PCBsL UiV

Critical Reviews in Toxicology. 24<2):87-149 ( 1994)

Polychlorinated Biphenyls (PCBs):Environmental Impact, Biochemical andToxic Responses, and Implications for RiskAssessmentStephen H. SafeDepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station,TX 77843-4466

ABSTRACT: Commercial polychlonnated biphenyls (PCBs) and environmental extracts contain complex mix-tures of congeners that can be unequivocally identified and quantitated. Some PCB mixtures elicit a spectrum ofbiochemical and toxic responses in humans and laboratory animals and many of these effects resemble thosecaused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons, which actthrough the aryl hydrocarbon (Ah)-receptor signal transduciion pathway. Structure-activity relationships devel-oped for PCB congeners and metabolites have demonstrated that several structural classes of compounds exhibitdiverse biochemical and toxic responses. Structure-toxicity studies suggest that the coplanar PCBs, namely,3,3',4,4'-tetrachlorobiphenyl (tetraCB), 3,3',4,4',5-pentaCB, 3,3',4,4',5,5'-hexaCB, and their monoortho analogsare Ah-receptor agonists and contribute significantly to the toxicity of the PCB mixtures. Previous studies withTCDD and structurally related compounds have utilized a toxic equivalency factor (TEF) approach for the hazardand risk assessment of polychlorinated dibenzo-/?-dioxin (PCDD) and polychlonnated dibenzofuran (PCDF)congeners in which the TCDD or toxic

TEQ = ZttPCDF, x TEF],) + U(PCDD, x TEF,},)

equivalent (TEQ) of a mixture is related to the TEFs and concentrations of the individual (i) congeners as indicatedin the equation (note: n = the number of congeners). Based on the results of quantitative structure-activity studies,the following TEF values have been estimated by making use of the data available for the coplanar and monoorthocoplanar PCBs: 3.3',4,4'.5-pentaCB, 0.1: 3.3'.4.4',5.5'-hexaCB. 0.05: 3.3'.4.4'-tetraCB. 0.01; 2,3.3',4.4'-pemaCB.0.001; 2.3',4,4',5-pentaCB,0.0001: 2.3,3',4,4',5-hexaCB, 0.0003; 2,3,3',4.4',5'-hexaCB, 0.0003:2',3,4,4'.5-pentaCB.0.00005; and 2,3,4,4',5-pentaCB, 0.0002. Application of the TEF approach for the risk assessment of PCBs mustbe used with considerable caution. Analysis of the results of laboratory animal and wildlife studies suggests thatthe predictive value of TEQs for PCBs may be both species- and response-dependent because both additive andnonadditive (antagonistic) interactions have been observed with PCB mixtures. In the latter case, the TEF approachwould significantly overestimate the toxicity of a PCB mixture. Analysis of the rodent carcinogenicity data forAroclor 1260 using the TEF approach suggests that this response is primarily Ah-receptor-independent. Thus, riskassessment of PCB mixtures that uses cancer as the endpomt cannot solely utilize a TEF approach and requiresmore quantitative information on the individual congeners contributing to the tumor-promoter activity of PCBmixtures.

KEY WORDS: PCBs, toxicology, structure-function, risk assessment, toxic equivalency factors.

1040-8444/94/S.50© 1994 by CRC Press, Inc.

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I. INTRODUCTION

Polychlorinated biphenyls (PCBs) are mem-bers of the halogenated aromatic group of envi-ronmental pollutants that have been identifiedworldwide in diverse environmental matrices.PCBs were produced by the chlorination of bi-phenyl and the resulting products were marketedaccording to their percentage of chlorine content(by weight).44143-:33-457 For example, Aroclors 1221,1232, 1242, 1248. 1254. and 1260 are commer-cial PCBs that were formerly produced by theMonsanto Chemical Company and contain 21,32.42.48,54, and 60% chlorine (by weight). Thelast two digits in the numerical designation for thedifferent Aroclors denotes the percentage of chlo-rine content. Aroclor 1016 is a redistilled versionof Aroclor 1242. with a chlorine composition of41 %. Similar commercial PCB mixtures have beenproduced by other manufacturers and these in-clude the Clophens (Bayer, Germany), Phenoclorsand Pyralenes (Prodelec, France), Fenclors(Caffaro, Italy) and Kanechlors (Kanegafuchi,Japan). Commercial PCBs also were manufac-tured in several other countries, including theformer U.S.S.R. and Czechoslovakia. Commer-cial PCBs exhibit a broad range of physicochemi-cal properties that are dependent, in part, on theirdegree of chlorination, and these properties con-tributed to the diverse applications of PCBs innumerous products. For example, PCBs have beenused as organic diluents, plasticizers, pesticideextenders, adhesives, dust-reducing agents, cut-ting oils, flame retardants, heat transfer fluids,dielectric fluids for transformers and capacitors,hydraulic lubricants, sealants, and in carbonlesscopy paper. Some of the uses of PCBs have re-sulted in their direct introduction into the envi-ronment; however, a significant portion of theenvironmental burden of these compounds hasresulted from careless disposal practices, acci-dents, leakage from various industrial facilities,and from chemical waste disposal sites. The totalamount of PCBs produced worldwide and theproportion that is present in the environment areunknown; however, it has been estimated thatapproximately 1.5 million metric tons have beenproduced worldwide.143

