o p u la tio n the g e o m e tric m e a n eq ua ls the m ed ia n. 14- Section IV Health Effects of PCB ' and P C D F Mixtures to establish a cause-effect relationship between exposure to RGB's in the workers' environment and any sign or symptom of acute disease of occupa tional origin (9 )." A study of occupationally exposed Bloomington, Ind. capacitor Work ers and other residents, reported, in 1978, did not note liver in ju ry , but found that levels of GGTP liver enzyme and plasma triglycerides were positively correlated with those of serum PCB's (1 0 ). No correlations were observed between serum PCB levels and five other liver function indica tors. A letter to the study participants from the U .S . Center for Disease Control noted th at human cancer risk would remain unknown until the extensive mortality study (reported below, re f. 15) then being conducted by NIOSH had been completed. A broader clinical study of 224 Bloomington, In d . capacitor workers was later conducted by NIOSH. The investigators reported in a prelimin ary d raft (1981) that the plant employees' serum L-PCB levels* were 8 to 50 times, and th eir serum H-PCB levels* 2 to 4 times, the community background level (1 7 ). A parallel study was also conducted of 92 em ployees in two electric utilities, 39 of whom were active in the maintenance, repair and overhaul of transformers (1 8 ). A d ra ft report covering both r studies (63) stated th at no clinical abnormalities directly attributable to PCB exposure were observed on physical examination. Serum SGOT, GGTP, triglycerides and HDL-choIesterol were within normal ranges. The firs t three of these parameters were correlated positively, and the last, negatively, with serum PCB levels. One report at variance with this pattern of clinical studies describes a recently published study of 80 Italian capacitor workers who were chron ically .exposed to French and Italian PCB's containing 42% chlorine. PCB concentrations in air were reported from 48-275 pg/m3 , and skin absorp tion was noted. Fifteen of the 80 exhibited skin abnormalities, including 4 diagnosed as chloracne. Sixteen other workers were judged to show more or less pronounced hepatic involvement, as deduced from symptoms, clini cal examination of the liv e r, and serum enzymes (1 9 ,2 0 ). In 1976 D r. Irvin g Selikoff of Mt. Sinai School of Medicine began a study of the health status of capacitor workers in the GE plants at Hudson F alls/F t. Edward, N .V . Three hundred tw enty-six volunteers, some of whom had a long history of occupational exposure to PCB's, were given extensive medical examinations. In\ one paper the investigators reported average PCB blood levels of 124 ppb' (lower homologs) plus 48 ppb (higher homologs) and noted a correlation between individual values and the esti mated job exposure. A number of dermatological findings were reported, some of which showed an association with blood PCB levels of the higher 'L -P C B (lo w e r h o m o lo g s } and H -P C B (h ig h e r h o m o lo g s} are d e fin e d as species h a vin g re s p e c tiv e ly sh o rte r a n d lo n g e r gas c h ro m a to g ra p h ic re te n tio n tim es th a n p ,p ` -D D E . 15- Section IV .Health Effects of PCB and PCDF Mixtures homologs. The authors noted a paucity of other abnormal findings on physical examination, including a very low prevalence of abnormal liver findings (1 3 ). In another 1979 paper the Mt. Sinai group reported that 14% of the workers examined had abnormal vital (lu n g ) capacity, compared with 5.6% cited for Morris' non-smoking normal population (14, 62). We believe the significance of this observation is uncertain. Medical surveillance by General Electric of a group of 174 heavily ex posed capacitor workers has consisted of multiple examinations over the last four years. The GE service of this group averages over 15 years, and ranges from 1 to 35 years. About 20% of this study population is overweight, shows elevated serum triglycerides and periodic, mild eleva tions of fasting blood sugar. H o w ever,'th e medical examinations have not revealed serious health problems related to PCB exposure. The pulmonary function tests of the non-smokers in this heavily exposed population were in the normal range. As previously noted, the serum PCB levels in this group are high (1979' arithmetic mean of 500 ppb with 10% of the individual analyses above 1000 ppb) and persistent. The only clinical parameter thus fa r found to be statistically correlated with the serum PCB level is that of serum tr ig ly cerides. The interpretation of this correlation is confounded by the fact that PCB's distribute equally among all lipid pools in the body, including those in the blood; and hence for any given PCB body burden the serum PCB level must vary directly as the level of serum lipids. A' rough correlation which is emerging from this study of GE capacitor workers is that people who are exposed to airborne PCB's for long periods may show an increase of about' 0.5 ppb in th eir blood fo r each 1 pg/m3 present. Thus long-term environmental exposure to air containing 2 pg/m3 PCB might be expected to add about 1 ppb to an average person's 2-24 ppb PCB background level, a small amount - compared with the normal background, and insignificant compared to levels reported in heavily ex posed capacitor workers (30-3000 ppb ref. 17). 5. NIOSH Mortality S tu d y. Three preliminary reports have sug gested a possible epidemiological association between PCB exposure and human cancer (3 3 ,5 5 ,5 6 ). All of these have been regarded as inconclusive because they involved small groups of people, few deaths, uncertain levels of exposure to PCB's and to other chemicals, short latency intervals, and lack of consistency in cancer site. The International Agency for Research on Cancer evaluated the evidence available through 1979 fo r PCB's causing cancer in humans as "inadequate", meaning "insufficient to allow any conclusion regarding carcinogenicity for humans" (3 0 ). The FDA's assess ment in 1979, based on review of both animal tests and the human reports, was that the question of carcinogenicity of PCB's was unresolved, though a matter worthy of fu rth e r inquiry (5 7 ). Shortly th ereafter, more defini tive evidence became available from a long-term NIOSH study of two PCBexposed capacitor worker populations. -16- __ __ Section IV Health Effects of PCB and PCDF Mixtures A report of this NIOSH mortality study (1 5 ), by fa r the most com prehensive ever conducted concerning human PCB exposure, provides the best current data on m ortality experience. This retrospective cohort, standardized mortality study includes 2567 PCB-exposed hourly capacitor workers in two plants7 one of which was the GE Hudson F a lls/F t. Edward, N .V . complex. The cohort was defined as all workers who accumulated at least three months employment in areas of the plant where there was potential for exposure to PCB's. Exposure in one plant began as early as 1938, in the other by 1946. A total of 39,018 person-years had been accu mulated by the January 1, 1976 study cutoff. Personal a ir samples in the plants in A p ril, 1977 ranged from 24 to 1260 pg/m3 and area air samples from 3 to 810 pg/m3 PCB's. The NIOSH study reported that the incidence of all cancer mortality fo r these plant populations was slightly lower than th at of the general U .S . population, or 39 deaths due to malignant neoplasms vs. 43.79 ex pected based on national norms adjusted for age and sex. For other causes of death the findings were as follows: from cardiovascular disease, 60 vs. 62.93 expected; from nervous system disease, 11 vs. 12.55 expected; from accidents, 13 vs. 18.29 expected; and from all other causes, 40 vs. 44.79 expected. Deaths from all causes were 163 vs. 182.35 expected. No statistically significant excesses of specific cancer types were observed, though the authors called attention to four rectal and three liver cancer cases (5 of 7 in one p lan t). We believe this observation should be followed up by extension of the study time span, because these reported rectal and liver cancer cases are too few to be statistically mean ingful. Liver cirrhosis deaths were higher than normal in one plant (with the possibility of some alcohol association noted) and lower in the other, with the total cohort experience about equal to national norms. None of the causes of death analyzed demonstrated a clear association with latency. There was no clear relationship between increasing lengths of employment in PCB-exposed jobs and the risk of mortality due to cancer or cirrhosis of the liver. While the mortality experience reported in this paper is reassuring, it should be recognized th a t even this large study does not yet encompass enough person-years of experience to exclude the possibility that there might have been increased risk of some uncommon type of disease. Fur th e r, the plant populations described were not segregated between those in lightly vs. those in more heavily exposed jobs, which might have provided more data concerning dose-related differences. r`' ^ ? : Section IV Health Effects of PCB and PCDF Mixtures C. Health Effects Summary To summarize, there is now available a scientific literature of several hundred papers describing many facets of the biological behavior of PCB's in animals: routes and rates of uptake and elimination; bioaccumulation and persistence; enzyme induction; other pharmacological effects; and the effects of molecular structures of individual PCB molecules or impurites on biological activity. This literature includes early toxicological studies that led to recommendations to limit continuous occupational PCB exposure to 500 or 1000 pg/m3 (depending on the degree of chlorination). Nearly 50 years of experience has shown that electrical-grade PCB's, at industrial occupational exposure levels, are not acutely toxic to humans. A continuing concern about these materials has been potential chronic effects, since exposure to PCB's leads to accumulation in the body and retention for long time periods. The largest available source of data on such effects is presented by capacitor worker populations. Thousands of such individuals received light to heavy exposures to PCB's of Aroclor types 1254, 1242, and 1016 over many years, and elevated levels of PCB's in th eir blood and fatty tissues continue to be observed. A number of clinical studies of such exposed worker groups have now been completed (2 ,3 ,4 ,5 ,6 ,7 ,8 ,9 ,1 0 ,1 3 ,1 4 ,1 6 ,1 7 ,1 9 ,2 0 ,6 3 ). Dermal reactions were noted in some cases. These included some rare observations of chloracne, especially in plants outside the U .S . Some studies report correlation of serum enzymes and triglycerides with serum PCB levels. In sum, the preponderance of these studies neither identify significant clinical disease associated with electrical-grade PCB exposure, nor provide persua sive evidence of health impairment. In addition, the NIOSH study of the long-term mortality experience of a large group of hourly capacitor workers at two plants showed no excess in total mortality, nor in mortality due to cancer, to* cardiovascular disease or to nervous system disease. A human hazard that was not recognized early was the possibility that PCB's used in high temperature environments, such as heat exchangers or baking operations at 270C and higher, could be partially oxidized to PCDF's with a consequent increase in toxicity. This factor makes the YUSHO ' episode not directly relevant to the usual U .S . occupational or environmental exposure. Even in such special cases the health risk ap pears to be fin ite. The Japanese and Taiwanese Yusho investigations both provide evidence that the PCDF threshold dose for inducing Yusho illness is 0 .6 -1 .5 mg. This may provide a benchmark for evaluating PCDF risk and for considering whether protective measures are needed when a PCDF level is identified in an environment (as, for example, in air with PCB's which-have been overheated, or as trace quantities in the edible portion of fis h ). The available analyses indicate that U .S . electrical-grade PCB's contained 0-2 ppm PCDF's as manufactured. Such levels may be consider- -18- Health Effects, of PC 8 and PCDF Mixtures ed .toxicologically insignificant since intake of about a kilogram of such PCB would be needed to acquire a threshold dose of PCDF. However, additional measurements are needed to check the DCDF levels in used PCB's. In view of the lack of evidence for health damage in people with heavy PCB exposure in the past (daily skin contact and inhalation of air containing 100-1000 pg/m3 ) , there does not presently seem to be a sub stantial basis for concern about the effects of exposure to environments containing electrical-grade PCB's at the greatly reduced levels typically encountered today. Accordingly, while a confirmed blood or fat tissue PCB analysis* significantly higher than the local average may indicate exposure, there is little reason to believe that significant adverse health effects will occur. In the light of our present knowledge there is no fu r th er examination procedure or therapy which is likely to be meaningful. While the lack of evidence fo r serious effects of electrical-grade PCB exposure on capacitor workers is encouraging, the studies available today do not completely rule out the possibility of subtle or infrequent effects in some individuals who were heavily exposed in the past, and more obser vation time is needed to reduce uncertainty about the very long-term ex perience of these people. Concerns about the reproductive experience of heavily exposed individuals also need to be addressed. The concluding section of this paper describes some on-going research programs that may resolve some of these uncertainties. *A n y u n c o n f ir m e d s in g le P C B a n a ly s is s h o u ld be r e g a r d e d c a u tio u s ly : a r e c e n t r o u n d - r o b m s t u d y b y t h e N . Y. S t a t e D e p a r t m e n t o f H e a l t h s h o w e d a t least o n e case w h e re 2 o u t o f W c o m m e rc ia l analyses o f the sam e s a m p le re p o rte d P C B values that w ere 2 0 -fo ld diffe re nt from the m edian. Sectio n X U.S. PCB Regulations The concern about environmental accumulation of PCB's and about possible human health effects led in 1976 to the enactment of Section 6(e) of TSCA. Section 6 (e ) directs EPA to prescribe PCB marking and disposal requirements; generally bans continued PCB use except in a "totally en closed -manner;" and generally bans PCB manufacture, processing and distribution. The PCB Disposal and Marking Rule and the PCB Ban Rule promulgated by EPA to implement Section 6(e) contain the following major features (58): - Most items that contain 50 ppm (0.005%) or greater PCB must be labeled. - All liquids th at contain 500 ppm (0.05%) or greater PCB and PCB-containing capacitors with 3 lbs. or more dielectric fluid must be disposed of in an EPA-approved high temperature incin erator. - All liquids that contain between 50 ppm and 500 ppm PCB must be disposed of in an EPA-approved high temperature incinerator, in a high efficiency boiler or in an* EPA-approved chemical waste landfill. - PCB-containing capacitors with less than 3 lbs. of dielectric fluid may be disposed of as municipal solid waste unless owned by a capacitor manufacturer or manufacturer of items th at contain such capacitors ( e . g . , microwave ovens, electronic equipment and fluorescent light ballasts and fix tu re s ). These manufac tu rers must dispose of th eir PCB-containing capacitors in an EPA-approved high-temperature incinerator. Waste oil that contains any detectable concentration of PCB's cannot be used as a sealant, coating or dust control agent. Most items and liquids that contain 50 