The chemical properties primarily responsiblefor many of the industrial applications of PCBs,

that is. their inflammability, chemical stability,and miscibility with organic compounds (i.e..lipophilicity), also are the same properties thathave contributed to their environmental problems.Once introduced into the environment, the stablePCBs degrade relatively slowly and undergo cy-cling and transport within the various compo-nents of the global ecosystem. Moreover, due totheir lipophilicity, these compounds preferentiallybioaccumulate and biomagnify in higher trophiclevels of the food chain.21'•350-461-462 The commer-cial PCBs and PCBs in environmental extractsare complex mixtures of congeners; moreover,due to various physical and biological (e.g., me-tabolism and biodegradation) processes, the com-position of the commercial and environmentalPCB mixtures may differ significantly. Thus, theimpacts of PCBs on the environment and biotaare due to the individual components of thesemixtures, their additive and/or nonadditive (syn-ergistic or antagonist) interactions with themselvesand other chemical classes of pollutants. There-fore, the development of scientifically based regu-lations for the risk management of PCBs requiresanalytical and lexicological data on the individualPCB congeners present in any PCB mixture andinformation regarding their interactive effects.There are significant challenges associated with acongener-specific approach for the analysis andrisk assessment of PCBs and these studies arecurrently ongoing in several laboratories and regu-latory agencies. This review focuses on some ofthe more recent studies that add to our under-standing of PCBs and also discusses problemsassociated with PCB toxicology and risk assess-ment that are ongoing and have not yet beenresolved.

II. PCBS: ENVIRONMENTAL IMPACT

The development of improved techniques forPCB analysis has played a pivotal role in under-standing the environmental fate and potentialadverse human health and environmental impactsof PCBs. In the mid-1960s, Soren Jensen firstdetected PCBs in environmental samples as aseries of complex peaks observed in a gas chro-matographic screening of environmental samplesfor DOT and related compounds.26 Subsequent

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studies in severai laboratories have identified PCBsin almost every component of the global ecosys-tem including air. water, sediments, fish, wildlife,and human tissues (see References 31. 37,41—+5.77. 171. 202. 220, 236, 261. 263. 264. 308. 374,433, 462. 524, 531-536. 575, 585). Most of theearly analyses utilized low-resolution packed col-umn gas chromatographic separation of the PCBmixtures in which concentrations were determinedby matching specific peak patterns and their inten-sities with the corresponding peaks in commercialPCBs or combinations of different commercialmixtures, whicn were used as standards.577 Thecriteria for the selection of commercial PCB stan-dards were variable: however, in many cases, thechoice was due to the similarities between thechromatographic peak patterns observed for thestandard mixture and the PCBs in the analyte.High-resolution analysis for PCB mixtures wasfirst reported by Sissons and Welti,503 and therehave been continued improvements in both theresolution capabilities of capillary columns anddetection methods.8-9'46-264'371-373-418-459-48"03 How-ever, the unambiguous identification of the 209possible PCB congeners required the synthesis ofall these compounds and their subsequent use asanalytical standards. This synthesis was reportedin 1984,r3 and subsequent studies have identifiedand quantitated all the PCB congeners present inseveral different Aroclor and Clophen mixtures.482

A total of 132 different individual PCBs wereidentified in these mixtures at concentrations>0.05% (w/w), and the congener composition ofeach PCB mixture was dependent on its chlorinecomposition.482 Inspection of the analytical datashows that some congeners occur in only one ofthe PCB mixtures, whereas others are detected inall of the mixtures.