ppm or greater PCB and that have been designated for disposal must be stored in com pliance with specific requirements. - PCB's contained in intact, non-leaking capacitors, transformers and electromagnets are being used in a "totally enclosed man n e r;" * therefore, such capacitors, transformers and electromag nets may remain in service. - The manufacture, processing, distribution and use of PCB's in concentrations below 50 ppm may continue without restriction *. ' A r e c e n t c o u r t d e c i s i o n r e q u i r e s E D4 t o r e - e x a m i n e t h i s d e t e r m i n a t i o n . -2 0 - i u j . ^ wi.iiip a m u m m ip ipjwup U.S. PCB Regulations Eleven uses of PCB's in other than a "totally enclosed manner" (including servicing transformers and electromagnets and PCB use in existing stocks of carbonless copy paper, in pigments and in heat transfer and hydraulic systems) may continue subject to certain conditions and time limits. The FDA has established tolerances for unavoidable residues of PCB's in several classes of food. Present tolerances are given below (5 7 ): Milk and Poultry Eggs Fish and dairyproducts shellfish(edible portion) 1.5 ppm (fa t basis) 3 ppm 0.3 ppm 5 ppm * ' In 1979 th e F D A re d u c e d the to le ra n c e to r fish and s h e llfis h to 2 p p m . P ut sta ye d the effective date o f the 2 p p m tole ra n ce p e n d in g re s o lu tio n o f oO /ections. v Section V I; On-Going Research ' Programs Notwithstanding the experience of 50 years usage and the extensive research which has been completed, some questions and uncertainties re main. General Electric and others are continuing research on some of these issues. The actual PCDF content of PCB's in existing capacitors and tra n s formers as well as in various environmental samples needs to be deter mined. Based on the reported PCDF content of Aroclors (0 -2 ppm ), one may postulate that PCDF's will be detected in such minute quantities that they should not be of concern. This postulate needs to be validated by analysis and evaluation, and GE is conducting an analytical research pro gram to make such data available. A number of medical research programs that will fu rth e r clarify the possible PCB health effects are continuing. With the cooperation of Gen eral Electric, New York State's Department of Health (D r . Philip R. T a ylo r) is analyzing fu rth er the epidemiology of the GE capacitor worker popula tion, and is extending the research to include reproductive experience. General Electric is continuing medical research with a group of heavily exposed capacitor workers; and some additional observations may become available from the Mt. Sinai School of Medicine's studies of other workers at the same location. The Michigan State Department of Health (D r . H .E .B . Humphrey) is extending and broadening its study of individuals who have ingested PCB's by eating fish. Another question concerns industrial exposures of transformer w ork ers. Transformer plants typically used Aroclor 1254 and 1260, usually, mixed with chlorobenzenes, for a portion of th eir production-, whereas Aroclor 1260 was not used in capacitors. Few epidemiological studies of transform er workers exposed to PCB's are available. The capacitor worker experience may be relevant, however, as Aroclors 1254 and 1260 contain substantially overlapping though not identical populations of PCB molecules. In addition, capacitor worker blood analyses show retention of the mole cules contained in Aroclor 1260. Lastly, some research programs are being directed at economically effective PCB containment and destruction processes in order to respond more effectively to Federal and State requirements. General Electric is active in some of these programs. V -2 2 - fy cK Ct ' .* ~ Section al I S-' References Cited !j C 1. J .H . Highland, et al, "Malignant Neglect", Alfred A. Knopf, New Y o rk , 1979, Chapter 3. 2. Hasegawa, H ., Sato, M ., and T s u ru ta , H ., PCB Concentration in the Blood of Workers Handling PCB, Occup. Health, TO, 50 (1972). (In Japanese). 3. Kitamura, M ., Tsukamoto, T . , Sumino, K ., Hayakawa, K . , Shibata, T . , and Hirano, I . , The PCB Levels Iri the Blood of Workers Employed in a Condenser Factory, Japan J. Ind. Health, 47, 354 (1973). (In Japanese). 4. Karppanen, E. and Kolho, L ., The Concentration of PCB in Human Blood and Adipose Tissue in Three D ifferent Research Groups, Proceedings of PCB Conference I I , Solna, Sweden, 1972, National Swedish Environmental Protection Board, Stock holm, 1973, pp. 124-8. 5. General Electric response to interrogatory #17, N .Y . State Dept, of Environmental Conservation Proceeding, File No. 2833, Dec. 1, 1975. 6. Ouw, H. K ., Simpson, G .R ., and Siyali, D .S ., Use and Health Effects of Arcelor 1242, a Polychlorinated Biphenyl, in an Elec trical In d u stry, Arch. Environ. Health, 31, 189 (1976). 7. Puccinelli, V ., On Chloracne, Med. d. Lavoro, 45, 131 (1954) (In Italian). 8. Hofman, M .F ., and Meneahini, C .L ., Concerning Folliculosis Caused by Chlorosubstituted Hydrocarbons, G. Ita l. Dermatol. S ifilo l, 103, 427 (1962) (In Ita lia n ). 9. South Carolina Dept, of Health and Environmental Control, Study of Sangamo Capacitor Division Workers, (Press R eport). Jan. 1978. 10. Polychlorinated Biphenyl Exposure - Indiana, Center fo r Disease Control, Morbidity and Mortality Weekly Report, Mar. 24, 1978. 11. Michigan Dept, of Public Health, Final Report on FDA Contract 223-73-2209, Evaluation of Changes in the Level of Polychlorin ated Biphenyls (PC B 's) in Human Tissue, 1975. V 12. Humphrey, H .E .B ., Evaluation of Humans Exposed to Halogenated Biphenyls, Am. Chem. Soc. D iv. Environ. Chem. Preprints, 20 No. 2, 272 (1980). -23- \Vv^ C r" o CM 13. Fischbein, A ., Wolff, M .S ., Lilts, R ., Thornton, J . , and Seliko ff, I . J . , Clinical Findings among PCB-Exposed Capacitor Manu facturing Workers, A n n ., N .Y . Acad. S c i., 320, 703 (1979). 14. Warshaw, R. Fischbein, A ., Thornton, J . , M i l l e r / A . , and Selikoff, I . J . , Decrease in Vital Capacity in PCB-Exposed Workers in a Capacitor Manufacturing Facility, Ann. N . Y . Acad. S ci., 320, 277 (1979). 15. Brown, D . P . , and Jones, M ., Mortality and Industrial Hygiene Study of Workers Exposed to Polychlorinated Biphenyls, Arch. Env. Health, 36, 120 (1981). 16. Lawton, R. W. , Ross, M. R ., and Feingold, J ., GE D raft Report (1981). 17. Smith, A . B . , Schloemer, J ., Lowry, L . K . , Smallwood, A. W. , Ligo, R . N . , Tanaka, 5 . , S tring er, W ., Jones, M ., and Glueck, C . J . , D raft report: Cross-Sectional Medical Survey of a Group of Workers Occupationally Exposed to Polychlorinated Biphenyls (PCB's) at an Electrical Equipment Manufacturing. Plant, National Institute for Occupational Safety and Health, Division of S ur veillance, Hazard Evaluations and Field Studies, Cincinnati, OH 45226, and Lipid Research Center, U niversity of Cincinnati Medical C enter. Cincinnati, OH 45267, 1981. is - Smith, A . B . , Schloemer, J ., Lowry, L . K . , Smallwood, A. W. , Ligo, R . N . , Tanaka, S ., Stringer, W ., Jones, M ., Hervin, R ., and Glueck, C . J . , Draft report: Cross-Sectional Medical Survey of Two Groups of Workers Occupationally Exposed to Polychlorin ated Biphenyls (PCB's) in the Maintenance, Repair, and O ver haul of Electrical Transformers, ib id ., 1981. 19. Maroni) M ., Colombi, A ., Cantoni, S ., Feriol, E ., and Foa, V ., Occupational Exposure to Polychlorinated Biphenyls in Electrical Workers. 1 Environmental and Blood Polychlorinated Biphenyls Concentrations, B rit. J. Ind. Med., 38, 49 (1981). Maroni, M ., Colombi, A ., Cantoni, S ., Ferioli, E ., and Foa, V ., Occupational Exposure to Polychlorinated Biphenyls in Electrical Workers. II Health Effects, ib id ., 38, 55 (1981). 21. NIEHS Conference on Polychlorinated Biphenyls , Environ. Health Perspec., (1972). 22. NIEHS Conference on Chlorinated Dibenzodioxins and Dibenzofurans, Environ. Health Perspec., 5, (1973). 23. Proceedings of the National Conference on Polychlorinated Biphenyls, November 19-21, 1975, Chicago, I I I . , EPA - 560/6-75-004, March, 1976. 24- *4 v* * V~ .,-- V'-.V/' r *Z Z S i --i.u . . - l- tz ^M in c n v ^ 'T 'irr.r' -` _*. *_ ' 24. Health Effects of Halogenated Aromatic Hydrocarbons, Ann. N. Y . Acad, of S e i., 320, (1979). 25. Proceedings of the Conference "PCB's Impacts on Health,." Sep tember 12, 1979, H artford, Conn.' Transcript by Conn. Dept, of Environmental Protection, Oct. 1, 1979. 26. "Halogenated Biphenyls, Terphenyls, Naphthalenes, Dibenzodioxins a n d 1 Related Products", Kimbrough, R . D . , Ed., Elsevier/ North Holland Biomedical Press, Amsterdam, 1980. 27. Fishbein, L ., Toxicity of Chlorinated Biphenyls, Ann. Rev. Pharmacol., 14, 139 (1974). 28. C riteria fo r a Recommended Standard: Occupational Exposure to Polychlorinated Biphenyls (P C B 's), DHEW (N IO S H ) Publ. 77-225, S ep t., 1977. 29. Polychlorinated Biphenyls and Polybrominated Biphenyls, In te r national Agency for Research on Cancer Monographs, 18, (1978). 30. International Agency for Research on Cancer Monographs, Sup plement 1 to Vols. 1-20, (1979). 31. Buser, H . R . , Bosshardt, H . P . , and Rappe, C ., Formation of Polychlorinated Dibenzofurans (PCDF's) from the Pyrolysis of PCB's, Chemosphere, 109 (1978). 32. Goldstein, J . A . , The S tructure-A ctivity Relationships of Halo genated Biphenyls as Enzyme Inducers, Ann. N . Y . Acad. Sei., 320, 164 (1979). 33. Monsanto Co. , Submission to the Subcommittee on Oversight and Investigations of the Committee on Interstate and Foreign Com merce, U. S. House of Representatives, Nov. 16, 1979. 34. "PCB's in the United States; Industrial Use and Environmental D istribution", V ersar, Inc. EPA Contract No. 68013259. U.S. Dept, of Commerce, NTIS PB 252012, Feb. 25, 1976. 35. Vos. J . G . , Koeman, J . H . , van der Maas, H . L . , ten Noeverde.de Brauw, M. C. and de Vos, R . H . , Identification and Toxicological Evaluation of Chlorinated Dtbenzofuran and Chlorinated Naptha- lene in Two Commercial Polychlorinated Biphenyls, Fd. Cosmfet. Toxicol., 8, 625 (1970). * v 36. Vos, J . G . , and Beems, R . B . , Dermal Toxicity Studies of Tech nical Polychlorinated Biphenyls and Fraction Thereof in Rabbits. Toxico. Appl. Pharmacol., 19 617 (1971). r -25- r 37. Bowes, , G . W . , M u I v i h i l l , M. J . , Simoneit, B . R . T . , Burlingame, A . L . , and Risebrough, R. W. , Identification of Chlorinated Dlben- ' zofurans In American Polychlorinated Biphenyls, N ature, 256, 305 (1 9 7 5 .) ----- C tC - s> C-- 38. D rin ke r, C . K . , W arren, M . F . , Bennett, G . A . , The Problem of Possible Systemic Effects from Certain Chlorinated Hydrocarbons, _ J. Ind. Hyg. Toxicol.- 19, 283 (1937). 39. Treon, J . F . , Cleveland, F. P. , Cappel, J.W. and Atchley, R:W., The Toxicity of the Vapors of Aroclor 1242 and Aroclor 1254, Am. Ind. H yg. Assoc. Quart, 17, 204 (1956). 40. Burse, V . W . , Kimbrough, R . D . , Villanueva, E . C . , Jennings, R. W. , Linder, R . E . , a n d Sorocool, G ., Polychlorinated Biphen yls, Storage, Distribution, Excretion, and Recovery: Liver Morphology A fte r Prolonged Dietary Ingestion, A rch. Environ. Health, 29, 301 (1974). 41. Kimbrough, R . D . , Linder, R.E. and Gaines, T . B . , Morphological Changes in Livers of Rats Fed Polychlorinated Biphenyls, Light Microscopy and U ltrastructure, A rch. Ind. Health, 25 354 (1972). "" 42. Kimbrough, R . D . and Linder, R . E . , Induction of Adenofibrosis and Hepatomas of the Liver in BALB/CJ Mice by Polychlorinated Biphenyls (A roclor 1254), J. Natl. Cancer In s t., 53 , 547 (1974). 43. Kimbrough, R . D . , Squire, R . A . , Linder, R . E . , Strandberg, J . D . , Montali, R. J. and Burse, V . W . , Induction of Liver Tumors in Sherman Strain Female Rats by Polychlorinated Biphenyl Aroclor 1260, J. N atl. Cancer In s t., 55, 1453 (1975). 44. "Bioassay of Aroclor 1254 for Possible Carcinogenicity." Carcin ogenesis Program, D iv. of Cancer Cause and Prevention, Nat1!. Cancer I nst., Report No. (N1H) 78-838, (1978). 45. Testimony of the General Electric Company, OSHA Carcinogen Policy Hearing, Wash., D . C . , Dr. T . R . Casey, Vice-President. Cancer Policy OSHA Docket H-090, Ex. 152. July 20, 1978. 46. General Electric Co. comments re Regulatory Council statement on Regulation of Carcinogens (44 FR 60038), Nov. 13, 1979, J. F. Young, Vice-President; and similar comment addressed to the Interagency Research Liaison Group, Nov. 28, 1979, and to the EPA,` Feb. 21, 1980. 47. Jones, J . W. , and Alden, H . S . , An Acneform Dermatergosis, Arch. Dermat. Syphrilol, 33, 1022 (1936). 48. Zack, J. A. and Suskind, R . R . , The Mortality Experience of Workers Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident, J. Occupat. M ed., 22, 11 (1980). -26- 49. Meigs, J. W. , Albom, J . J . , and K artin, B . L . , Chloracne from an Unusual Exposure to Aroclor, J. Am. Med. Assoc., 154: 1417 (1954). 50. Birminaham, D . J . , Occupational Dermatology: C u rren t Problems, Skin, | (Feb. 1964). 51. Kuratsune, M ., Yoshimura, T . , Matsuzaka, J ., and Yamaguchi, A ., Epidemiologic Study on Yusho, A Poisoning Caused by Ingestion of Rice Oil Contaminated with a Commercial Brand of Polychlorinated Biphenyls, Environ. Health Perspec., 1, 119 (1972). 52. Kuratsune, M ., Masuda, Y . , and Nagayama, J ., Some of the Recent Findings Concerning Yusho, Proceedings of the National Conference on Polychlorinated Biphenyls, November 19-21, 1975, Chicago, III. EPA-560/675-004, March, 1976, p. 14. 53. Food and Drug Administration, "Polychlorinated Biphenyls (PCB's); Unavoidable Contaminants in Food and Food Packaging Materials; Reduction of Temporary Tolerances," Fed. Reaister 42, 17488 (1977). 54. Kamps, L . R . , T ro tte r, W. J. , Young, S . J . , Carson, L . J . , Roach, J . A . G . , Sphon, J . A . , Tanner, J . T . , and McMahon, B ., Poly chlorinated Quaterphenyls Identified in Rice Oil Associated with Japanese "Yusho" Poisoning, Bull. Environ. Contam. T o xico l., 20 589 (1978). 55. Bahn, A . K . , Rosenwaike, I . , Herrmann, N ., G rover, P ., Stellman, J ., and O'Leary, K . , letter, "Melanoma A fte r Exposure to PCB's", New Eng. J. Med., Aug. 19, 1976; Lawrence, C ., Comment, "PCB? and Melanoma"; Bahn, A . K . et al . , reply, ibid. , Jan. 13, 1977. 56. Urabe, H ., Koda, H . , and Asahi, M. , Present State of Yusho Patients, N . Y . Acad, of Sei. Ann. , 320, 273 (1979). 57. Food and Drug Administration, "Polychlorinated Biphenyls (PCB's); Reduction of Tolerances, Fed. Register, 44, 38330, June 29, 1979. 58. Environmental Protection Agency, "Polychlorinated Biphenyls (PCB's) Manufacturing, Processing, Distribution in Commerce, and Use Prohibitions, Fed. Register, 44, 31514, May 31, 1979. 59. Lan, C . , Shieh, L ., C^en, P . H . , Chen, Y . , An Epidemiological Study on Polychlorinated Biphenyls Poisoning in Taichung Area, Clin. Med. (T a ip e i), 7, 96 (1981). 60. Chen, P . H . , Chang, K . T . , and Lu, Y . D . , Toxic Compounds in the Cooking Oil which Caused PCB Poisoning in Taiwan. I. Levels of Polychlorinated Biphenyls and Polychlorinated Diben2ofurans, ib id . , 7, 71 (1981). -27- 61. Kreiss, K ., Zack, M. M . , Kimbrough R . D . , Needham, L . L . , Smrek, A . L. and-Jones, B . T . , Association of Blood Pressure and Polychlor inated Biphenyl Levels, J.Am. Med. Assoc., 245, 2505 (1981). 62. Morris, J . F . , Kolski, A. and Johnson, L . C . , Spirometric Standards for Healthy Nonsmoking A dults, Am. Rev. Respirat. Di s. , 103, 57 (1971). 