PCBs have been identified as residues fromextracts of diverse environmental samples. In allcases, the PCBs are present as complex mixturesof isomers and congeners and, until recently, mostroutine analytical surveys reported "total PCB"levels using the peak matching technique withcommercial Aroclors as standards.577 The PCBlevels in extracts are dependent on the nature ofthe environmental sample and the location. Inlocalized areas with high levels of PCB contami-nation, there is an increased concentration of PCBsin various environmental extracts. For example.

atmospheric PCB levels in an electroindustrialplant in Belakrajina (Yugoslavia) averaged 2000ug/m3. and the levels over a PCB-containing wastelandfill were 22 to 70 (ig/m3. In contrast. PCBlevels 300 m from the factory and in a nearbyresidential area were 4 to 7 and 2 to 5 Hg/m3,respectively.254 Moreover, as noted earlier. PCBsbioconcentrate in higher trophic levels of the foodchain and this has been aptly demonstrated withinthe North American Great Lakes ecosystem. Forexample. PCBs were biomagnified 12.9-fold fromplankton to fish in a Lake Michigan food web.164

Regulatory agencies and environmental sci-entists have recognized that the composition ofPCBs in most environmental extracts does notresemble the composition of the commercial prod-ucts. Individual PCBs exhibit different physico-chemical properties that influence their rates ofpartitioning, uptake, and retention in environmen-tal matrices, and their rates of breakdown by vari-ous environmental pathways (e.g., photolysis,microbial degradation, and metabolism).82-84'l03-233

The results in Table 1 summarize the congener-specific analysis of Aroclor 1260 and PCBs inhuman breast milk samples collected from moth-ers living in the Great Lakes region and theU.K.1-'1-461 The results demonstrate that the PCBcomposition of the commercial Aroclor differsmarkedly from the distribution of PCB congenersin extracts from the two breast milk samples. Forexample, some compounds, such as 2.4,4',5-tetrachlorobiphenyl. are present in relatively highconcentrations in human milk (3.7 to 11% oftotal PCBs) but are a minor component (0.03%)of Aroclor 1260. Other congeners, such as2,2',3.3',4.5,6'-heptaCB and 2,2',3,4,5,5',6-heptaCB, are major components of Aroclor 1260(5.5 and 4.1% of total PCBs, respectively) but aretrace components of human milk extracts (<0.4%to nondetectable for both compounds). The high-resolution analytical data also show significantdifferences in the composition of the PCBs ob-tained from North American or U.K. human milksamples and this no doubt reflects differences incomposition of the PCBs present in food productsfrom these countries. For example, the combinedlevel of 2.2',5-triCB,2.2',4-triCB, and 4,4'-diCBin the U.K. sample was 13.7%, whereas theselower chlorinated congeners were not detected inthe North American samples. There were some

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TABLE 1Quantitative and Qualitative Analysis of PCBs on Aroclor 1260 and Extracts from HumanMilk Samples'" «1

Congenername*

PCB-015PCB-018PCB-017PCB-024PCB-016PCB-029PCB-026PCB-028PCB-021PCB-033PCB-053PCB-022PCB-045PCB-046PCB-052PCB-043PCB-049PCB-048PCB-044PCB-037PCB-042PCB-041PCB-040PCB-100PCB-074PCB-070 +PCB-095PCB-091PCB-056 +PCB-084PCB-101PCB-099PCB-119PCB-083PCB-097PCB-087PCB-085PCB-136PCB-110PCB-154PCB-082PCB-151PCB-144 +PCB-107PCB-149

%inAroclor 1260

__

0.120.050.010.040.020.020.04d.010.090.040.010.070.020.250.020.060.290.110.040.040.250.030.020.03

076 0.152.70.07

060 0.140.652.50.13

—0.040.450.450.131.41.70.020.112.5

135 1.50.037.4

% of Totalin human

_—

————8.8

—2.2

—0.65

—0.251.9

—0.660.370.782.9

—1.3

——11.00.61

——0.71

—0.974.80.08

——0.82

——1.0

——0.590.510.31

—

PCBsmilk"

9.44.3

—

4.7

3.9

1.8

3.7C

2.24.01.9

1.3d

0.9"

1.8

Congenername*

PCB-118PCS- 134PCB-114PCB-131PCB-122PC B- 146PCB-153PCB-141PCB-176PCB-137PCB-130PCB-138PCB-158PCB-129PCB-178PCB-175PCS- 187PCB-183PCB-128PCB-167PCB-185PCB-174PCB-177PCB-171 +PCB-156PCB-173PCB-200PCB-157PCB-172PCB-180PCB-193PCB-191PCB-199PCB-170PCB-201PCB-203PCB-196PCB-189PCB-195PCB-207PCB-194PCB-205PCB-206PCB-209

%inAroclor 1260

0.490.35

—0.070.121.39.62.50.330.22

—6.50.700.201.20.494.52.30.470.164.15.51.9

202 1.20.450.060.78

—0.789.10.470.100.336.82.93.12.50.153.10.0801.70.110.850.06

% of Totalin human

6.5—

—•0.531.9

12.00.29

—0.870.59

10.00.55

———1.51.40.330.850.110.390.610.374.87

——0.470.315.30.190.90

—5.30.850.790.182.40.31

—0.480.060.240.9

PCBsmilk"

4.2

0.33

12.7

10.1

6.31.20.8

2.5'

11.1

3.51.8

0.7"

Congener names adapted from Ballschmiter and Zell.46

Human milk sample collected and extracted by Michigan Department of Public Health under CooperativeAgreement CR807192 with the Large Lakes Research Station, U.S. Environmental Protection Agency.61/74 combined.77/110 combined.82/151 combined.156/202 combined.194/205 combined.