63. Smith, A . B . , Schloemer, J ., Lowry, L . K . , Smallwood, A . W. , Ligo, R . N . , Tanaka, S ., S trin g e r, W ., Jones, M ., H ervin, R. and Glueck, C . J . , Metabolic and Health Consequences of Occupational Exposure to Polychlorinated Biphenyls. (PCB's), NIOSH, Div. of Surveillance, Hazard Evaluations and Field Studies 4676 Columbia Pkwy. , Cincinnati, OH 45226, and Lipid Research Center, Univ. of Cincinnati Medical C enter, Cincinnati, OH 45267 (1981). i \ Hum an Exposure to Polychlorinated Biphenyls at Toxic Waste Sites: Investigations in the United States P A U LA . STEHR-GREEN, Dr.P.H. VIRLYN W. BURSE Centers for Disease Control Public Health Service U.S. Department of Health and Human Services Atlanta, Georgia EDITH WELTY, M.D. U.S. Public Health Service Indian Hospital 3200 Canyon Lake Drive Rapid City, South Dakota ABSTRACT. Beginning in 1982. environmental and population data were evaluated from waste sites contaminated with polychlorinated biphenyls (PCBs). Pilot exposure assess* ment studies were conducted at 12 sites where risks of human exposure were thought to be greatest. Serum PCB levels in persons at highest risk of nonoccupationally related ex posures (because of their self-reported frequencies and types of activities in contaminated areas) at 10 sSes were within background ranges, even though environmental contamina tion levels as htgh as 2.5 parts per billion (ppb) in monitoring well water samples and 330,000 ppb in soil samples were measured. At (he 2 remaining sites, elevated serum levels, were found in these high-risk persons^ which require further evaluation bv community sur veys. These results illustrate that, despite elevated environmental contaminant levels, un less uptake of chemicals above background exposure levels can be demonstrated, adverse health effects cannot be attributed to waste site chemicals. However, health risks due to background exposure levels, as well as n populations with elexated PCB body burdens need further study. P O LY C H LO R IN A T E D BIPHEN YLS (PCBs) are lipidsoluble. aromatic compounds comprising 209 possible forms. Each chlorinated structure has several isomers and congeners depending on the number of chlorine atoms in the ortho, meta. or para positions on the two benzene rings. Pollution with PCBs is worldwide; PCBs have been found in soil, water sediments, and fresh water and marine fish, as well as in human adipose tissue and serum.' Laboratory studies have shown an association of PCBs with cancer,2'* adverse reproductive outcomes,117 and other organ-specific damage59 in experimental animals. However, the toxicity varies considerably both among congeners within each isomer group and mong the different groups; furthermore, different Copyright retained by U.S. Government. species of animals have widely varying susceptibility to these compounds."** A major concern is whether en vironmental contaminations induce adverse human health effects. Although some studies of high-dose oc cupational exposures have been performed, the health effects in exposed humans, especially at low levels over long time periods, are not as well understood as effects in experimental animals. Ironically, PCBs may be ideally suited for the study of exposure at toxic waste sites. Analytical measurement of serum PCB levels is a sensitive, stable technique10 that is performed routinely in selected clinical labora tories through the United States. Serum PCB level is a reliable indicator of bodv burden, because fat and serum P C B ie ve ls equilibrate and .remain at. a relatively constant ratio for many years..";'1 Background levels nr whole"blood and serum PCBs are reasonably well de- 420 PLAINTIFF'S , EXHIBIT ; Archives of Environmental Health lined h\ data a\ailablf n>r vharacti/rim l human fxipu* lation*. ` ' Suitable questionnaire* can icieniify sources of exposure and possible confounding factors. Finally. PCBs are among the most common environmental con taminants at toxic waste sites in the United Slates: when this study was started. PCBs had been identified at 31 % of the sites on the United States Environmental Protection Agency's (EPA) National Priority List oi waste sites scheduled for remedial actions. The purpose ot this report is to summarize the results oi a series ot investigations that was intended to assess the extent and magnitude ot human exposure to waste sites contaminated with PCBs throughout the United States. Materials and methods To evaluate the potential human health impact posed by PCB-contaminated waste sites, we used a standardized protocol designed for studying exposures and health ef fects in communities near these sites. The strategy'" consists of four sequential phases: (1) site evaluation. (2) pilot exposure studies. (3) com m unity surveys, and (4) cohort studies. Results reported herein focus on phase I and II activities under this protocol. Beginning in 1982. we reviewed site descriptions and environmental sampling data from waste sites which contained PCBs. EPA regional offices had identified 126 such sites, located in 31 of the 50 states, the District of Colum bia, and the 4 United Stales territories. In addi tion, subsequent to this systematic review of the avail able environmental sampling data, other PCB-contam inated sites were identified by state environmental agencies or local health departments. To be selected for detailed study of human exposure (i.e.. phase II exposure assessment studies), waste sites had to meet the following criteria:12 1. Identified populations at risk of exposure must in clude a. ^ 1 0 0 persons living in areas immediately ad jacent to the waste site or b. > 50 people known to i. have regular contact with contaminated on-site soils, or ii. be using contaminated well water for drinking, food preparation, and bathing, or iii. regularly eat contaminated native fish, or iv. regularly be using contaminated surface waters tor recreation. AND 2. Environmental sampling data for the site had to document on-site PCB contaminations in a. soil at levels > 1,000 parts per million (ppm), or b. surface/ground water at levels > 1 part per billion (ppb), or c. the food chain at levels > 5 ppm ^ with unrestricted public access to the site. OR 3. Cnurunnu-ntal dim pling data had to document PCB contamination of accessible off-site environ mental pathways in a. soil at levels > 1.000 ppm, or b. surface/ground water at levels > 1 ppb. or c. ` the food chain at levels > 5 ppm. For each of the waste sites which met these criteria, a pilot exposure study was conducted using standard methods for collection of demographic and exposure data and for collection and laboratory analysis of bio logical specimens. Studies were conducted by local and state health departments, in consultation with the Centers for Disease Control (CD C ) and the Agency for Toxic Substances and Disease Registry (ATSDR). At each selected site, population groups at-risk of ex posure in surrounding communities were identified us ing information obtained from health departments and environmental agencies. Potentially exposed persons were initially contacted by telephone, through citizens' groups, or the news media; using questionnaires, infor mation was obtained from these persons regarding po tential exposure through various environmental path ways. On the basis of their responses, individuals who had the highest risk of exposure (i.e.. those with the greatest reported frequency and duration of activities which might lead to contact with the contaminated areas) were chosen to participate in the pilot studies. After obtaining informed consent from participants, blood was collected for serum PCB assay. Serum PCB levels were quantitated by standard methods10 against Aroclor 1260 or 1254 standards. A more complete siteexposure history, demographic information, medical history', relevant occupational history, and a history of non-site-related contact with materials that contain PCBs were also collected. Medical histories included questions about illnesses described in previous human and animal studies as possibly PCB-related, tobacco and alcohol use. and current use of medications. Results Twelve sites met the selection criteria for evidence of high risk of human exposure to PCB-contaminated areas, as specified above. The environmental sampling and .population distribution data indicated that the likelihood of exposure through inhalation (e.g.. breathing volatilization and combustion products from the sites), ingestion (e.g., consumption of contam inated native fish or animal and vegetable products raised in contaminated areas), and/or dermal absorp tion (e.g., direct contact with PCB-containing trans former fluids and contaminated soil) was high at all these sites (Table I). Detailed exposure assessments of potentially affected persons were conducted at these 12 sites; the number of persons who were studied at each of the selected sites ranged between 9 and 114, with a median of 39. As noted in Table 2, no evidence for an increased prev alence of nonoccupationally exposed persons with Novnhcr/Dccctnbcr 1988 (Vol. 43(No. 61) 421 Table 1.--Sommar* ni Environmental Sampling Results; PC8-Con(aminjted Waslc Silos al W hh Exposure Assessments Wore Performed Loc.it x in icountv and statei Soil (ppmi Environmental data i|*ak PCB concentrations! On-Mie On-Mte Ground water tppbi Sunace water (ppbi Food chain (ppmi Soil Ippmi Ground water Ippmi Sunace water (ppbi Sebastian. AR Wavne. GA Contaminated oils spraved directly in residential area. 3.436 NA 1.5 NA Monroe. IN (3 sitesi Newport. MA Nono Ik. .MA . Ashtabula. OH Allegheny. Pa Chester. PA Pickens. SC Marion. WV 330.000 99.C00 220.000 2.5 18 NA twaten 520 (sediment! NA 400 NA (storm seweri 22.000 (sediment! NA NA NA NA 32.000 NA 8.390.000 (sludge! NA NA NA NA 36.000 NA NA NA (soil) 420.000 (work areas) NA NA 77.200 NA (sludge) PCBs discharged directly into area surface waters. 22.226 NA NA NA 133.000 149 3.500 NA' <0.3 NDt NA 8.5 (rainwater runoff) 12.2 NA 3 0.1 U06 6.400 130 205 NA 6.100 (water) 66.500 (sediment) NA 55Q.OOO (sediment) NA 7.0 NA 300.000 (sediment) NO 86.000 (sediment) NA 0.9 22.080 (sediment) NA 17 -NA - results not available or samples not collected. tN D - result below detection levels. Food Cham (ppmi NA NA 200 Iftshi 730 ttishi NA 1.9 (plants) NA 6.6 0.3 (vegetables) 15 (fishi 1.7 (chickent serum PCB levels significantly elevated above back ground was found in 10 of the 12 sites. In contrast.-evi dence from two sites (located in Newport County. Massac husetts and Monroe_Coumy. Indiana) suggested That environmental contaminations had resulted in hu man exposures above expected background levels. O n the basis of a preliminary survey in Newport County, Massachusetts, the principal routes of ex posure to PCBs had been identified as being direct oc cupational exposures and the consumption of con taminated fish. Thus, workers at the two local electrical capacitor plants and persons who reportedly ate the most locally caught fish comprised the high-risk group in a pilot exposure assessment conducted at this site.1' The geometric mean serum PCB level for these 51 per sons was 18.1 ppb; of these persons, 35% had serum \ concentrations > 20 ppb, and 6% had levels 100 ppb. Among the 42 persons without any occupational exposures, the geometric mean PCB concentration was 12.9 ppb, with 21% having levels 20 ppb. A ll of hese mean levels and proportions of serum PC B con centrations > 20 ppb are statistically significant above expected background levels. After conducting an initial screening survey in Mon roe County. Indiana, w e chose a group of 61 persons who were considered to be at highest risk of exposure because they reported participating most frequently in characteristic activities involving one or more con taminated environmental pathway (e.g,. swimming in contaminated surface waters or eating contaminated fish).Ib The geometric mean serum PCB level for this high-risk group was 10.9 ppb with 19.7% of the par ticipants having serum PCB levels1^ 20 ppb: compared with background levels in representative populations, this was greater than expected (p < .01). When we ex cluded 10 workers with known occupational exposures to PCBs from the analysis of this high-risk cohort, the geometric mean serum PCB level dropped slightly to 9.0 ppb. Among these 51 persons. 9.87 Had serum lev els > 20 ppb: this, however, was not statistically signifi cantly greater than expected (p - .12). In addition, 9 of 55 (16.4%) persons selected randomly from the ap proximately 1,000 persons living within '/: mile of the three contaminated areas had elevated serum PCB lev els, which is statistically different (p < .01) from the proportion expected. 422 Archives of Environmental Health Discussion Result;, oi popukition-bdseri stu d ie s"'' k iv e demon strated that most people without occupational expo sures have serum PCB levels in the low parts per billion range, with a median between 5-7 ppb. Approximately 95% of the values are befow 20 ppb. and increase with age." " For com parison, in a group of 781 Michigan residents with no known exposures, e.g., the mean serum PCB level was 6.0 ppb. 30% had PCB lev els ^ 10 ppb. 7% had levels ^ 20 ppb, and 2% had levels ^ 30 ppb." In 10 ot the 12 site-specific investigations conducted under this protocol, no excess proportion of potentially exposed persons was found to have serum PCB levels > 20 ppb attributable to nonoccuparional exposures* from the sites in spite of high PCB levels in soil or leachate on the sites. As a result, we concluded that there was no need for further studies. The "negative" studies reassured community residents at risk of ex posure that they had not absorbed more chem ical con taminants than a local or national reference popula tion; however, this reassurance must be qualified by our lack of knowledge of potential long-term health risks that may result from "normal" tissue levels of PCBs. In the two settings where we found an elevated pro portion of unusually exposed persons, further evalua tion is required. In Monroe County, Indiana, the find ings might be attributable to the historical prevalence of occupationally related exposures. Nevertheless, the findings oi the pilot studv recommend in\e>tig.ition of the magnitude and extent of exposure and health ef fect;. in the residential community through a popula tion-based survey; this study is currently in progress. In Newport County, Massachusetts, where wastes con taining PCBs introduced into surface waters con taminated the maritime food chain, another important community survey is nearing completion. Exposures via this route, rather than by direct contact with con taminated soil or water, have been shown to result in especially high serum PCB levels and related health ef fects.*1' `1 The results of the community survey will allow interpretation of the local contamination situa tion within the context of previous studies of persons exposed to PCBs through the food chain. Because we did not directly assess human exposure at sites not selected in phase I, we could not evaluate the sensitivity, specificity, and predictive value of the strategy to triage sites for further study. Also, given the relatively small sample sizes in these pilot studies, sig nificant human exposure or increased incidence of health effects attributable to waste site chemicals may not be detected at sites chosen for study. Furthermore, although not studied under this protocol, workers on waste sites and emergency crews which must enter waste disposal sites during fires and explosions may represent a subpopulation at particularly high risk of toxic exposures. Assessment of these groups should be pursued with studies specifically designed to evaluate the unique types, nature, and magnitude of their expo sures. For these and other reasons, it would be impru- Table 2.