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congeners, such as 2.2'.3.4.4'.5'-hexaCB and2.2'.4.4'.5.5'-hexaCB, that constituted > 10% ofthe total PCBs in both milk samples and also aremajor components of Aroclor 1260 (6.5 and 9.6%.respectively). Several high-resolution congener-specific analyses of numerous fish and wildlifesamples from different parts of the world alsohave revealed both similarities and differences inthe relative concentrations of the PCB congeners.However, in most extracts from biota, the pre-dominant compounds are 2,2',3.4,4'.5'-hexaCB.2.2',4,4'.5,5'-hexaCB. and 2,2',3,4.4',5.5'-heptaCB(Figure

2.2'.3 .4,4'.5-h«xoCB 2.2'.4,4 ,5.5 -hexoCB 2.2',3.4,4 .S.S'-heptoCB<*1M) (1153) <«I80>

FIGURE 1. PCB congeners that persist in humantissues.

Three PCB congeners, 3,3',4,4'-tetraCB,3.3',4,4',5-pentaCB. and 3,3',4,4',5,5'-hexaCB,elicit toxic responses similar to those reported for2.3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) andwere not routinely detected or quantitated in ana-lytic surveys for pCBs.'90-194'421"123-447-453-455-456-4*0-599

However, several recent studies have reportedanalytical methods for the detection and quanti-tation of these congeners and several of theirmonoortho-substituted analogs in commercialPCBs. environmental samples, and in hu-mans 30-149-15l-2l8'226-269-272-:'54'477-51|-531-537-s39.s81 Thepotential adverse impacts of these non-ortho-co-planar PCBs and their monoortho analogs are dis-cussed in more detail in Section V of this review.

The results in Table 2 illustrate the levels of thecoplanar PCBs in human milk or adipose tissuesamples from different locations, including upperNew York State. Ontario. Quebec, and Ja-pan_i49.:i8.::6.:ft9.ro.i54.477.5:3.533.535.537.539.58i There wasconsiderable variability in the range or mean con-centrations of these compounds and this may bedue to several factors, including differences in labo-ratory analytical procedures. Fish and wildlifesamples taken from different locations also exhibitlarge differences in the relative concentrations ofthe coplanar PCBs. These no doubt reflect thevariable environmental distribution of PCBs, whichis dependent on several factors including the mag-nitude of local and regional inputs, differentialrates of environmental breakdown, the importanceof transport processes, and the composition of PCBresidues in the food chain species. Moreover, therealso are difficulties in quantitative analyses of themixtures derived from different environmentalmatrices.

Thus, analysis of environmental samplesclearly demonstrates that their PCB compositionis highly variable and does not resemble the com-position of the commercial PCB mixtures. Cur-rently, environmental standards for PCBs are de-rived from the results of animal studies with com-mercial PCB mixtures (e.g., Aroclor 1260).However, risk assessment of PCBs in food prod-ucts or environmental samples should take intoaccount the potential adverse impacts of the indi-vidual congeners and their concentrations in thesesamples and should not rely solely on the toxicityof a known commercial mixture such as Aroclor1260 or Clophen A60. However, in some cases,the toxicity or carcinogenicity of the commercialmixtures may be appropriate. The toxic equiva-lency factor (TEF) approach, which is now beingused as an interim measure for the risk assess-

TABLE 2Relative Concentrations of Coplanar PCBs in Human Milk and Adipose Tissue Samples

________Congener and concentration (ng/g)_______3,3',4,4'- 3,3',4,4'5- 3,3',4,4',5,5'-

Samples (TTf (126)* (169)* Ref.

Upstate New York (milk) 0.16-0.49 Nondetectable Nondetectable 226Ontario (adipose tissue) Nondetectable 0.124-0.303 0.113-0.198 581Quebec (milk) , 0.008 0.081 0.032 149Japan (adipose tissue) 0.094-0.86 0.12-0.73 0.036-0.20 269

3 IUPAC numbering scheme for PCB congeners.

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ment of PCDDs and pCDFsr-"1-"-"*""15-4" hasbeen discussed as a model for congener-specificrisk assessment of PCBs.3-4'462-562 The TEF modelfor specific structural classes of compounds suchas PCBs presupposes a common mechanism oftoxic action and additivity for the toxic effects ofthe individual congeners in the mixture. Beforethe potential utility and pitfalls of this model forrisk assessment of PCBs can be discussed, thebiochemical and toxic effects of PCBs (mixturesand congeners) in humans, laboratory animals,and other model systems must be understood.

III. PCBs: ADVERSE HUMAN HEALTHEFFECTS

The development and validation of a morescientifically based approach for the risk assess-ment of PCB congeners require information onthe adverse effects of PCB mixtures on exposedhuman populations and laboratory animal mod-els. These data, coupled with the results of studieson the effects of individual PCB congeners inanimal and cell model systems, can be utilized toidentify specific structural classes of PCBs thatmay be etiologic agents in PCB-induced adverseeffects in humans.

There have been three major scenarios inwhich humans have been exposed to PCB mix-tures and these include (1) exposure of workerswho produced PCBs or utilized PCB-containingproducts; (2) accidental exposure of individuals;and (3) environmental exposure of populationsthrough contaminated food, air, and water. Theadverse human health effects of PCBs on sev-eral groups of occupationally exposed workershave been extensively documented and re-

viewed.2'3-83-285-309449450-543-584 PCB exposure in theworkplace can result in exceedingly high bodyburdens of these compounds and this human popu-lation is the most highly exposed group. The re-ported effects of PCBs on occupationally exposedhumans are variable and dependent on the objec-tives and design of each study (Table 3). Some ofthe effects that have been reported include chlor-acne and related dermal lesions; diverse hepaticeffects, including increased serum levels of liverenzymes and lipids, induced hepatic drug-me-tabolizing enzymes, and hepatomegaly; decreasedbirthweight in the offspring of occupationallyexposed mothers; decreased pulmonary function;and eye irritation. Worker exposure to PCBs didnot affect mortality.101'102 Many of the responsesin the exposed workers were reversible and, insome studies, no significant correlations wereobserved between PCB levels (serum or adiposetissue) and a response. For example, Emmett andco-workers160'161-166 examined serum and adiposetissue PCB levels in transformer repair workers.It was shown that PCB levels were highest incurrently exposed workers, lowest in unexposedworkers, and intermediate in post-exposed work-ers. However, there was no significant correlationbetween PCB levels and symptoms of putativePCB-induced toxicosis. These studies also quan-titated the concentrations of several individualPCB congeners in the three different groups andthe relative concentrations of the major congenerswere similar. The adverse health effects of PCBson workers exposed at toxic waste sites or duringaccidents or fires involving PCB-containing equip-ment, such as transformers or capacitors, alsohave been investigated.172-282-396-519-520 Althoughsome neurobehavioral dysfunction may have beenassociated with PCB exposure (firemen),282 there

TABLE 3Effects of PCBs on Occupationally Exposed Workers

Effects

Chloracne and related dermal lesionsDiverse hepatic responses, including hepatomegaly, increased liver andserum enzymes and lipids, induction of drug-metabolizing enzymes

Decreases in pulmonary functionDecreased birth weight in offspring of occupationally exposed mothersEye irritationNo increased mortalityVariable effects on cancer formation

Ref.

170, 213, 347,40117, 125, 160, 170, 213,321,401508, 521

574541, 542213101, 10238, 39, 70, 139, 207, 495, 601

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were no correlations between PCB levels and anysign of PCB-induced effects. Fitzgerald and co-workers1" reported a number of problems re-ported by firemen: however, these were notdirectly linked to PCB exposure.

Several studies have reported or reviewed theincidence of cancer in workers exposed toPCBs.-< -9•""•'<»-'02-i-'».M7.4S2.W.601 In the cohorts con-taining the largest number of workers, the resultsindicated that no overall increases in cancer-re-lated mortality could be correlated with occupa-tional exposure to PCBs. However, in several ofthese studies, there are increased incidences ofspecific cancers, including melanomas,38-39 andthe grouping of liver, gall bladder, and biliarytract cancers,101-102 gastrointestinal tract cancer inmales, and hematologic neoplasms.70 Some of theincreases in cancer incidences at specific siteswere not statistically significant and it also wasevident that the carcinogenic effects observed inthese workers were different for each study. Theseresults suggest that in the highly exposed workerpopulation. PCBs do not cause a consistent in-crease in one or more cancers and, therefore, theircarcinogenicity in humans has not been estab-lished. However, the carcinogenic effects of cer-tain mixtures of PCBs in laboratory animals havebeen amply demonstrated452-495 and for this reasoncontinued monitoring of occupationally exposedworkers is warranted.