--Summary of Biological Sampling Results: PCB-Conlaminated Waste Sites at Which Exposure Assessments Were Performed Location tcount\ and state* PCS measurements in human sera (Quantitated as Aroclor 1260> Number ot subiects Range (ppbt Geometric mean "o < 20 ppb Notes Sebastian AR Wavne. Ga Monroe. IN (3 sues* Newport. MA Norfolk, MA Ashtabula. OH Allegheny. PA Chester. PA Pickens. SC Marion, WV 20 2-11 5.8 lb 3-343 20.9 4 3-11 5.1 61 3-75 10.9 51 3-51 9.0 55 2-47 9.0 51 2-343 18.1 42 2-63 119 90 1-30 4.2 89 1-13 4.1 S9 1-45 4.4 57 1-15 4.1 9 ND*-5 2.7 23 1-79 5.9 22 1-31 66 1-24 V 4.4 27 N O -30 24 1-23 2.6 5.0 100 69 Total high-nsk arouo 100 Nonworkers only 80 Total high-risk group 90 Nonworkers onl> &4 Subiects selected randomly ! from at-risk population '1 65 Total high-risk group 79 Nonworkers oni\ 99 Total high-risk group 100 Nonworkers only 97 Total high-risk group 100 Nonworkers only 100 Includes five children 91 Total high-risk group 95 Nonworkers only 97 Subjects selected randomly from at-risk population 96 Quantitated as Aroclor 1254 96 Note: Non-deiectable serum concentrations were assumed to be one-half the detection limit for calculation of geometric means. NO - result below detection levels. November/December 1938[Vol. 43(No, 6)J 423 dt*nt lo inter too hrcudlv trom ihese e\jx*m*nce> .int! vunclude that toxic waste dbpo>al are not gener ally hazardous. Nevertheless, results obtained at sites selected through this triage process may help to direct iollow-up epidem iologic studies and in the development of inter ventions and remedial actions at all waste sites, whether or not they are studied. This is an especially important benefit in local and state health department jurisdictions, where priorities tor the use of limited pro fessional and financial resources must be carefully balanced. In all settings, unless uptake of chemicals occurs, ad verse health effects cannot be attributed to waste site chemicals. In general, the experiences related herein reinforce the proposition that public health officials las well as concerned citizens) need to consider other fac tors in addition to environmental contamination levels when evaluating human health risks due to chemical waste dump sites. These factors include: 1. the physical and toxic characteristics of waste site chemicals: 2. the volatility and spread of waste site chemicals via different environmental pathways: 3. access to and frequency, duration, and type of use of contaminated areas: 4. absorption potentials of these chemicals in biolog ical systems: and 5. the presence of human populations at risk of ex posure. especially sensitive subpopulations (such as ^ ch ild re n and pregnant or lactating women!. The authors acknowledge the assistance of all the professional start members in the state and local health departments that participated in this studv. We also thank the regional EPA offices, the Public Health Advisors detailed to the regional EPA offices by a TSDR. and members or the start' of the Oivision of Environmental Health laboratory Sci ences. Center for Environmental Health and iniury Control (CEHlCi. CDC. We are particularly indebted to David Fornev. ATSDR: Dr. Henry Falk and Dr Paul Wiesner. CDC. and Dr. Renate Kimbrough EPA. for assistance in the design and conduct of this studv and m tne preparation ot this manuscript. Use of trade names i* tor identification onis and does not constitute endorsement bv the Public Health Service or the U.S. Department ot Health and Human Services. This report was supported m pan bv funds from the Comprehensive Environmental Response Compensation, and liability Act trust tund through an Interagency Agreement with the Agency* tor Tome Sub stances and Disease Registry. Public Health Service. Submitted tor publication March 15. 1987; revised: accepted lune 7. 1988. Requests for reprints should be sent to: Dr. Stehr-Green. Centers tor Disease Control. 1600 Clifton Road. Atlanta. CA 30333. References 1. Wasserman, M.; Wasserman. D.: Cucos. S.; and Miller. H, J. 1979. W orld PCBs map: Storage and effects in man and His bio logical environment in the 1970s. Ann NY Acad Sci 320:69- T2-*. 2, National Cancer Institute (NCI1. 1977. Bioassay of Aroclor 125* for possible carcinogenicity, Washington, DC: U.S. Department ^ of Health and Welfare. Springfield, VA: National Technical Infor mation Service. CAS No. 27323-18-8. PB-279 624/lCA. NCI-CC TR-38. DHEW. Publ. NCI. NIH-78-838. t K.tniti'ntC*. R U "u.. I* R A l mivi R \ stf.iniiSn-fC J P Xlunt.iii K I .md Si.fM- \ . W l `i " Induction 01 lai-f lumof'<n Mn-mi,in 'iM in m i- h\ iv iiu hlurmau-d hipht-nyl Arm lor 126(1 J V ifl l jrn t*r Inu 55 1453-54. 4 Morgan R. \V Ward. J. M.; and Hartmann, P. E. 1*181. A nxlor 125-t induced intestinal mriaplasia and adenocarcinoma in the glandular stom.x'h 01 F3-U rats. Cancer R<*> 41:51)52-59. 5. Wellman R. H. and Nnrback. D. H. 1981. Sequential light and electron microxcopic analysis 01 hepatocellular carcinoma in duced b\ Aroclor 1260 The Tmirolncixf 1:65. 6. Kimhrough. R, D.: Bucklev. !.. Fishbein. L., et al. 1978. Animal toxicology, Em iron Health Per>pec( 24:173-85. 7. Linder. R. E.: Carnes. T. B.: and Kimbrough. R. D. 1974. The ef fect 01 polvchlormated biphenvls on rat reproduction, food Owner Tokico/ 12:63-77. B. Kimbrough. R, D.. Ed. 1980. Ha/ogenated Biphem*l>. Terphenvh. .Vaphrha/ene>. Dtbenzodiaxtm and Related Products. Topic* m Environmental Health. IV.-Amsterdam: Elsevier/Nonh Holland. 9. Kimbrough. R. D. 1985. Laboratory and human studies on poly chlorinated biphenvls tPCBsi and related compounds. Environ Health Perspect 59:99-106. 10. Needham. L. L: Burse. V. W.: and Price. H. A. 19B1. Determina tion of polychlorinated and polvbrominated biphenyls in serum by temperature-programmed gas chromatography. I Assoc Ot- Hctal Anal Chem 64:1131-37. -- 11. Wolff. M. 5.: Thornton. I.: Fischbetn. A.; Litis. R.; and Selikoft, 1.1. 1982. Disposition of polychlorinated biphenyl congeners in oc cupationally exposed persons. Toxicol Appl Pharmacol 62:294-306. 12. Wolff. M. S.: Fischbem. A.: Thornton, j.: Rice. C.: lilis. R.: and Selikoft, 1. ). 1982. Body burden of polychlorinated biphenyls among persons employed in capacitor manufacturing. Arch Or- Cup Environ Heaith 49:199-208. 13. Finklea. Pnester. L. E.: Creason. 1. P.: Hauser, T.; Hinners. T.: and Hammer. D. I. 1972. Polychlorinated biphenyl residues in human plasma expose a maior urban pollution problem. Am / Public Health 62:645-51. 14. Kreiss. K.; Roberts. C.: and Humphrey. H. E. B. 1982. Senal PB8 levels. PCB levels, and clinical chemistnes in Michigan's PBB co hort. Arch Environ Health 37:141-47. 13. Wolff. M. S.. Anderson, H. A.: and Selikoff. 1. I. 1982. Human tissue burdens of haiogenated aromatic chemicals m Michigan. JAMA 247.2112-116. 16. Stehr-Creen, P. A. and lybarger. J. A. Evaluation of exposure to toxic waste sites: A suggested investigative approach. Submitted to Pu6/fc Health Rep (1987i. 17. Telles. N. C. 1982. The \ e Bedford Stud\ --Preliminary Find ings. Boston. Massachusetts: Massachusetts Department of Public Health. Environmental Health Assessment. 18. Stehr-Green. P. A : Welly. E. R.: Steele. G.: Ross. D.: and liddle. 1986. A pilot studv 01 serum polvchlorinated biphenv! levels in persons at high risk of exposure in residential and occupational environments Arch Em iron Health 41:240-44 19. Baker. E. L.. Jr.: Landngan. P, ).: Ctueck. C. J.. et al. 1980. Meta bolic consequences of exposure to polychlorinated biphenvls tPCBt m sewage s/udge. Am j Epidemiol 112:553-63. 20. Kreiss. K.; Zack, M. M.; Kimbrough. R. D.: Needham. L. L. Smrek. A. L; and (ones. B. T. 1981. Association of hiood pressure ' -- , and PCB levels. IAMA 245:2505-09 ^2]/ Michigan Department 01 Public Health. I960. Evaluation 01 Changes 0/ the level of Pol\ chlorinated Biphenyls 1PCB1 in Hu man Tissue. Final Report on FDA Contract 223-73-2209. Lansing. Michigan. ( 22^ Vernon. A. A.; liddle. J. A.; Falk. H,: Conrad. ]. L.: 8ayse. D. D.: and Heath. C. W. 1961. High levels of polychlorinated biphenyls in serum specimens. Kansas. 6PI-80-23-2. Atlanta. GA: Centers x for Disease Control, U.S. Department of Health and Welfare. I**-- Public Health 5ervice. I 23. Masuda. Y.: Kagawa. R.; Shimamura. K.: Takada, M.; and Kurat- v-- sune. M. 1974. Polychlorinated biphenyls in the blood of Yusho -- patients and ordinary persons. Fukuoka Igaku Zassht 65:25-27. I 24.s Kfeiss, K.: Zack. M. M.: Kimbrough, R. D.: Needham, L L: N-- Smrek, A. L.; and Jones. B. T. 1981. Cross-sectional study of a community with exceptional exposure to DOT. JAMA 245: 1926-30. 424 Archives of Environmental Health } f Corporate Research and Development Schenectady. New York FOLLOW-UP STUDY OF CAPACITOR WORKERS EXPOSED TO POLYCHLORINATED BIPHENYLS (PCBs) by R.W. Lawton, MD*; M.R. Ross, RN, CO HNt; and J. Feingold, M D t Chemical Laboratories Report No. 86CRD028 April 1986 'Formerly with CRD, Chemical Laboratories tCapacitor Products Department, Hudson Falls, New York Formerly with Capacitor Products Department Technical Information Series Class 3 Company Proprietary x GENERAL /i W ELECTRIC CLASSES OF GENERAL ELECTRIC TECHNICAL REPORTS CLASS 1 - GENERAL INFORMATION Available to anyone on request. Patent, legal, and commercial review required before issue. CLASS 2 - GENERAL COMPANY INFORMATION Available to any General Electric Company employee on request. Available to any General Electric Subsidiary or Licensee, sub ject to existing agreements. Disclosure outside General Electric Company requires approval of originating component. CLASS 3 - LIMITED AVAILABILITY INFORMATION Original distribution to those individuals with specific need for information. Subsequent Company availability requires originating component approval. Disclosure outside General Elec tric Company requires approval of originating component. CLASS 4 - HIGHLY RESTRICTED DISTRIBUTION Original distribution to those individuals personally responsi ble for the Company's interests in the subject. Copies serially numbered, assigned, and recorded by name. Material content, and knowledge of existence, restricted to copy holder. Requests for Class 2, 3, or 4 reports from non-resident aliens or disclosure of Class 2, 3, or 4 reports to foreign locations, except Canada, requires review by the Export Control Coordinator of the originating component. G E N E R A L ^ ELECTRIC C h in e ra i Electric Company Corporate Research and Development Schenectady, New York 12345 TECHNICAL INFORMATION SERIES A lThO i Lawton, RW* Rosa, M Rt Feingold, J t tlllJECT health effects of PCBs TTTU Follow-Up Study of Capacitor Workers Exposed to Polychlorinated Biphenyls (PCBs) nw cisA iiM : roxm ^tM Chemi.ca. l . L.aboratories ^ 86CRD028 ATI April 1986 CECLA ^ MX Paci 27 conraArc KESlAftCH *.<0 DtAlLOTMtNT SCHIAECTaOY. TV A population of capacitor workers exposed to PCBs, studied previously in 1976 and 1979, was reexamined in 1983. Mean workplace area air levels of PCBs had declined to 16 ^g/mJ by 1983. Although PCB body burdens of the higher PCB congeners (Aroclor 1260) have remained relatively constant, lower PCB congener body burden dropped, probably as a consequence of metabolic clearance. Serum PCB concentrations, calculated on the basis of total serum neutral lipids, were not statistically associated (< 5 % ) with 23 biochemical or 12 hematological variables measured except for the percentage of basophils. The significant intervening variables -- which included average age of the population (49.5 years), sex, obesity, and alcohol consumption -- accounted for many of the laboratory findings outside the normal ranges. No statistically significant as sociations were found of scrum PCB levels with blood pressure. "Formerly with CRD. Chemical Laboratories tCapacitor Produes Department, Hudson Falls. New York Formerly with Capacitor Products Department polychlorinated biphenyls (PCBs), capacitor workers, occupational exposure, health effects INFORMATION PREPARED FOR Additional Hard or Microfiche Copies Available from Technical Inform ation Center Bldg. 5 Room 321, Schenectady, NY 12345 FOLLOW-UP STUDY OF CAPACITOR WORKERS EXPOSED TO POLYCHLORINATED BIPHENYLS (PCBs) R.W. Law ton, MD; M.R. R o s s , RN, COHN; and J . F e i n g o l d , MD INTRODUCTION P o ly c h lo rin a te d b ip h en y ls (PCBe) were th e on ly ch em icals s in g le d o u t by name f o r s p e c i a l a t t e n t i o n in a ban on th e s u b s t a n c e by th e T o x ic S u b sta n c e s C o n tro l A ct (TSCA) o f 1 9 7 6 . T h is a c t io n a r o s e from a s e r i e s o f ev en ts beginning w ith the o b se rv a tio n o f environm ental p e r s is te n c e by Ja n s e n C l) in 1966, fo llo w e d by an o u tb r e a k o f a p p a r e n t PCB p o is o n in g in Ja p a n i n 1968 (2 ) . T h is e p is o d e (Yusho d i s e a s e ) i s now known t o h ave r e s u lt e d from r ic e o i l contam inated by th e rm ally degraded PCBs from a le a k in g h e a t exch an g er. The o x id a t iv e d e g ra d a tio n o f th e PCBs r e s u lt e d in th e p ro d u ctio n o f p o ly c h lo rin a te d d ib e n z o fu ra n s (PCDFs) (3).. A s im i l a r PCDF p o is o n in g e p is o d e s u b s e q u e n t ly o c c u r r e d in Taiw an ( 4 ) . Some s p o r a d ic r e p o r t s o f c h lo ra c n e th o u g h t to - b e r e l a t e d to PCBs a p p e a r in r e t r o s p e c t t o be c a u se d e i t h e r by PCB w hich had been c o n ta m in a te d in p ro d u ctio n (5) o r by th erm ally d egrad ed PCBs ( 6 ,7 ) . The f i n a l ev en t l e a d i n g t o th e PCB ban was th e d e m o n s tr a tio n by Kim brough e t a l . (8 ,9 ,1 0 ,1 1 ) o f a d e n o fib r o s is , hepatoma fo rm atio n , and h e p a tic . carcinom a in r a t s w ith m assive d oses of the la r g e ly n on -m etabollzab le A ro clo rs (1254 and 1 2 6 0 ). T hese f in d in g s have r e c e n t ly been co n firm ed in PCDFf r e e PCBs by S c h a e f f e r e t a l . (1 2 ) who o b s e r v e d t h a t h e p a t i c c a r c in o g e n i c i t y was only a s s o c ia t e d w ith the h ig h ly c h lo r in a te d Isom ers and was accom panied by a su p p re ssio n o f th e spon tan eou s in cid en ce o f tum ors in o th er organ s and t i s s u e s . H i s t o r i c a l l y , PCBs have been c o n sid e re d a r e l a t i v e l y s a f e su b s t a n c e . F o llo w in g th e com m ercial in tr o d u c tio n o f PCBs in th e 1 9 3 0 s, th e ir production in the U .S. through 1975 to ta le d about 1 .4 b illio n pounds ( 1 3 ) . A ir s t a n d a r d s c o n t r o l l i n g PCB u se in th e w o rk p la c e w ere b a se d f o r many y e a r s on th e an im al s t u d i e s o f D rin k e r e t a l . (1 4 ) t h a t in 1937 In d ic a te d r e l a t i v e l y low t o x i c i t y . D rin ker was th e f i r s t to c l e a r l y s e p a r a t e th e e f f e c t s o f PCBs from th o se o f th e c h lo r o n a phthalenes (15). A fte r en viron m en tal p e r s is t e n c e o f PCBs was d em o n strated by Je n se n (1 ), Monsanto (th e p r in c ip a l U .S. m an ufacturer o f PCBs. produced under th e t r a d e name A r o d o r ) re sp o n d e d by m aking a v a i l a b l e in 1970 a r e d i e - ' t i l l a t i a n p ro d u c t, A ro clo r 1016. Thie p ro d u ct was fo r u se in c lo s e d s y ste m s ( c a p a c i t o r s and t r a n s f o r m e r s ) , r e p l a c i n g A r o c lo r s 1254 and 12412 which had been in u se . The A ro clo r 1016 p ro d u ct c o n s is t e d o f iso m ers a l l w ith l e e s than fiv e c h lo rin e atoms per m olecule, e lim in a tin g the ap p aren tly p e r s is t e n t h ig h e r co n g e n e rs. Enhanced b io d e g r a d a tio n o f A ro c lo r 1016 was shown by d im in ish ed accu m u latio n and by r a p id and more com plete d e p le tio n in r a t fe e d in g e x p e rim e n ts ( 1 6 ) . The c le a r a n c e mechanism was found to in v o lv e mixed fu n c tio n o x id a se in d u ctio n (1 7 ). In th e environm ent, a e r o b ic b act a r i a have been shown to d e g ra d e many o f th e lo w er PCB c o n g e n e r s by ^^oxy9 u a se In d