Several thousand individuals were poisonedwith PCBs in two separate accidents in Japan andTaiwan when PCB-containing industrial fluid ac-cidentally leaked into rice oil that was subse-quently sold to consumers.312'314438439 The symp-tomology of victims of the Yusho (Japan) andYu-Cheng (Taiwan) accidents has been exten-sively investigated and includes severe and per-sistent chloracne, dark brown pigmentation ofnails, distinctive hair follicles, skin thickening,various ocular problems, numbness in some ex-tremities, and numerous subjective complaints thatmay be associated with neurological problems. Inaddition, offspring of Yu-Cheng mothers weresmaller, exhibited modest learning deficits, anddisplayed some of the same toxic symptoms ob-served in their mothers.438439 The rather severeeffects caused by the PCB-contaminated rice oilindicated that there were differences in the toxicpotency of PCB-contaminated rice oil and "nor-

mal" industrial PCBs. Many of the acute andchronic effects observed in Yusho and Yu-Chengvictims were not observed in the occupationallyexposed population even though serum PCB lev-els in Yusho/Yu-Cheng patients and industrialworkers exposed to PCBs were comparable andin many cases higher in the latter group. Forexample, the PCB serum levels in occupationallyexposed workers can be as high as 2000 ppb forlower-chlorinated congeners, whereas the meanPCB blood levels of Yu-Cheng victims taken ashort time after the accident varied from 39 to101.7 ppb.;29 suggesting that chemical contami-nants other than PCBs played an important role inthe etiology of Yu-Cheng/Yusho poisoning. More-over, the distribution of PCB congeners in Yushopatients was similar to that observed in otherexposed populations.315 Several papers havereported that the highly toxic polychlorinated di-benzofurans (PCDFs) are present as trace (ppm)impurities in many commercial Japanese and NorthAmerican PCB preparations.87-88-120-361-364-368 PCDFsand polychlorinated quaterphenyls were subse-quently identified in the PCB industrial fluid thatcontaminated the rice oil in both the Yusho andYu-Cheng poisonings.120-127-'29-273-361-363 The ratioof PCDFs/PCBs in the Yu-Cheng and Yusho oilswas 2.4 x 10~3 and 9.0 x 10~3, respectively, whereasthe ratio in the commercial PCB, Kanechlor 400,was 3.3 x 10"5. indicating the relatively higherconcentration of the PCDFs in the Yusho oil (note:in Aroclors, this ratio is on the order of 2 x 10~*).Moreover, adipose tissue and serum analysis ofYusho/Yu-Cheng victims, workers, and normalindividuals clearly showed that although their PCBlevels were comparable, the corresponding PCDFconcentrations were consistently higher in theYusho and Yu-Cheng patients.273311 Laboratorystudies using rodents,47311 different fractions ofsimulated "rice oil PCBs" (containing the PCDFfraction), or reconstituted PCB and PCDF mix-tures that resemble the distribution of these com-pounds in Yusho patients have demonstrated thatthe PCDFs were significantly more potent than thePCB fraction. Thus, although PCBs were involvedin the Yusho and Yu-Cheng poisonings, the evi-dence suggests that the major etiologic agents inthese incidents were the PCDF contaminants thatwere present in relatively high concentrations inthe industrial fluid that leaked into the rice oil.

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Based on the relatively mild adverse humanhealth effects of PCBs on occupationally exposedworkers, it is unlikely that adult exposure to rela-tively low environmental levels of PCBs wouldbe associated with any adverse health effects.One recent study167 indicated that PCB and pesti-cide levels were significantly elevated in humanbreast lipids from breast cancer patients. The sig-nificance of this correlation and the relationshipbetween organbchlorine pollutant exposure levelsand human breast cancer has not been establishedand requires further investigation, particularlysince some PCBs exhibit antiestrogenic activity.310

Jacobson and co-workers designed a series ofstudies to examine the developmental effects as-sociated with exposure to environmental contami-nants including PCBs by examining the offspringof mothers who consumed Lake Michigan sportsf,sn_ 169.246-252 ^^ resuits showed that there wasa correlation between cord serum PCB levels andseveral parameters such as decreased birth weightand head circumference and neurodevelopmentaldeficits in infants, which included poorer perfor-mance on the Brazelton Neonatal BehavioralAssessment Scale, on the psychomotor index ofthe Bayley Scales of Infant Development, and onPagan's Visual Recognition Memory Test. Rogan,Gladen, and co-workers also showed a correla-tion between the levels of prenatal PCB exposureof North Carolina infants from the general popu-lation and tests for neurodevelopment deficits,although not the same as those observed byJacobson and co-workers.183184-44(M42 In a follow-up study on the Michigan children at 4 years ofage, the children with the high levels of prenatalexposure to PCBs showed deficits on theMcCarthy Scales involving both verbal and nu-merical memory.230-251 In contrast, in the NorthCarolina children who exhibited neurodevelop-mental deficits as infants, no significant correla-tions were observed between PCB levels andpoorer grades on McCarthy scores at 3, 4, or 5years of age.183 Moreover, in the studies by Roganand co-workers, there was no correlation betweenPCB levels and lower birth weights or head cir-cumference. The reasons for the differences in thetwo studies are unclear and weaken the conten-tion that PCBs are the cause of the developmentalproblems in infants, and it is possible that some

other compounds not determined by chemicalanalysis may have contributed to or been respon-sible for the observed responses.