u ction (1 8 ), and an aero b ic b a c t e r ia appear cap ab le o f d e c h lo r in a t in g many o f th e h ig h e r c h l o r i n a t e d c o n g e n e rs ( 1 9 ) . The e f f e c t o f th e Yusho d i s e a s e i n c i d e n t on PCB r e g u l a t i o n may h a re been q u i t e d i f f e r e n t i f th e r o l e o f PCDFs had been d i s c o v e r e d e a r l i e r . The i d e n t i f i c a t i o n o f PCDFs a s th e t o x i c a g e n t in Yusho d i s e a s e was n o t made u n t i l 8 y e a r s a f t e r th e e r e n t . I t i s now known t h a t U .S . com m ercial PCBs c o n ta in e d a p p ro x im a te ly 1 to 2 ppa o f PCDFs (A roc lo r 1016 con tain ed n e g lig ib le amounts o f PCDFs). In Y usho, the concen t r a t i o n o f 'PCDFs in th e PCBs p r e s e n t i n r i c e o i l was s u b s e q u e n t ly fo u n d t o be 0.9% , and in b lo o d sa m p le s o f T a iw a n e se p a t i e n t s , PCDF c o n c e n t r a t io n s v a r ie d from 24 to 100 p p t. In e x p e rim e n ts on m onkeys, PCDFs p r e f e r e n t i a l l y accum ulated in the l i r e r and were 2500 tim es more p o w erfu l a s a c h lo r a c n e g e n th a n PCBs (2 3 ) . An e n t i r e i s s u e o f th e A m erican J o u r nal o f Industrial M edicine (V o l. 5 , No. 1 /2 , 1984) re v ie w s th e c u r r e n t s t a t u s o f th e Ja p a n e se and T aiw an ese e r e n t s , and c l e a r l y i n d i c t PCDFs r a th e r than PCBs a s th e c a u s a t iv e a g e n t. A n oth er f a c t o r t h a t u l t i m a t e l y a f f e c t e d PCB r e g u l a t i o n i s th e f a c t t h a t many o f th e c r o s s - s e c t i o n a l human s t u d i e s o f o c c u p a t i o n a l o r e n - * v iro n m en tal exp o su re to PCBs have been l a r g e l y d e s c r i p t iv e in n a tu re ( 2 4 - 2 8 ) . Where s t a t i s t i c a l a n a l y s i s h a s been p e rfo rm e d ( 2 9 - 3 3 ) , th e c o r r e la tio n s re p o rte d in e a r lie r s tu d ie s o f serum le v e ls o f t r i g l y c e r i d e s , c h o l e s t e r o l , and some l i v e r enzym es w ith th e g r o s s serum PCS l e v e l (serum w e ig h t b a s i s ) a p p e a r now t o be r e l a t e d t o th e p a r t i t i o n i n g b e h a v io r o f PCBs in th e serum l i p i d s (3 3 , 3 4 ). In p a r t i c u l a r , th e s t u d i e s o f Chase a t a l . (32) showed th a t th e c o r r e la t io n s o f th e g r o s s serum PCB l e v e l s w ith th e serum t r i g l y c e r i d e s , c h o l e s t e r o l , and g lu t a m ic o x a l a c e t i c t r a n s a m in a s e d i s a p p e a r e d when th e a d ip o s e t i s s u e PCB l e v e l was used as the Independent v a r ia b le . We h ave r e p o r t e d r e s u l t s in c a p a c i t o r w o rk ers in w hich th e serum . PCB c o n c e n t r a t io n was c a l c u l a t e d in te rm s o f th e t o t a l serum n e u t r a l l i p id (33) and have found th a t the a s s o c ia t io n s w ith serum t r ig ly c e r id e s and c h o le s te r o l were f u lly accounted fo r by such - p a r titio n in g . R e sid u a l a s s o c ia t io n s w ith serum y-glu tam yl tr a n sp e p tid a se and b ilir u b in s were fo u n d d u rin g h ig h a c t i v e e x p o su re t o A r o c lo r 1016 in 1 9 7 6 , w hich we i n te rp re te d as evidence fo r glucuronyl tra n sfe ra se in d u ctio n , e le v ate d g lu cu ro n id atio n , and a c c e le ra te d h e p a tic c le aran c e . Such s t a t i s t i c a l r e la tio n s had la r g e ly d isap p eared in the r e s u lt s o f the 1979 stu d y . The p re se n t stu d y i s an a n a ly s is o f c l i n i c a l c r o s s - s e c t io n a l d a ta o b ta in e d in 1983 on th e same c a p a c it o r w orker p o p u la tio n 6 .5 y e a r s a f t e r th e c e s s a t i o n o f PCB u s e . T h is s tu d y p r o v id e s a d d i t i o n a l s i g n i f i c a n t lo n g itu d in al inform ation r e la tin g to the lon ger term e ffe c t s of th e ir occupational exposure. MATERIALS AND METHODS Study P opulation The stu d y p o p u la tio n was s e l e c t e d in e a r ly 1976 to in c lu d e a l l th o s e w o rk ers w ith o c c u p a t io n a l e x p o s u r e to PCBs, a b o u t 10% o f th e work f o r c e o f two c a p a c i t o r m a n u fa c tu rin g p l a n t s in u p p e r New York S t a t e . C r it e r ia fo r s e le c tio n and exposure c l a s s i f i c a t i o n a t t h is tim e r e s u lt e d in three groups: Jobs re q u irin g prolonged d ir e c t derm al co n tact in are as w ith high a i r le v e ls , such as h an dlin g and s e a lin g wet c a p a c ito r s and ca p a c it o r sa lv a g e and r e p a ir (h igh exposu re)  M aintenance men, forem en , and e n g in e e r s whose d u t ie s g e n e r a lly in T o lr e d b r i e f h ig h e x p o su re and c o n t a c t (medium e x p o su re ) W orkers whose jo b s d id n o t r e q u i r e d i r e c t c o n t a c t b u t who w ere l o cated a t the p erip h ery o f zones w ith high a i r le v e ls (low expo sure) I n i t i a l l y , 194 w orkers p a r t ic ip a t e d on a v o lu n ta ry b a s i s . The po p u la tio n was r e s tu d ie d in 1979, and th e 1976 and 1979 d a ta - to g e th e r w ith a fu rth e r d e sc rip tio n o f exposure c o n d itio n s - are p resen ted e ls e where (33) . For th e p re se n t stu d y ( l a t e 1983) th e p o p u la tio n was c o n ta c te d by l e t t e r and teleph on e and ag a in in v ite d to p a r t ic ip a t e . B ecause o f r e tirem en t, se p a ra tio n , r e f u s a l, or death only 154 w orkers were su b se q u e n tly exam in ed. Some w o rk ers r e f u s e d p o r t i o n s o f th e e x a m in a tio n so t h a t com plete d a ta were o b ta in e d on on ly 146 work e rs (115 m a le s, 31 f e m ales) . Compared to t o se w ith com plete d a ta in 1976 (176 w orkers) p a r t i c i p a t i o n was 83i5. C lin ic a l Measurements The c l i n i c a l exam in ation c o n s is te d o f an updated m ed ical h is t o r y , p h y s i c a l e x a m in a tio n by th e p l a n t p h y s i c i a n , ECG, c h e s t x - r a y , s p ir o m e t r y , 23 b io c h e m ic a l m e asu re m e n ts, CBC and d i f f e r e n t i a l , and a ro u tin e u r i n a l y s i s . Body w eigh t was m easured in l i g h t in d o o r c lo th in g , and h e ig h t m easured w ith out sh o e s. A s in g le s y s t o lic and d i a s t o l i c b lo o d p r e s s u r e was m easu red in th e s e a t e d p o s i t i o n t o th e n e a r e s t 5 mm Hg. P a r t i c i p a n t s were in s t r u c t e d to be f a s t i n g f o r th e p re c e d in g 12hour p e rio d w ith w ater ad lib itu m . Only one n o n -fa s t in g w orker was id e n tifie d . The u pdated m ed ical h is t o r y was d ir e c t e d p r im a r ily to the d e s c r ip tio n o f smoking h a b i t s , a lc o h o l consum ption, and the use o f m e d ic a tio n s. Smoking h i s t o r i e s had n ot changed s in c e th e p re v io u s e x a m in a tio n . Smok.e ra and ex-sm o k ers made up 71.9/5 o f th e stu d y g ro u p . F o rty -tw o p e r c e n t o f the p o p u la tio n consumed a lc o h o l on a r e g u la r b a s i s , p r im a rily in the form o f b e e r . Ve fo u n d i t c o n v e n ie n t t o d e s c r i b e co n su m p tio n in te rm s o f a " s i x - p a c k p e r week" s c a l e ( F ig u r e 1 ) . Two w o rk e rs a d m itte d co n sum ption in e x c e ss of fo u r six -p a c k s per week. F if t y - s ix workers reported the use of m edications c o n sistin g of 42 gen eric drugs (Table 1 ). T h irteen workers used a n a lg e sic s, an tih istam in e s, and a n ta c id s. Seventeen re p o rte d a p h y sic ia n 's d ia g n o sis o f hy p e rte n sio n , and 26 used a n tih y p e rte p slv e s and o th er c a r d io v a s c u la r drugs ( d i u r e t i c s , b e t a - b lo c k e r s ) . A lso re p o rte d were a n t i a r t h r i t i c s and gou t m ed icatio n s (1 0 ), a n t ib a c t e r ia l m ed icatio n s (2 ), and s t e r o id s (3 ). F iv e w orkers took diazepam , and one p h en y to ln . From a rev iew o f the l i t e r a t u r e , from s t r u c t u r a l a n a lo g y , and from h a l f - l i f e c o n s i d e r a t i o n s , we c l a s s i f i e d 20 d ru g s w ith r e s p e c t to t h e i r mixed fu n c tio n o x id a se a c t i v i t y . There were 22 d ru gs f o r which l i t t l e in form ation could be found. [These 22 d ru gs (T able 1) were c l a s s i f i e d a s h av in g no e f f e c t s . ] Some o th e r known e f f e c t s a r e a l s o r e l e v a n t t o h h is s t u d y : P r o p r a n o lo l i n h i b i t s i t s own m e ta b o lism b u t n o t in th e p r e s ence o f some o th e r d ru g s ( 3 4 ). I n s u lin la c k d e p r e s s e s drug m e ta b o lic a c t i v i t y , b u t th y r o id hormone may i n c r e a s e o r d e c r e a s e drug m e ta b o lism fcL ^ r\ _ s j c ie n c ie a in r i b o f l a v i n C36) , v ita m in C (37) , and v ita m in E (3 8 ) d e c r e a s e drug o xid ation . In o r d e r t o d e te rm in e th e PCB body b u rd e n , we c a l c u l a t e d th e t o t a l body f a t from th e w e ig h t - h e ig h t r e g r e s s i o n e q u a tio n a o f Hume and W eyers (3 9 ). Those eq u a tio n s, based on t o t a l body w ater d e te rm in a tio n s, depend upon th e a ssu m p tio n o f a d e q u a te body h y d r a t io n . We u s e d th e u r i n a r y s p e c if ic g ra v ity as the m easure o f h y d ration in th ese stu d ie s and found i t to be e q u iv a le n t to the c a lc u la te d serum o sm o la lity d e riv e d from con v e n t i o n a l a ssu m p tio n s ( 4 0 ) . Two o t h e r m ethods w ere c o n s i d e r e d f o r d eterm in in g t o t a l body f a t : th e model o f Moore e t a l . and th e Benn p ro ced u re (4 2 ). The Moore t o t a l f a t model (41) ( r e g r e s s io n e q u a tio n s in w eigh t and age) s a y be a more d e s i r a b l e c l i n i c a l model b u t p r e s e n t s p ro b lem s in ag e e o l l n e a r i t y in r e g r e s s i o n . The Hume and W eyers m odel u sed in our stu d y i s more a l l i e d to th e body m ass in d e x . S a t i s f a c t o r y body mass in d ic e s were c a lc u la te d fo r the p o p u la tio n u sin g th e Benn p ro c e d u re o n ly when u n u su a l h e ig h t - f o r - w e i g h t v a l u e s w ere rem oved. Serum _PCB M easurem ents Packed column g as chrom atography was conducted on a serum sam ple from each worker by H azleton L a b o ra to rie s Am erica I n c ., M adison, W iscon s i n , by m ethods p r e v i o u s l y d e s c r i b e d ( 4 3 ) . Serum PCB l e v e l s w ere e s t im a t e d u s in g th e s t a n d a r d A r o c lo r s (1 2 4 2 , 1 2 5 4 , and 1260) and th e sum o f s e le c t e d peak h e ig h ts method o f q u a n tita tio n to p ro v id e c o n s is t e n t m ethodology over th e p e rio d from 1976 through 1983. T h is method o f q u a n tita tio n e v a lu a te s the serum le v e l in term s o f the m ost p e r s is t e n t p eaks and o v e r e stim a te s the a c tu a l PCBs p r e s e n t. A lthough m ethods o f ad ju stm en t o f the d a ta have been p roposed (4 3 ), fo r th e p u rp o se o f mul tip le reg ressio n these ad d itio n al c a lc u la tio n s a lte re d the in te rc e p ts but not the c o e ffic ie n ts in the re g re ssio n e q u atio n s, and have th e re fo re been o m itte d . R e p e t it iv e m easurem ents on a serum p o o l and s e r i a l d i l u t i o n e x p e rim e n ts h ave i n d i c a t e d a 95!? p r e d i c t i o n i n t e r v a l f o r th e g r o s s serum PCB l e v e l o f a p p r o x im a te ly r5 0 !? f o r t h e s e PCB m e a su re m e n ts. A fte r packed column ch rom atograph y was co m p leted , th e e x t r a c t e d sam ples were retu rn ed to our la b o ra to ry fo r c a p illa r y g as ch rom atogra p h y. A f t e r a d d i t i o n a l c le a n u p by an H3S 0 4 w ash, th e a n a l y s i s was p e r form ed u sin g p ro c e d u re s d e s c r ib e d e lse w h e re (19) . T h ese p r o c e d u r e s have, r e s u lte d in the I d e n t ific a t io n o f 130 isom er peaks in sta n d a rd chrom ato gram s . Peaks were numbered ac c o rd in g to th e system o f B a lls c h m ite r and Z e ll (44) and t h e ir i d e n t i t i e s a ssig n e d from a number o f so u rc e s (45, 4 6 ) , in c lu d in g r e c e n t GC-MS d a t a (R . W agner, J . C a rn ah an : p e r s jp n a l com m unication) . \' PCBs a r e ly o p h i l ic and a r e d is s o lv e d and d i s t r i b u t e d in serum p r i m arily in the lip o p ro te in s (47, 4 8 ). I t has been estim ated th a t the l i p i d p h a se f o r PCB p a r t i t i o n i n g in serum can be a p p ro x im a te d by th e t o t a l serum n e u t r a l l i p i d s (49) . At e q u ilib r iu m th e PCB' c o n c e n t r a t io n in t h is serum l i p i d phase was found to be s u b s t a n t ia lly e q u iv a le n t to i t s c o n c e n tra tio n in ad ip o se t i s s u e l i p i d s . Serum c h o le s t e r o l l i p i d s (com prising fr e e p lu s e s t e r l f ie d c h o le s te r o l) were e stim a te d from normal v alu es (50) as 1 .5 tim es the c lin ic a l t o t a l c h o le ste r o l, and the t o t a l serum n e u t r a l l i p i d s g iv e n a s th e sum o f th e serum c h o l e s t e r o l l i p i d s and th e c l i n i c a l serum t r i g l y c e r i d e s . The PCB body b u rd e n was c a l c u l a t ed a s th e p r o d u c t o f th e PCB c o n c e n t r a t io n in t o t a l serum n e u t r a l l i p i d s and the t o t a l body f a t . In m u l t i p l e r e g r e s s i o n s t u d i e s , we e v a l u a t e d two m e a su re s o f e x p o s u r e d e r iv e d from th e PCB m e a su re m e n ts: th e g r o s s serum PCB l e v e l r e p o rte d by th e la b o r a to r y as ppb on a serum w eigh t b a s i s , and th e serum l i p i d PCB v a lu e in ppm, th e p h a r m a c o lo g ic a lly a c t i v e c o n c e n t r a t io n ( S i ) . An a d d i t i o n a l m easure o f e x p o su re was d e r i v e d from th e e x p o s u r e c a te g o rie s assig n ed in 1976 (T able 2 ). s t a t i s t i c a l A nalysis S t a t i s t i c a l a n a ly s e s were p erfo rm ed on a H oneyw ell 6 0 0 /6 0 0 0 com p u t e r , u s in g STATPAC ( 5 2 ) , a v e r s a t i l e g e n e r a l s t a t i s t i c a l p a c k a g e , which p ro v id ed d is t r ib u t io n p lo t t in g , m u ltip le and ste p w ise lin e a r r e g r e s s io n s , and a n a ly s is o f v a r ia n c e . The 23 b io ch em ical and 12 hem ato l o g i c a l m easurem ents were u sed as dependent v a r ia b le s in m u ltip le backw ard-stepw ise re g re ssio n s in the presence of se le c te d confounders, and each was exam in ed 'fo r s t a t i s t i c a l a s s o c ia t io n s w ith each of the t h r e e m e a su re s o f PCB e x p o s u r e . The c r i t e r i o n f o r s t a t i s t i c a l s i g n i f i c a n ce was F (i-x) 0 .9 5 = 3 . 9 , so t h a t th e 9556 c o n fid e n c e i n t e r v a l f o r a s i g n if ic a n c e c o e f f ic i e n t d id n o t in c lu d e z e r o . The r e s u l t s a r e g iv e n a s p a r t i a l c o r r e l a t i o n s t h a t w ere s i g n i f i c a n t a t a p p r o x im a te ly 0 .1 6 5 . We s e le c t e d the backward ste p proced u re as the b e s t method f o r m anaging th e m u ltip le c o lln e a r itle s in the d ata. The dependent v a r ia b le s were examined f o r t h e ir d is t r ib u t io n s u s in g cum ulative p ercen tage p lo ttin g and were lo g -tran sfo rm e d a s re q u ire d . F in a l d i s t r i b u t i o n s e l e c t i o n s were made on th e b a s i s o f r e s i d u a l p l o t s a t the end o f the step w ise r e g r e s s io n s . O u tlie r s were not rem oved. A ll PCB m e a su re s w ere lo g - t r a n s fo r m e d and p ro d u ce d a l i n e a r d i s t r i b u t i o n on cummulatlve percen tage c o o rd in a te s. Other lo g tra n sfo rm a tio n s in clu d ed serum t r i g l y c e r i d e s , th e l i v e r enzymes (GPT, GOT, and GGTP), t o t a l b i l i r u b i n , serum g lo b u l i n , b lo o d g l u c o s e , BUN, B U N /c r e a tin in e r a t i o , th e w h ite b lo o d c o u n t, e o s i n p h i l s , and th e MCHC ( s e e T a b le 6 f o r a b b r e v i a tion s) . In th e s t a t i s t i c a l a n a l y s i s we c o n s id e r e d a v a r i e t y o f in d e p e n d e n t v a r ia b le s as confounders (T able 2 ). These were screen ed by r e g r e s s io n u s in g g r o s s serum PCB l e v e l s a s th e d e p e n d e n t v a r i a b l e . F o r t h i s a n a l y s i s we- u se d th e 1976 r e l a t i v e e x p o s u r e e s t im a t e b a s e d on a n a l y s i s of the in d iv id u al job a c t i v i t i e s , as w ell as p lan t lo c a tio n s a t th at tim e. S e r v ic e tim e was u sed in l i e u o f a g e ; th e l a t t e r was u sed f o r th e a n a ly s is o f c l i n i c a l v a r ia b le s (age and se r v ic e tim e c o v a rie d : R = 0 .7 4 ) . Serum album in was e v a lu a te d a s an indepen dent v a r ia b le o n ly l.n th e PC B-dependent r e g r e s s i o n s . ^ Two c l a s s i f i c a t i o n s o f jo b s t a t u s were u se d in o r d e r t o t e s t th e e f f e c t s of the d u ratio n of se p a ra tio n or r e tire m e n t: one in v o lved only workers r e tir e d p rio r to 1979; the oth er in volved a l l w orkers r e tir e d p r io r to t h is stu dy. Because a l l s a la r ie d w orkers were m ale, and the fem ales worked p rim a rily a t only one p la n t, both the s a la r ie d /h o u r ly and p la n t l o c a t i o n c l a s s i f i c a t i o n s c o v a r ie d w ith s e x (A = 0 . 2 5 and 0 .3 5 , r e s p e c t i v e l y ) . C e r ta in w o rk ers w ith i n t e r c u r r e n t i l l n e s s e s t h a t we e x pected to Influen ce the r e s u lts - e .g ., d ia b e tic s , e x -a lc o h o lic s, p o st su rg ery p a t ie n t s , e t c . - were id e n t if ie d and coded. f f V ./ 9a ./ RESVLXS PCS E x p o su re Over th e c o u r s e o f o u r o b s e r v a t i o n s , mean PCB a i r l e v e l s in c a p a c i t o r m a n u fa c tu r in g a r e a s f e l l from n e a r l y 700 fig/m3 d u r in g a c t i v e PGB u s e i n 1976 t o arou n d 16 p.g/m3 s h o r t l y b e f o r e th e p r e s e n t s t u d y ( F i g ure 1) . T h is d e c lin in g exposure a s a s s o c ia t e d w ith e x te n siv e c le a r a n c e o f th e lo w e r PCB hom ologs a s m e asu re d by th e g r o s s serum l e v e l s (p a c k e d column GO o f A ro c lo r 1242. F ig u r e 2 I n d i c a t e s a d e c lin e in th e mean body burden of lo v e r ch lo rin ate d congeners from 5 .6 to 0 .5 2 g over the 8 -y e a r p e r io d , w ith a somewhat slo w er r a t e o f d e c lin e in th e fe m a le s ( t r ia n g le s ) . In c o n tra st, body burdens o f the h igh er ch lo rin ate d congeners (q u an titated as A roclor 1260) have been r e la tiv e ly co n stan t (approxim ately 0.13 g ) . A roclor 1254 burdens have d eclin ed slow ly as a consequence o f the co m p o sitio n o f t h i s A ro c lo r, which o v e r la p s both Aro c lo r 1242 and 1260. C a p i l l a r y g a s ch ro m ato g rap h y was p e rfo rm e d on a sam p le o f 10 m ale w orkers w ith r e l a t i v e l y norm al serum l i p i d l e v e l s (mean serum t r i g l y c e r id e s = 9 2 .9 m g/dL; mean serum c h o l e s t e r o l = 1 7 4 .1 m g/d L ). I d e n t i f i c a tio n and average com position of the m ost p e r s is te n t isom ers of the r e s i d u a l serum PCBs a r e g iv e n in T ab le 3 . T h ese e s t im a t e s o f p e r s is t e n c e a re e q u iv a le n t to th o se r e p o rte d by W olff e t a l . (5 9 ). The mean v a lu e s a re a l s o compared to th e r e l a t i v e f r a c t i o n o f t h e s e iso m e rs in th e A r o c lo r 1242 and 1260 s t a n d a r d s . IUPAC Ho. 1 8 0 , a p ro m in e n t h e p t a c h lo r o b ip h e n y l in A r o c lo r 1 2 6 0 , h a s a l s o been in c lu d e d . We fo u n d t h a t the th re e m ajor r e s id u a l peaks o f A ro clo r 1242 and the s ix o f A ro clo r 1260 accou n ted f o r 62.5% and 80.4% o f the co m p o sitio n s in serum compared to 10.4% and 55.3% in th e s ta n d a r d s. These p e r s i s t e n t p eak s in the c a p i l l a r y chrom atogram s r e p r e se n t th e m easured p eak s in packed column a n a l y s i s u s in g th e sum o f th e p e ak h e ig h t s m ethod o f q u a n t i t a t i o n . An approxim ate ad ju stm en t f o r the packed column d a ta o f 1983 (F ig u re 2, Table 4) using th ese r e la tiv e com positions in d ic a te s m u ltip lie rs of 0.166 and 0 .6 8 8 fo r A roclor 1242 and 1260, r e s p e c t iv e ly , to d e riv e a c tu a l serum le v e ls and body b u rd en s. The m ost p e r s is t e n t ch em ical s tr u c tu r e ap p ears to In v o lve the 2 ,4 ,5 c o n fig u ra tio n . Isom ers rep o rted as to x ic in an im als ( 3 ,4 ,5 ,3 ', 4'; 3 ,4 ,5 ,3 ',4 ',5 ') were not found. Sm all peak s a s s o c ia t e d w ith 3 ,4 ,4 ' and 3 , 4 . 3 ' , 4 ' ( a l s o t o x i c in a n im a ls ) w e r e * i d e n t i f i e d in t h e s e human s a m p le s . These p eak s accou n ted f o r o n ly 0.5% o f th e serum co m p o sitio n b u t con tain ed other coelutin g isom ers. In T a b le 4 , we c o n t r a s t th e g r o s s serum PCB l e v e l s (p a c k e d colum n method) found in v a rio u s groups o f w orkers compared to the stu d y p o p u la t io n . C le r ic a l w orkers employed an av erag e o f 24 y e a rs a t the s i t e showed e le v a te d le v e ls o f the low er hom ologs a s the r e s u l t o f the gen e r a l e l e v a t i o n o f a i r l e v e l s w ith in and o u t s i d e th e p l a n t s . New em p lo y e e s (av era g e s e r v ic e tim e o f 2 y e a r s) showed e le v a t io n s th ough t to be a c o n seq u en ce o f r e s i d u a l p l a n t a i r l e v e l s s i n c e th e PCB b an . L a b o r a t o r y w o rk ers a t a n o th e r f a c i l i t y a c t i v e l y e n g a g e d in PCB r e s e a r c h showed e le v a tio n s o f both low er and h igh er hom ologs. For the p o p u la tio n o f t h i s stu d y (1 9 8 3 ), low er and h ig h e r g r o s s homolog l e v e l s were 18 and 3 .4 tim e s th e n o n p la n t c o n t r o l s , th e fo rm e r h a v in g d e c lin e d 92% s i n c e 1 976. Serum PCB l e v e l w ere c o n d it io n e d by a v a r i e t y o f f a c t o r s . We perform ed m u ltip le lin e a r backward ste p r e g r e s s io n s in which th e g r o ss serum PCB l e v e l was ta k e n a s th e d ep en d en t v a r i a b l e w ith th e 21 in d e p e n d en t v a r i a b l e s shown in T a b le 2 . T ab le 5 shows th e s i g n i f i c a n t in d e p e n dent v a ria b le s as p a r tia l c o rre la tio n s fo r the th ree exam inations (1976, 1 979, and 1983) u s in g A r o c lo r 1242 f o r a p o p u la t io n (1 3 6 ) h a v in g com p le t e d a ta (1976 N = 1 3 5 ). The a s t e r i s k s in d ic a t e s i g n i f i c a n t v a r i a b le s fo r the h igh er homologs (A roclor 126Q ). E xposure, as m easured by the exposure c a te g o ry , was th e prim ary d eterm in an t o f A ro clo r 1242 l e v e l. S e rv ic e tim e was th e m ajor c o r r e la t e f o r A ro c lo r 1260 ( p a r t i a l R = 0 .5 3 ) . Whether th e w orker was f a s t i n g or n o n -fa stin g (1976) was s ig n if ic a n t only fo r th e low er hom ologs. Serum l i p id le v e ls were s ig n if ic a n t in a l l c a se s as a consequence o f the phy s i c a l d i s t r i b u t i o n o f PCBs in th e l i p o p r o t e i n s . In 1983, an in v e r s e a s s o c ia tio n w ith serum album in was found in a l l c a s e s . There was a p o s i t iv e a s s o c ia t io n w ith .body f a t fo r both low er and h ig h e r hom ologs in 1979, but only fo r th e low er homologs in 1983. B ecause a l l th e s a la r ie d w orkers were m ale, se x and th e h o u r ly /s a la r ie d v a r ia b le s were red u n d an t. Serum PCB l e v e l s w ere i n v e r s e l y a s s o c i a t e d w ith sm oking i n th e c a s e o f th e lo w er .h o m o lo g s. .We found no dependence o f serum PCB l e v e l s on th e h e p a tic enzyme l e v e l s , a lc o h o l consum ption, o r m e d ic a tio n u s e . B ioch em ical and H em atological F in d in gs Means, stan d ard d e v ia tio n s, and ran ges o f the b io ch em ical and h e m a to lo g ic a l m easurem ents made on th e stu d y p o p u la tio n in 1983 were c o m p ile d . Of more i n t e r e s t were th e number o f v a l u e s t h a t e i t h e r e x ceeded or were l e s s than the age- and se x -a d j us te d sta n d a rd s o f th e l a b o r a t o r y , w hich a r e shown in T a b le 6 . We n o te e l e v a t e d serum t r i g l y c e r i d e , c h o l e s t e r o l , GPT and GGTP le v e ls *. E le v a t e d l e v e l s o f o t h e r en zymes (serum GOT, a l k a l i n e p h o sp h a se , and LDH) w ere n o t o b s e r v e d . T h e re , were e l e v a t i o n s in b lo o d g lu c o s e ( f i v e w o rk ers were known d i a b e t i c s ) and u r ic a c id . Although album in and g lo b u lin le v e ls were n orm al, the alb u m in -g lo b u lin r a t i o was e le v a te d in 21 c a s e s . The B U N /cre atin in e r a t i o was e le v a t e d in 11 c a s e s . E le v a tio n s in serum p o ta ssiu m and c h lo rid e le v e ls were found in m ales. In h em ato lo gy we fou n d re d u c e d re d c e l l c o u n ts among m a le s w ith e le v a t e d MCV and MCH v a l u e s . White c e l l c o u n ts w ere low in 16 c a s e s , w ith a r e la t iv e n eu tro p en ia and e le v ate d lym phocytes, m onocytes, and eo sin o p h ils. U rinary s p e c if ic g ra v ity averaged 1.022 -- 0.006'. C a lc u la t ed body f a t fo r m ales and fem ales averaged 2 1 .4 -- 7 .0 and 2 2 .1 -- 9 .5 k g, r e sp e c tiv e ly ; as a p ercen tage of body w eight the e q u iv a le n t v a lu e s were 2 5 .3 5 -- 4 .7 5 and 3 2 .3 5 - 8 .5 5 . R egressio n and R e su lts A sso c ia t io n s w ith PCBs The b io ch em ical and h e m a to lo g ica l v a r ia b le s were exam ined as dependent v a ria b le s in m u ltip le lin e a r backward ste p r e g r e ssio n . Each a r i a b l e was exam ined f o r i t s a s s o c i a t i o n w ith th e serum PCB l e v e l a s an Independent v a r ia b le in in d iv id u al' an aly ses fo r the g ro ss serum le v e l and the serum l i p i d le v e l in the p resen ce o f s e le c t e d co n fo u n d e rr. The re su lts are given in Table 7 as p a r tia l c o rre la tio n s, fo r th ose ca se s where a s t a t i s t i c a l l y s i g n i f i c a n t a s s o c i a t i o n betw een a PCB m easu re and th e c l i n i c a l v a r ia b le was o b se rv e d . The d a ta o f T ab le 7 are f o r A r a c lo r 1242 (lo w e r h o m o lo gs) and A r o c lo r 1260 ( h ig h e r h o m o lo g s ) . No a d d i t i o n a l a s s o c ia t io n s were found w ith A ro clo r 1254 and no a s s o c ia t io n s found u s in g th e 1976 e x p o su r e c a t e g o r y when e i t h e r w ere u se d a s th e in d e p e n d e n t exposure v a ria b le . F or both the low er and the h ig h er homolog g r o ss serum le v e l , s i g n if ic a n t a s s o c ia t io n s e x iste d w ith both th e t r ig ly c e r id e s and c h o l e s t e r o l . C on version to th e serum l i p i d v a lu e s in d ic a t e d no r e s i d u a l a s s o c i a t i o n s n o t a c c o u n te d f o r by th e PCB d i s t r i b u t i o n s i n th e t o t a l n e u t r a l l i p i d s . In th e 105 r e g r e s s i o n s u s in g th e PCB c o n c e n t r a t io n in serum t o t a l n e u tr a l l i p i d s , only a s in g le s i g n i f i c a n t a s s o c ia t io n was fou n d: t h a t betw een th e low er homolog v a lu e s and th e p e rc e n ta g e o f b a so p h ils . However, t h is a s s o c ia tio n depended upon the c l a s s i f i c a t i o n o f the jo b s t a t u s (w o r k in g /e e p a r a te d ). Removal o f jo b s t a t u s a s an in dependent v a r ia b le , or the in c lu sio n of re c e n t r e t i r e e s , removed the serum l i p i d PCB" a s s o c i a t i o n i n d i c a t i n g c o l i n e a r i t y o f th e PCB l e v e l and j ob s t a t u s . The ab sen ce o f s i g n if ic a n t a s s o c ia t io n s w ith serum b ilir u b in l e v e l s and GGTP and th e serum l i p i d PCB l e v e l o b s e r v e d in 1976 and 1979 (2 ) were ap p a re n tly n ot due to the a d d itio n o f alc o h o l consum ption and m edi c a tio n u se as independent v a r ia b le s in t h is stu d y . Removal of th e se l a t t e r v a r ia b le s from the p resen t r e g r e ssio n d id n ot in flu e n c e the resu lt. We a l s o i n v e s t i g a t e d th e s t a t i s t i c a l a s s o c i a t i o n s o f PCB l e v e l s w ith the s y s t o lic and d ia s t o lic blood p re ssu re used a s dependent v a r i a b l e s (T a b le 8 ) . No m easu re o f PCBs was s i g n i f i c a n t l y a s s o c i a t e d w ith e ith e r p r e s s u r e . Both s y s t o lic and d i a s t o l i c p r e ssu r e s were p o s it iv e ly a s s o c ia te d w ith o b e sity and the u se of a n tih y p e rte n siv e m e d ic a tio n s. S y s t o lic p re ssu r e s were h igh er in th o se re p o rtin g use of t r a n q u iliz e r s (MED), and d i a s t o l i c p r e s s u r e s were h ig h e r in th o se r e p o r t in g a p h y sician 's d iag n o sis of hypertension. A sso c ia tio n s w ith Confounders The i n t e r r e la t io n s o f the indepen dent v a r ia b le s w ith the c l i n i c a l m easurem ents were dom inated by the age and se x d iffe r e n c e s and by a l c o h o l co n su m p tio n and o b e s i t y . We n o te d t h a t 12 c l i n i c a l v a r i a b l e s had no s i g n if ic a n t independent v a r ia b le o th er than age o r se x , in c lu d in g serum c h o l e s t e r o l , SGOT, SGPT. and LDH, and t h a t 13 v a r i a b l e s w ere a s ig n i f ic a n t fu n c tio n o f age. At the tim e o f the p re se n t stu d y the a v e r age p o p u la tio n age was 4 9 .5 y e a r s. O b esity (body f a t ) was s i g n i f i c a n t l y a s s o c i a t e d w ith e le v a t e d serum t r i g l y c e r i d e s , GGTP, b lo o d g l u c o s e , and u r ic a c i d . C h o le ste ro l le v e ls were e le v a te d p r im a r ily as a fu n c tio n o f a g e . D ia b e tic a and e x -a lc o h o lic s tended to have h igh er t r i g l y c e r id e s , u r ic a c id s and serum phosphate le v e ls . A lcoh ol consum ption in flu e n c e d th e l e v e l s o f GGTP and t o t a l b i l i r u b i n and was a s s o c i a t e d w ith a m acro c y t o a l s ( e l e v a t e d MCV) and a d e c r e a s e d r e d c o u n t. We o b s e r v e d p o s i t i v e a s s o c i a t i o n s o f MFQ in d u c e r s w ith th e BUN and th e B U N /c r e a tin in e r a t i o and an in v e rse a s s o c ia t io n with serum p o ta ssiu m which appeared m ost lik e ly to be r e la te d to the use of n o n -ste ro id a l an tiin flam m atory drugs (60) and d i u r e t i c s co m p licated by th e u se o f p o ta ssiu m supplem en ts in some i n d i v i d u a l s . We c a l c u l a t e d th e serum o s m o l a r it y f o r th e members o f s th e p o p u la tio n and found th e mean to be 2 9 7 .1 r 4 .7 mOsm/kg w ate r (ra n g e : 2 8 2 -3 1 0 ), which was e le v a te d o ver the e x p e cte d ran g e o f 2 9 0 -2 9 5 . Serum o e m o la rity was found to s u b s t i t u t e f o r u rin a ry s p e c i f i c g r a v it y a s an Indepen dent v a r ia b le in m u ltip le r e g r e s s io n . hTSCUSSIQW A group of. c a p a c ito r w orkers d ir e c t ly exposed to PCB* h as been fo llo w e d w ith c l i n i c a l e x a m in a tio n s and serum PC8 l e v e l s o v e r a p e r i o d of n ea rly 8 y e a rs. At the tim e of the p re se n t stu d y , 6 .5 y e a rs had e la p s e d s i n c e