Rogan. Hsu and co-workers have investigatedthe comparable developmental deficits in infantsexposed to PCDFs/PCBs in the Yu-Cheng poi-soning incident in Taiwan.129438-439-600 Many of thetoxic responses observed in the mothers also wereseen in the infants, and the exposed children ex-hibited some of the same developmental deficitsreported in the low-level PCB-exposed childrenin North Carolina. Although many of the toxicresponses noted in the Yu-Cheng incident wereprobably due to the highly toxic PCDFs, the tox-ins responsible for the developmental deficits areunknown. The prenatal exposure of the Yu-Chenginfants to PCDFs would be significantly higherthan the children in the North Carolina study;however, the magnitude of the neurodevelop-mental deficits in both groups was similar andindicates that the highly toxic PCDFs may not bethe major etiologic agents responsible for thedevelopmental problems. Thus, it has been sug-gested that there may be an association betweenin utero exposure to PCBs and developmentaldeficits observed in infants and young children.However, due to several factors, including theinconsistent results between the various studies,further research is required to determine the iden-tity of the etiologic agents.

IV. PCB MIXTURES: TOXIC ANDBIOCHEMICAL EFFECTS

A. Toxicity of Commercial Mixtures

The toxic and biochemical effects of variouscommercial PCB mixtures have been extensivelyinvestigated in various laboratory animals, fish,and wildlife species. Unfortunately, only limiteddata are available on the toxic effects of otherPCB mixtures that resemble environmental PCBresidues or of fractionated PCB mixtures. One ofthe major problems associated with the toxicity ofcommercial PCBs is related to the relative levelsof PCDFs identified as contaminants in severalcommercial PCB preparations. In most studies,the PCDF content was not determined and its

94

contribution to PCB-induced toxic responses isunknown, but in most cases its effects may berelatively minor.453

Commercial PCBs elicit a broad spectrum oftoxic responses that are dependent on several fac-tors including (1) the chlorine content and purityof the commercial mixture: (2) the animal speciesand strain; (3) the age and sex of the animal; and(4) the route and duration of exposure to thecommercial mixture. The results in Table 4 sum-marize many of the toxic responses observed inlaboratory animals after exposure to commercialPCBs and these effects include acute lethality,hepatomegaly, fatty liver and other indicators ofhepatoxicity, porphyria, body weight loss, dermaltoxicity, thymic atrophy, immunosuppressive ef-fects, reproductive and developmental toxicity,carcinogenesis, other genotoxic responses, modu-lation of diverse endocrine-derived pathways, andneurotoxicity. The development of PCB-inducedtoxicity is dependent on a number of factors, asnoted previously; however, the data suggest thatthe liver is a common target organ, and varioussymptoms of hepatoxicity have been observed instudies with diverse laboratory animal species.Detailed discussions and analyses of PCB-in-duced toxic responses have been previouslyreviewed283-447-452-453-455-456-460-49"99 and are not fur-ther elaborated in this article; however, the effectsof various factors on the toxicities mediated byPCB mixtures are briefly discussed.

1. Species/Strain-Dependent Responses

The dermal toxicity of PCBs has been notedin occupationally exposed workers213-347-401 andalso has been observed in laboratory animals,including some strains of mice, rabbits (ears), andmonkeys.10-422-424 PCB-induced dermal toxicitiesare most pronounced in monkeys, and these ef-fects include alopecia, edema, distinctive hairfollicles, hair loss, hyperkeratosis, and fingernailloss (see Table 4). In contrast, most other labora-tory animals are insensitive to PCB-mediateddermal effects, and this response pattern is remi-niscent of TCDD and related HAHs, which actthrough the aryl hydrocarbon (Ah)-recep-tor. 194.422.423.448

2. Sex-Dependent Effects

Many of the toxic effects caused by PCBs areobserved in both males and females; however.some responses can be sex-specific. After chronicadministration of Aroclor 1260 to male and fe-male Sprague-Dawley rats, the incidences of hepa-tocellular adenocarcinomas and trabecular carci-nomas were 51 and 40% in female rats and 4 and0% in male rats, respectively.394 In contrast, anincreased incidence of gastric intestinal metapla-sia and adenocarcinoma was observed in bothmale and female F344 rats maintained on dietscontaining Aroclor 1254.573 Thus, the carcino-genic effects of commercial PCBs can be bothsex-dependent and -independent, depending onthe animal species used, the target organ site, andpossibly the composition of the PCB mixture.