th e c e s s a t i o n o f PCB u s e . P a r t i c i p a t i o n i n th e p r e s e n t stu d y was v o lu n t a r y , and o n ly 83% o f th e 1979 p o p u la t io n was r e c o v e r e d so th a t in d iv id u a ls w ith ad verse e f f e c t s could have been removed by the s e l f - s e l e c t io n p r o c e ss. However, the log-n orm al d is t r ib u t io n s o f the p o p u la t io n serum PCB l e v e l s and th e n orm al d i s t r i b u t i o n o f th e r e s i d u a l s fo llo w in g m u lt ip le s t e p w is e r e g r e s s i o n which we o b s e r v e d s u g g e s t t h a t the s t a t i s t i c a l requirem ents fo r a d ose-resp on se r e la tio n , i f p re se n t, had been m et. S in c e th e PCB b an , th e PCB a i r l e v e l s in th e w o rk p la c e have c o n tin u o u sly d e c lin e d , r e s u lt in g in an av erag e r e s i d u a l a r e a a i r l e v e l j u s t p r i o r t o th e p r e s e n t s tu d y o f o n ly 16 p.g/m3 ( F ig u r e 2) . We found t h is d e c lin e in exposu re to be accom panied by a d ram atic re d u c tio n in c a l c u l a t e d PCB body b u rd e n s among t h e s e w o rk e rs a s m e a s u r e d .b y p a c k e d column chrom atography in term s o f A ro c lo r 1242 (F ig u re 3) . The h ig h e r c h lo rin a te d sp e c ie s (c a lc u la t e d as A ro clo r 1260) showed r e l a t i v e l y con sta n t v a lu e s. A roclor 1254 f e l l in between as a consequence of i t s o v er lap p in g Isom er com position w ith both A ro clo r 1242 and 1260. A ro clo r 1260 was never used in c a p a c ito r m an u factu rin g; th e le v e ls f o r th a t su b stan ce re p re se n t e ith e r p r io r exp o su res to A roclor 1254 (used between 1946 and 1954), the g rad u al accum ulation of tr a c e s o f the h ig h er c h lo r i nated isom ers found in A roclor 1242, the prim ary c o n stitu e n ts of the d i e l e c t r i c f l u i d u se d betw een 1954 and 1 9 7 0 , o r e x p o su re t o PCBo in th e environm ent, which tend to be the h ig h ly c h lo r in a te d s p e c ie s . PCB body b u rd en s were c a l c u l a t e d from th e serum PCB l e v e l s t h a t were e s t im a t e d by th e sum o f th e s e l e c t e d p eak h e ig h t s m ethod o f q u a n t i t a t i o n . With th e same m eth o d o lo g y , a c o m p a riso n o f g r o s s serum PCB l e v e ls w ith o th er sm all worker p o p u la tio n s (T ab le 4) in d ic a te d h ot only the m agnitude o f the exposure in the study p o p u la tio n , bu t th e g e n e ra lly e le v a te d le v e ls o f the low er homologs in lo n g - se r v ic e em ployees and t h e i r a c c u m u la tio n in new em plo y ees a s th e r e s u l t o f e x p o s u r e t o th e p lan t r e s id u a ls . Such le v e ls in the g en eral p la n t p o p u latio n preclu ded the u se o f an in - p la n t c o n tr o l group f o r the conduct o f t h i s stu d y . The q u a n t i t a t i o n m eth o d o lo g y , h ow ever, o v e r s t a t e d th e a c t u a l PCB c o n c e n t r a t io n p r e s e n t . The s e l e c t e d p e ak s ( o r m easurem ent r e p r e s e n te d th e m ost p e r s i s t e n t o n e s. T h is problem was p r e v io u s ly s tu d ie d in a sam ple o f w orkers w ith h ig h PCB l e v e l s , and t h e s e p e r s i s t e n t p e a k s w ere found to p r o v id e a p p r o x im a te ly 25% and 70% o f th e A r o c lo r 1242 and 1260 c o m p o si t i o n s , r e s p e c t i v e l y ( 4 3 ) . No d a t a , h ow ever, a r e a v a i l a b l e f o r th e co n v ersio n f a c t o r s a t low serum l e v e l s . C a p illa r y g a s chrom atography r e s u l t s on th e s e r a o f a r e p r e s e n t a tiv e sam ple of w orkers in the* study p o p u latio n should be co n sid ered p re lim in ary and were co m p licated by sam ple co n tam in atio n . However, they I n d ic a t e d th e n a tu r e and m agn itu d e o f th e PCB c l e a r a n c e p r o c e s s and a p p ro x im a te d th e p r e s e n t r e s i d u a l serum PCB c o m p o s itio n . The r e s i d u a l iso m er c o m p o sitio n (T a b le 3) p ro v id e d th e PCB c o n c e n t r a t io n t o which any  p r e se n t b io ch em ical or h e m a to lo g ic a l fin d in g s sh'ould be a s c r ib e d . I s o m ers fo r which t o x ic p r o p e r tie s h are been in d ic a te d in e x p e rim e n tal an im als were not I d e n tifie d . As we have n o te d e lse w h e re (4 9 ) and have shown in T a b le 5 , th e g r o s s serum PCB c o n c e n t r a t io n i s s t r o n g l y d e p e n d e n t on th e serum l i p i d c o n c e n tr a tio n , which fo llo w s from th e e q u ilib r iu m d i s t r i b u t i o n o f PCBs th ro u g h o u t th e body f a t . C o n v e rsio n t o th e serum l i p i d PCB c o n c e n t r a tio n ( t o t a l serum n e u tra l l i p id b a s is ) f u lly accou n ts fo r the o bserv ed a s s o c i a t i o n s betw een th e g r o s s serum PCB l e v e l s and th e serum t r i g l y c e r id e s and c h o le s t e r o l l e v e l s m easured c l i n i c a l l y (T a b le 7 ) . By a n a lo gy w ith o th e r f a t - s o l u b l e a g e n ts , th e p h a rm a c o lo g ic a l a c t i v i t y o f PCBs i s m ost e f f e c t iv e ly re p re se n te d by i t s co n cen tratio n in l i p id s (4 9 ,5 1 ). T h ese a s s e r t i o n s a r e a t v a r i a n c e w ith th e c o n c lu s io n s o f o t h e r s who h ave tended to a s c r ib e any observed h y p e rlip id e m ia in exposed p o p u la tio n s to th e b i o l o g i c a l e f f e c t s o f PCBs r a t h e r than th e p a r t i t i o n i n g b e h a v io r o f PCBs in serum l i p i d s . M u ltip le sep -w ise r e g r e s s io n s w ith both serum t r ig ly c e r id e s and c h o le ste ro l as independent v a r ia b le s alw ays re su lte d in the se le c tio n of serum t r ig ly c e r id e s as the s ig n if ic a n t a s s o c ia tio n w ith the g ro ss serum PCB l e v e l , a lth o u g h serum c h o l e s t e r o l , when u se d a l o n e , h ad an e q u a l l y stro n g a s s o c ia t io n w ith g ro ss serum PCBs. T h is problem in c o lin e a r it y , which h as been noted by K r e is s e t a l . (3 0 ), i s r e so lv e d by th e u se o f r th e t o t a l serum n e u tr a l l i p i d s a s th e dependent v a r ia b le (T ab le 5 ) . The p r e f e r e n t i a l s e l e c t i o n o f th e serum t r i g l y c e r i d e s may be b a s e d on s o l u b i l i t y c o n s id e r a tio n s . The in v e r s e a s s o c ia t io n w ith serum album in presum ably r e f le c t s the p ro te in bin din g observed w ith oth er organ oe h lo r id e o ( 5 3 ) , which h as now a p p e a r e d a s a s i g n i f i c a n t p a r t i t i o n i n g v a r i a b l e - f o l l o w i n g c le a r a n c e o f th e m e t a b o liz a b le i s o m e r s . We n o te a l s o th e p o s i t i v e a s s o c i a t i o n o f g r o s s serum PCB l e v e l s w ith amount o f body f a t , su g g e stin g t h a t in the more o b ese w ork ers, PCBs were l e s s r e a d il y m o b iliz e d and e q u ilib riu m n ot a s s u r e d . However, our o b s e r v a t io n s bn .1 c h a n g e s in serum l i p i d s in th e a b se n c e o f s u b s t a n t i a l w e ig h t l o s s (4 9 ) , 3 the p r o p o r tio n a lity of the l i p id co n ten t of organ s and t is s u e s and th e ir PCB c o n c e n t r a t io n s ( 4 7 ) , and s t u d i e s d u rin g c a c h e x ia and s t a r v a t i o n (5 4 ,5 5 ) a l l s u p p o r t th e q u a l i t a t i v e i f n o t q u a n t i t a t i v e t h e s i s o f PCB p a r titio n in g in serum and t is s u e l i p i d s . G ro ss serum PCB l e v e l s w ere a l s o found t o be s t r o n g l y and i n v e r s e ly dependent on smoking (T ab le 5 ) . T h is a s s o c ia t io n was o n ly found f o r th e lo w er PCB co n g e n e rs (A r o c lo r 1242) and i s th o u g h t t o be d i r e c t l y r e la t e d to the in d u ctio n o f mixed fu n c tio n o x id a se s by both n ic o tin e and th e v a r io u s c o n s titu e n ts o f c i g a r e t t e smoke. S tu d ie s by McLemore e t a l . (5 6 , 57) on a lv e o la r m acroph ages, p e r ip h e r a l ly m p h o cy tes, and pulm onary b io p s y t i s s u e have d o c u m e n te d .in d e t a i l MFC in d u c t io n by c i g a r e t t e smoke. Although alc o h o l consum ption and m edication use appeared as s i g n i f i c a n t in d ep en d en t v a r i a b l e s in r e l a t i o n to some c l i n i c a l p a r a m e t e r s , n e i t h e r were s i g n i f i c a n t l y a s s o c i a t e d w ith serum PCB l e v e l s . U sin g th e serum l i p i d PCB c o n c e n t r a t io n a s th e in d e p e n d e n t e x p o s u r e v a r i a b l e , we fou n d v i r t u a l l y no s t a t i s t i c a l l y s i g n i f i c a n t a s s o c i a tio n o f any A ro clo r w ith the m easured bioch em ical and h e m a to lo g ic a l v a r ia b le s (w ith the s in g le ex cep tio n o f the p ercen tage o f b a so p h ils and A roclor 1242), d e sp ite the c lin ic a l v alu es reported o u tsid e the normal la b o r a t o r y ra n g e s (T a b le 6 ) . In a d d it io n , no s i g n i f i c a n t a s s o c i a t i o n s were found w ith the 1976 exposu re c a te g o r y , an e stim a te o f 'p rio r expo- I u r * n t h e s e w o r k e rs. One e f f e c t o f th e c o n v e r s io n o f th e g r o s s serum c o n c e n tra tio n to the serum l i p i d c o n c e n tra tio n was to e lim in a te a s s o c i a t i o n s 1b a s e d s o l e l y on c o v a r ia n c e w ith th e serum l i p i d c o n c e n t r a t io n ( 3 3 ) . Such c o v a r ia n c e may have a c c o u n te d f o r th e g r o s s serum PCB a s s o c i a t i o n s w ith some l i v e r enzymes o b se rv e d by o t h e r s . T hese 1983 r e s u l t s c o n tr a s t w ith the fin d in g s in 1976 du rin g a c tiv e exposure where the cen t r a l o b se rv a tio n s, (a p o s it iv e a s s o c ia t io n o f serum l i p i d PCBs w ith serum GGTP and an i n v e r s e a s s o c i a t i o n w ith th e serum b i l i r u b i n ) a p p e a r e d t o r e f l e c t m icrosom al enzyme in d u ctio n ., enhanced g lu c u ro n ld e - c o n ju g a tin g c a p a c i t y , and a c c e l e r a t e d h e p a t i c e l i m i n a t i o n . Such e f f e c t s w ere much dim in ish ed in 1979 and were ab se n t in the c u rre n t d a ta , su g g e stin g th a t th e c le a r a n c e o f th e m ost e a s i l y m e ta b o liz e d lo w e r PCB c o n g e n e r s was su b sta n tia lly com plete. We w ere u n a b le t o c o n firm th e a s s o c i a t i o n betw een PCB l e v e l s and e ith e r the s y s t o lic or d ia s t o lic blood p re ssu re found by K re iss e t a l . (3 0 ). Although blood p re ssu re m easurem ents c o n siste d of one c a su a l ob s e r v a t i o n , we found s t r o n g a s s o c i a t i o n s f o r b o th w ith o b e s i t y and th e use o f h y p e rte n siv e m e d ic a tio n s. S y s t o lic blood p re ssu re was r e la t e d to th e u s e o f MFO I n d u c e r s , p re su m ab ly t r a n q u i l i z e r s s u c h 'a s d ia z e p a m . D ia s t o lic blood p re ssu r e s were a s s o c ia te d w ith a re p o rte d p h y sic ia n 's d ia g n o sis, o f h y p erten sio n and were low er in sm okers and ex-am okers. The o c c u r r e n c e o f c h a n g e s in th e WBC and d i f f e r e n t i a l m e r i t s a t t o n t lo n (T a b le 6 ) . In Yusho a s l i g h t l e u k o c y t o s i s (2 ) o r e l e v a t e d WBC (4 ) was fo u n d . In o c c u p a t i o n a l PCB e x p o s u r e s , norm al h e m o g lo b in s and h e m a t o c r it s (2 7 ,3 1 ) and norm al RBC (2 7 ) w ere r e p o r t e d . WBC d i f f e r e n t i a l s were e ith e r not m easured (26) or not re p o rte d (2 4 ,2 7 ,2 9 ,3 1 ,3 2 ). M aroni e t a l . (2 8 ) r e p o r t e d norm al WBCa and d i f f e r e n t i a l s . B e c a u se no s t a t i s t i c a l l y s i g n i f i c a n t a s s o c i a t i o n s w ith serum l i p i d PCB l e v e l s w ere found, th ese changes could rep re se n t e ffe c t s of oth er exposures in the w o rk p lace, p erh ap s tric h lo ro b e n z e n e (TCB, p r im a r ily th e 1 :2 :4 iso m e r ), which was used a s a c o n s titu e n t o f th e s u b s t i t u t e d i e l e c t r i c betw een 1977 and 1983. In 15 e x p o se d w o rk e rs a t t h e s e p l a n t s , serum TCB l e v e l s ran ged from 0 .5 5 to 6 .7 5 ppb, w hereas in 16 o f 18 n on exposed w o rk e rs, the le v e ls were 0 .4 ppb, the d e te c tio n li m i t . However, no changes in hem oglobins or h em o crits were o b se rv e d in r a t s fe d 10 to 40 m g/kg/day TCB f o r 90 d a y s (58) w here i t was shown t o be a p o te n t MFO in d u c e r . The c l i n i c a l fin d in g s of n eu tro p en ia w ith e le v a te d lym phocytes and m onocytes to g e th e r w ith a reduced w hite count and the p ercen tage of b a so p h ils rem ains u n exp lain ed . Given the in te n se ex p o su re and the m assiv e c le a r a n c e o f PCBs in th is population in the p a st, the r e la tiv e absence of s t a t i s t i c a l a s s o c i a t i o n s o f c l i n i c a l v a r i a b l e s w ith serum PCB l e v e l s a t p r e s e n t i s n o tew o rth y . T h ese c a p a c i t o r p la n ts^ c o n su m e d ab o u t 15J5 o f th e U .S . PCB p ro d u ctio n (1 3 ), and the stu d y p o p u la tio n p ro b ab ly r e p r e se n ts one o f the most h ig h ly exposed p o p u la tio n s t h a t w ill e v e r be e n c o u n te re d . The c l i n i c a l f in d in g s o f h y p e r lip id e m ia w ith l i v e r enzyme and u r ic a c id e le v a tio n s appear to r e la t e p rim a rily to a g e , o b e s ity , sm oking, and a l cohol consum ption. A d d itio n al stu d ie s o f the h em atological fin d in g s ap p e ar w arran ted fo llo w in g th e p h a se - o u t o f tr ic h lo r o b e n z e n e t h a t was com p leted in 1983. ACKNOWLEDGMENTS The au th o rs v ls h to e x p re ss t h e ir a p p r e c ia tio n to Dr. T. ran d er Hoeven (D epartm ent o f Pharm acology and T o x ic o lo g y , Albany M edical C o l le g e ) f o r the c l a s s i f i c a t i o n s o f M FO-inducing d r u g s, R. Wagner f o r th e p e rfo rm a n c e o f PC5 a n a l y s e s by c a p i l l a r y GC, and H elen W alton f o r h e r help in m anuscript p rep aratio n . \ RFTF*gNCES 1 . J s n s e n , S . A new. c h e m ic a l h a z a r d . New S c L . 3 2 :6 1 2 , 1 9 6 6 . 2 . P<7H PojiiQninfl and P o l l u t i o n . Ed. K. H ig u c h i, A cadem ic P r e s s , New York, 1976. 3 . N agayam a, J . , M aeuda, Y. , and K u r a ts u n e , M. D e te r m in a tio n o f c h lo rin a te d d ib en zofu ran s in K an echlors and "Yusho o i l . " E n viron . 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The u s e and h e a l t h e f f e c t s of A roclor 1242, a p o ly c h lo rin a te d b ip h en y l, in an e l e c t r i c a l in d u s t r y . A reh . g b t . Hgalfch 3 1 :1 8 9 -1 9 4 (1 9 7 6 ). 27. F ish b ein , A ., Wolff, M.S., L i l i s , R ., Thornton, J . , and S e l i k o f f , I . J . C l i n i c a l f i n d i n g s among P C B -exp osed c a p a c i t o r m a n u fa c tu r in g w ork ers. Ann. N.Y. Acad. ^Sci. 3 2 0 :7 0 3 -7 1 5 (1 9 7 9 ). 2 8 . M aroni, M ., C olum bi, A ., A r b o s t i , G ., C a n to n i, S . , and F o a , V. Oc cu p atio n al exposure to p o ly c h lo rin ate d bip h en yls in e l e c t r ic a l work e r s : I I . H e a lth E f f e c t s . B r i t . J . In d . Med. 3 8 :5 5 - 6 0 ( 1 9 8 1 ) . 2 9 . B a k e r, E . L . , J r . . L a n d r ig a n , P . J . , G lu e ck , C . J . , Z ack , M.M., J r . , L i d d le , J . A . , B u r s e , V.W., H ouaew orth, W . J . , and Needham, L . L . 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C lin ic a l and m etab o lic a b n o rm a litie s a s s o c ia te d w ith o c c u p a tio n a l exposure to p o ly c h lo rin a te d b ip h en y ls (P C B s). J . Qccup. Med. 24:109-114 (1962). 33. Law ton, R.W., R o ss, M . R . , F e in g o ld , J . , and Brown, J . R . , J r . E f f e c t s o f PCB e x p o su re on b io c h e m ic a l and h e m a t o lo g ic a l f i n d i n g s in c a p a c ito r w orkers. Environ. H ealth P ersp . 60:165-184 (1985). 3 4 . S ch n eck , D.W., a n d _ P r ic h a r d , J . F . The i n h i b i t o r y e f f e c t o f 1 p r o p r a n o lo l p r e t r e a t m e n t on i t s own m e ta b o lism in th e r a t . J . Fharm. Ex p . T h e r a p . 2 1 8 :5 7 5 , 1 981. 35. K ato, R ., and G ile t t e , J . R . Sex d iffe r e n c e s in the e f f e c t s of ab i norm al p h y s io lo g ic a l s t a t e s on th e m etab o lism o f d ru g s by r a t l i v e r m lc ro so m e s. J . P h a m . Ewe . T h e r a p . 1 5 0 :2 8 5 , 1 965. 36. P a te l, J . M . , and Fawar, S . S . 'R ib o fla v in and drug m etabolism in a d u lt m ale r a t s . Biochem. Pharm acol. 2 5 :1 4 6 7 , 1974. 37. Conney, A.H., B ray, G.A., Evans, C ., and Burns, J . J . M etabolic in t e r a c t i o n betw een L - a s c o r b ic a c id and d r u g s . Ann. N.Y. A cad. S c i . 92:115, 1981. 3 8 . C a r p e n te r , M. P. , and Howard, C.N. V itam in E, s t e r o i d s and l i v e r mi c ro so m a l h y d r o x y l a t i o n s . Am. J . C l i n . N u t r . 2 7 :9 6 6 , 1974. 39. Hume, R ., and Weyer, E. R e l a t io n s h i p betw een t o t a l body w a te r and su rfa c e a re a in normal and obese s u b j e c t s . J . Clin. P ath . 2 4 :2 3 4 238, 1971. 40. The Merc k M an u al. R. Barkow, E d . , Merck and C o . , Rahway, N . J . , 1977 p. 1184. 41. M oore, F . D . , e t a l . The Body C e ll Mass and I t s Su p p o rtin g E n viron m ent. P h i l a d e l p h i a , 1963, W.B. S a u n d e r s , P. 16 6 . 42. Benn, R . T. Soma m a th e m a tic a l p r o p e r t i e s o f w e ig h t - f o r - h e i g h t i n d i c e s u se d a s m e asu re s o f a d i p o s i t y . B r i t . J . S o c . Med. 2 5 :4 2 - 5 0 ,i 1971. ; 4 3 . Law ton, R.W., Brown, J . F . , J r . , ' R o s s , M. R. , and F e in g o ld , J . Com p a r a b i l i t y and p r e c i s i o n o f serum PCB m e a su re m e n ts. Arch. E n v i r o n . H ealth 40:29-37, 1985. 44. B a ls c h m it e r , K. and Z e l l , M. A n a ly s is o f p o l y c h l o r i n a t e d b ip h e n y ls by g la s s c a p illa r y gas chrom atography: com position o f te c h n ic a l aro c lo r and cloph en . F reaen iu a z. A nal. Chen. 3 0 2 :2 0 -3 1 , 1980. 45. D r in k e r , J . C . , and H llle b r a n d , M . J . J . C h a r a c t e r i z a t i o n o f PCB com i p o n e n ts in clo p h e n f o r m u la tio n s by c a p i l l a r y GC-MS and GC-ECD t e c h n iques. Environ. Sci. Technol. 17:449-456, 1983. 4 6 . S a f e , S . , Mu1 1 i n , M ., S a f e , L . , P o c h in e , C ., M cC rin d le , S . , and Ram kes, M. High r e s o l u t i o n PCB a n a l y s i s : p h y s i c a l b e h a v io r o f PC3s_ in the Great, Lakes . D. M ackay, e t a l . C e d e . ) , Ann A rb or S c ie n c e P u b . , Ann A rb o r, 1 9 8 3 , p . 1 - 1 3 . 47. Morgan, D.P ., and Roan, C.C. C h lo rin ated hydrocarbon p e s tic id e r e s i d u e in human t i s s u e s . A rc h . E n v ir o n . H e a l t h . 2 0 :4 5 2 - 4 5 7 , 1 9 7 0 . 4 8 . M athew s, H . B . , S u r l e s , J . R . , C a r v e r , J . G . , and A n d e rso n , M.W. P o ly c h lo rin a te d biphenyl tra n sp o rt by blood com ponents. T o x ic o l. Ap p l . P h a rm a c o l. 4 1 :2 0 1 , 1977. 4 9 . Brown, J . F . , J r . , and Law ton, R.W. P o l y c h l o r i n a t e d b ip h e n y l (PCB) p a r t itio n in g between ad ip o se t is s u e and serum . B u l l . E n viron . Contan . T o x ico l. 33:277-280, 1984. 50. Henry, R . J . C lin ic a l C h em istry; Prin c ip le s and T ech n ics. H arper and Row, New Y ork , 1968, p p . 8 3 6 -8 4 4 . 51. Ferguson, J . -The use of chem ical p o te n tia ls as in d ic e s of t o x i c i t y . P r o e . Ro t . So c . B 1 2 7 :3 8 7 -4 0 3 ( 1 9 3 9 ) . 5 2 . N elso n , W.B. , Morgan, C . B . , and Brown, J . M . , J r . I n t e r a c t iv e STATPAC f o r Com puter A n a ly s is - U se r G u id e . G e n e ra l E l e c t r i c C o r p o r a t e R e s e a r c h and D evelopm ent R e p o rt )fo . 76CRD266, S c h e n e c ta d y , New Y o rk , 1977. 5 3 . S k a l s k y , H . L . , F a r i s e , M.W., B la n k s , R . V . , and G u z e lia n , P . S . The r o le o f plasm a p ro te in s in the tr a n sp o r t and d is tr ib u t io n o f ch ordecone (K epon e*) and o th e r p o ly h alo g e n a te d h y d ro carb o n s. Ann. N.Y. Acad. S c i . 320:231-237, 1979. 5 4 . H e sse lb e r g , R .L. and S c h e rr, D.D. PCBs and p,p'-DDE in th e blo o d o f c a c h e t i c p a t i e n t s . B u l l . E n v iro n . C on ta.ni To x i c o l . 1 1 :2 0 2 - 2 0 5 , 1974. 55. Imamura, M ., and Tung, T.C. A t r i a l o f f a s t in g cure fo r PC8p o is o n e d p a t i e n t s in T aiw an. Am. J . In d . Med. 5 :1 4 7 - 1 5 3 , 1984. 56. McLemore, T . L . , Warr, G.A., and M artin , R.R. In d u ction o f a r y l hy d ro c a rb o n h y d r o x y la s e in human pu lm on ary m acro p h ag es and p e r i p h e r a l lym phocytes by c ig a r e tte t a r s . Cancer L e tte r s 2 :1 6 1 -1 6 8 , 1977. 57. McLemore, T . L . , M artin, R.R., T o p p e ll, K . L . , B u sh il, D . L . , and Can t r e l l , E.T. Comparison o f a r y l hydrocarbon h y d ro xy lase in d u c tio n in c u l t u r e d b lo o d ly m p h o cy tes and pu lm on ary m a c ro p h a g e s. J . C l i n . Tra r e s t . 60:1017-1024, 1977. 58. C a rlso n , G . P . , and T a r k i f f , R.G. E f f e c t s o f c h lo r in a te d ben zen es on th e m e ta b o lism o f f o r e i g n o r g a n ic com pounds. T o x i c o l . A p p l .--P h a r macol . 36:383-394, 1976. 59. Wolff, M.S., Thornton, J . , F ish b e in , A ., L i l i s , R., and S e l i k o f f , I . J . D isp o sitio n of polych lorin ated biphenal congeners in occupa tio n a lly exposed p erso n s. T o x lc o i. A ppl. Pharm acol. 62:294-306, 1982. 60. C l i f e , D.M., and S t o f f , J . S . R enal syndrom es a s s o c ia t e d w ith nons t e r i o d a l a n t iin fla m m a t o r y d r u g s . NEJM 3 1 0 :5 6 3 - 5 7 2 , 1 9 8 4 . ! ALCOHOL CONSUMPTION SCALE on F ig u re 1 . Alcohol consum ption s c a le . Major consum ption was b e er re p o rte d a s six-packs per week. Scale (0-7) used as a dummy variable in re gression analysis. 17 s' J * 3 F ig u re 2 . Area a i r l e v e l s (a s A r o d o r 1242) In w o rk p lace ( lo g |ig/m 1 SD) in r e l a t i o n to PCB ban. Geometric means a re ^ g lv e n i n p a re n th e s e s . TWA v a lu e s In 1977 (g e o m e tric mean = 168 pg/ui ) m easured by HIOSH. V alues In 1978 measured over a number or months. 10.0 iT PCB BODY BURDEN (GRAMS) 1.0 0.1 AROCLOR 1242 AROCLOR 1254 AROCLOR 1260 DDE 1976 1978 - 1980 1982 YEARS 1984 1986 Figure 3. PCS body b urdens in c a p a c ito r w orker p o p u la tio n c a lc u la te d a s th e p ro d u c t o f th e serum PCB c o n c e n tr a tio n i n t o t a l serum n e u tr a l l i p i d s (ppm) and th e t o t a l body f a t (kg) g iv e n a s th e 95% c o n f i dence I n te r v a l of th e p o p u la tio n mean ( b a r ) . Males TM sq u a re ; fem ales tria n g le s . 19 !\ Table 1 CLASSIFICATION OF MEDICATION USE (GENERIC NAMES) R eported by Study P o p u la tio n A ccording to Mixed F u n c tio n O xidase (MFO) In d u c tio n o r D e p re s s io n ; MFO A c tiv ity E stim a te d from L i t e r a t u r e , S t r u c t u r a l A nalogy, and H alf-T im es; No In fo rm a tio n A v a ila b le on 22 Drugs Weak D e p re ssa n t No In fo rm a tio n B utalbital* Cim etidine* Indom ethacin* Q u inine* S p iro n o la c to n e No E f f e c t A c e ty ls a lic ic Acid Ib u p ro fe n t Phenacetin* Weak In d u c e r Brompheniramine * C affeine Chlorpheniram ine* Chlorpropamide * C y clo b en zap rin e HC1* C ortisone D iphenhydram ine H ydroxyzine* Meprobamate Acetaminophen A llopurinol C yclandelate E th o h ep ta z in e H ydrochlorothiazide H ydroflum ethiazide In s u lin M etolazine M ethylchlothiazide M ethyldopa N itroglycerin P en icillin P entaerythrltol T etranitrate Phenylpropanolam ine P lro x ic a n P ro z o s in HC1 P ro p ra n o lo l R eserp in e S u lfa d ia z in e Thyroid V itam ins W arfarin Strong Inducer Diazepam Phenytoin S tru c tu ra l analogy tPDR \ 20 T a b le 2 CANDIDATE CONFOUNDING VARIABLES AND COMPUTER CODING V a ria b le s S c re e n ed f o r A s s o c ia tio n s w ith Serum PCB L e v e ls (T ab le 5) PCS Exposure G ross serum PCB Serum l i p i d PCB PCB body burden Exposure category Serum L ip id s T riglycerides C holesterol Total n eu tral lip id s A bbreviation GSPCB SLFCB BBFCB EXE TRI Choi TNL M easure R eported value (ppb) C a lc u la te d v a lu e (ppm) C alculated value (g) Code: 0 low e x p .; 1 med. e x p .; 2 high exp. C lin ical value C lin ical value C alculated value (TRI + 1.5 Choi) Serum Albumin Body F a t Alb C lin ic a l v alu e Fat C alculated value (Hume and W eyers) Body H y d ra tio n Time S ervice time Age SPG U rin ary sp . g r a v ity C lin ical value ST Y ears Age Y ears Sex Sex Code: 1 m ales; 2 - fem ales Sa l a r led/H ourl y S/H Code: 0 S a la r ie d ; 1 - Hourly Job S tatus JS Code: 0 - Working; 1 - Separated . P lant Location PL Code: 0 - F t. Edward; 1 - Hudson F a lls D isease S tatu s DS Code: 0 No d is e a s e ; 1 In tercu rren t disease Smoking Code SC Code: 0 * Nonsmokers; 1 a&okers and ex smokers A lcohol Consumption A l t Code: 0 * None; 1-7 occasional to heavy M edications Med Code: -1 Weak d e p re s s a n t 0 No e f f e c t 1 Weak In d u c e r 2 * Strong inducer \ Table 3 PERSISTENT PCS CONGENERS IN CAPACITOR WORKERS EVALUATED AS PERCENTAGE COMPOSITION IN SERUM VS AROCLOR 1242 AND 1260 STANDARDS Serum P e rc e n ta g e C om positions Are th e Mean o f 10 W orkers; Parentheses In d ic a te C oeluting Isomers No. Cl IUPAC No. 3 28 (31) 4 70 (76) 5 99 5-6 118, 149 (106) 6 153 (1 0 5 , 132) 6 138 (160, 163, 164) 7 171 (156) 7 180 8 194 S tru c tu re 2 ,4 ,4 ' (2 .5 .4 ') 2 ,4 .5 ,4 ' (3 .4 ,5 ,2 ') 2 ,4 ,5 .2 ',4 ' 2 , 4 , 5 , 3 ', 4 '; 2 ,3 ,6 ,2 ' , 4 1,5 ' (2 ,3 ,4 ,5 ,3 ') 2 .4 .5 ,2 '.4 ', 5 ' (2 .3 ,4 .3 ',4 '; 2 ,3 ,4 ,2 ' ,3 '. 6 ') 2 ,3 ,4 .2 ',4 * .5 ' (2 ,3 ,5 ,6 ,3 '.4 '; 2 ,3 ,4 ,5 ,6 ,3 '; 2 ,3 ,6 ,3 ', 4 ', 5 ') 2 .3 .4 .5 .6 .2 '.3 '.4 ' (2,3 ,4 ,5 ,3 ',4 ') 2 ,3 ,4 ,5 ,2 ',4 ',5 ' 2 ,3 ,4 ,5 ,2 ',3 ', 4 ' ,5 ' Percentage Com position S td . P o p u la tio n A roclor 1242 8.1 21.5 1.6 33.0 0.7 8.0 A roclor 1260 11.5 14.7 16.1 39.9 12.0 14.6 2.5 12.4 0.8 4.2 6.4 0.6 * fV - 22 H \ Table 4 t GEOMETRIC MEAN GROSS SERUM PCB LEVELS IN VARIOUS STUD! POPULATIONS U n c o rre cte d V alu es a s R ep o rted by L a b o ra to ry (Sum o f S e le c te d Peak H e ig h ts Method) Tear r o d o r 1242 r o d or 1260 S ervice M easured Ji ' (ppb) (ppb) (years) No Exposure (Nonplant Control) Laboratory Personnel (N onplant) Employed s in c e PCB Ban Employed, Not Exposed Exposed 1976 1984 1981 1981 1976 1979 1983 18 10 16 18 176 171 146 6.7 11.2 28.3 50.4 1469.0 273.0 120.6 9.2 12.9 7.8 7.5 - 35.1 31.5 0 0 2 24 14 17 22 \ 0*3 Table 5 STATISTICALLY SIGNIFICANT ASSOCIATIONS OF GROSS SERUM AROCLOR 1242 WITH CANDIDATE CONFOUNDERS (TABLE 2) FOR COMPARABLE POPULATION IN 1976, 1979, AND 1983 V alues Are P a r t i a l C o r r e la tio n s a t End o f Backward-Step M ultip le L inear R egression; R2 f o r F in a l R e g re ssio n E q u a tio n G iven B elov 1976 _ 1979 _ 1983 N PCB Mean (ppb) Total N eutral Lipid 135 1518 528 136 289 517 136 124 505 Exposure Total N eutral Lipid Fasting/N onfasting Fat H ourly/Salaried Sex S e rv ic e Time Smoking Albumin 0,73* 0.27* 0.21 - - - - -- 0.52* 0.30 - 0.21* 0.18 0.18 0.21* -O'. 2 4 -- 0.48* 0.25* - 0.19 0.25* 0.23* -0 .1 8 -0 .2 0 * a2 58.8 52.5 47.1 S ig n ifle a n t a ss o c ia tio n s w ith g ro ss serum A roclor 1260 k \ 24 Tabla 6 BIOCHEMICAL AND HEMATOLOGICAL VALUES REPORTED AS OUTSIDE AGE- AND SEX-ADJUSTED LABORATORY STANDARDS- Clinleal Variation Unita Trlglycnrldnn Total ebolootirol saPT SCOT GCTP Aik. Phoophntnan LOB Blood glucoao Uric K i d Total bilirubin Olrect bilirubin Total protola Albumin Globulin A/G ratio BUN Craatlaina B/C ratio tin X Cl Cn P BBC Bnaoglobln Henatocrlt mcv MCB HCBC V9C Dlfforoatlal Piffle Lymphocytaa Koooeptao Coaloophili Buaophlla Urinalyola Albumin Aeatsaa 3a 10 IT 1 11 1 a 10 to 0 0 0 0 0 is 4 1 a 0 14 11 0 a 0 a 4 4 IO 0 4 3 13 14 11 0 l 0 High Pannina a a i 0 6 1 a 8 a 0 a 0 a 0 3 0 0 s 2 4 0 0 3 0 1 2 3 3 0 2 2 a l 3 0 0 0 Total 44 12 IB 1 ia a 4 18 ia 0 0 0 0 0 ai 4 1 11 a ia li 0 4 0 3 a 7 13 0 a 8 21 18 14 0 1 0 Unita 0 a 0 0 1 a 0 0 a 0 0 1 a a 0 2 0 1 1 1 3 0 3 a 3 a 0 1 1 11 18 8 0 0 a a 0 Low Pannino 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 2 1 0 0 1 0 o 0 3 0 0 0 o 2 8 a 2 0 0 0 0 0 Tonni 0 2 a 0 1 2 0 a 2 0 0 2 0 0 0 4 1 1 1 2 2 0 3 11 3 a 0 1 3 ia 21 7 0 0 0 0 0 Smith Kline Lnborntoriee, Znc . King of Fniaau, Hot*: All blood ebtalatrlai datarsiaad oa onrum; u u r m t i oa EOTA venoua blood. A b k rtflK lM ; PA. hautolegy SOOT - MPT - OCTP - LOB - A/G ratio BUM B/C ratio - Mu Cl Cn - rum glutnmlc'osulncatlc K - tranoamlanaa P- arum glutami c-pyr u n e SBC - t n maun lanan BOB - arum gamma glutamyl HCT - traaapoptidnao UCY - rum lactic dabydrogonnaa nlbumla/globulln ratio UCH - blood urna altrogna blood urna nltrogaa/ KCHC - creatinine ratio rum nodiurn sac - rum chlorldo PUB - rum calcium rum potanolum aorta phoaphata rad call count hemoglobin hematocrit moan corpuncular rad call t o luma moan corpuacular rad caLl hemoglobin mean corpuacular rad call haaeglobin coneantration ahita blood call count po1ymorphonuc1ear bit# cill count 25 r Table 7 STATISTICALLY SIGNIFICANT PARTIAL CORRELATIONS OF BIOCHEMICAL AND HEMATOLOGICAL MEASURES (DEPENDENT VARIABLES) WITH VARIOUS MEASURES OF EXPOSU DERIVED FROM SERUM PCB LEVELS, IN PRESENCE OF CONFOUNDERS The R e la tio n o f th e P ercen tage o f B a so p h ils and th e Serum L i p i d PCBs ( A r o c lo r 1242) Was Removed When th e W o rk in g /S e p a ra te d C a te g o r y Was D e la te d a s an In d e p e n d e n t V a r ia b le (Shown by P a r e n t h e s e s ) ; P a r t i a l R ( 0 .9 5 ) = 0 . 1 6 5 Dependent Variatola Gfl n PCS SL PCS Aga Arcelor 1343 Lag Trlglycarlda* 140 0.31 Gholaatarol 140 0.30 - Baaophila (X ) 140 - C-0.10) Aroclor 13S0 - Log Triglyceridaa diolaaral Log BUN Log S/C Bntlo 140 0.36 140 0.37 140 0.31 140 0.30 * 0.30 - 0.34 0.30 0.31 Iadapandant Variable SX S/H PL JS DS Fat SC Ale Had SPG 0.10 - 0.33 0.37 - c-o.io) -0.30 0.3 - - O 33 O 29 -- -0.17 - - 0 31 - -- - - O 30 O 28 Abbreviation; S/H PL ~ JS OS - a la r iad o r h o u rly o rb a r p la a h l o c a t i o n mm a t 1970 w o rkin g o r aaparatad abaanca o r praaaaca a t la t a r c u rra n t diaaaaa C - aaokara or nonanokara A le - alcohol eoaauapeioa cada Had - uaa of a l d function oxldaaa drag SPO .- pacific gravity of urla# -- r- Table 8 SIGNIFICANT PARTIAL CORRELATIONS OF SYSTOLIC IRE AND DIASTOLIC BLOOD PRESSURE AMONG 19 INDEPENDENT VARIABLES S y sto lic blood pressure D ia sto lic blood pressure Fat 0.28 0 .3 1 Age 0.22 - o 1o0 HMed Med 0.17 0.17 S e x ' HHY *0 .1 9 0.19 SC -0 .1 7 A bbreviation : HMed - d i u r e t i c . b e t a - b l o c k e r a HHY r e p o r t e d h i s t o r y Med - MFO in d jic e r a of hypertension, (diazepam ) SC sm oking code t - *t DISTRIBUTION LIST CORPORATE RESEARCH AND DEVELOPMENT Schenectady, NY 12301 J Bergeron JF Brown, Jr ID Careioli RS Clark H Fnkbeiner CL Fisher S Hamilton AS Hay RW Lawton (2) MR MacLaury J Magee, Jr WH Smith TIC Distribution Whitney Information Services (MF) CAPACITOR PRODUCTS DEPARTMENT Hudson Falls, John Street, NY 12839 J Feingold MR Ross 86CRD028 N X J; R.W. Lawton, MD FOLLOW-UP STUDY Report No. 86CRD028 M.R. Ross, RN, COHN OF CAPACITOR WORKERS EXPOSED TO April 1986 J. Feingold, MD POLYCHLORINATED BIPHENYLS (PCBs) u C9 CD I