3. Age-Dependent Effects

Several studies have shown that there was acorrelation between developmental deficits in in-fants and young children and cord serum PCBlevels.169-183-184-246-252-440^42 These data suggestedthat prenatal in utero exposure, and not postnatalexposure through breast milk, was important forthe impaired development in humans. Compa-rable results were obtained in rats that were pre-and postnatally exposed to Clophen A30.326-327

The PCB mixture caused alterations in activeavoidance learning and retention of a visual dis-crimination task in prenatally exposed offspring,whereas postnatal exposure did not cause anydetectable behavioral changes. These data fromthe human and animal studies were complemen-tary and suggest that the fetus may be more sus-ceptible to PCB-induced neurodevelopmentaldeficits than are infants or older animals.

4. Structure-Dependent Toxicities

Commercial PCB mixtures differ with respecttheir chlorine content and their relative distribu-tion of individual congeners. Egg production inWhite Leghorn pullets was decreased in animalsmaintained on a diet containing Aroclor 1232,

95

TABLE 4Toxicity of Commercial PCBs

Response

LDM, 1.14. 1.30 ml/kg (F, M)LD50, 1.05. 1.15 g/kg (F. M)LDso, 4.25 g,kg (M)LDso, 1.3-25 g/kg (M. F/age-dependent)10,0, 0.358-10 g/kg (M. F)LDso, 4.0 g/kg (F)LDso, 11.3g/k/g(F)LDso, 1.57-1.875 g/kg (F, M)LDso, 0-8-1.2 g/kgLDso, 2.0-3.17 g/kgLDso, 1.26-2.0 g/kgLDso, 0.79-1.27 g/kgLDso, 0.79-1.27 g/KgLDso, 1.26-2.0 g/kgLDso, 1.26-3.16 g/kgLDso, 2.5 g/kgLDso, 0.5-4.0 g/kg

Effect on fetal viabilityFetal toxicitySevere reproductive failureReproductive problems

Fetal death and resorptionReduced litter sizeFetal death and reduced litter weightCleft palateFetal resorptionFetal resorptionAbortions in chronically fed animalsReproduction failureReview of reproductive toxicity fromanimal studies

Effects on male fertilityDelayed first vaginal opening and lowertestis weights

Decrease in reproductive efficiencyDecreased reproductive ability andsmaller reproductive organs

Decreased weight of seminal vesiclesResorptions. abortions, and lower birth weightsMultiple testicular abnormalitiesImpaired ovulationDecreased reproductive successDecreased egg hatchability

Repressed sex accessory glands

PCB mixture Species

Lethality

Kanechlor 400 RatKanechlor 300Aroclor 1242 RatAroclor 1254 RatAroclors 1254 and 1260 RatAroclor 1221 RatAroclor 1260Kanechlor 400 MouseAroclor 1254 MouseAroclor 1221 RabbitAroclor 1232Aroclor 1242Aroclor 1248Aroclor 1260Aroclor 1262Aroclor 1268Aroclors 1221. 1242. and 1254 Mink

Reproductive Toxicity

Aroclor 1254Aroclor 1254Aroclor 1242Aroclors, 1016, 1221,1242, and 1254

Aroclor 1254Aroclors 1254 and 1260Aroclor 1254Kanechlor 500Aroclor 1254Clophen A60Aroclor 1254Clophen A50

Aroclor 1254Clophen A50

Aroclor 1254Aroclor 1254

Clophen A60Aroclor 1248Aroclor 1254Clophen A30Aroclor 1254Aroclors 1232, 1242.1248, and 1254

Aroclor 1254 Rat

Ref.

283

105,283199329387

283325387

32, 228

RabbitMonkeyMinkMink

RabbitRatRatMouseRatMouseMonkeyMink

RatGuinea pig

Mourning doveMouse

MouseMonkeyFishMonkeyRing doveHen

565, 5665537632

5653295155764040029281195

464341

307330

40053467370349328

201

96

TABLE 4 (continued)Toxicity of Commercial PCBs

Response PCB mixture Species

Inhibition of Body Weight Gain or Body Weight Loss

Short-term feeding10 days14-21 days14-30 days2-5 weeks6 weeks6 weeks4 weeks38 days

2-3 monthsChronic dietary feeding

2 years21 months1 year20 weeks-40 monthsUp to 245 days20 weeks20 weeks

Acute, subchronic, and chronic studies viavarious routes of exposure

Elevated urinary coproporphyrinsHepatic porphynn fluorescenceIncreased kidney porphyrinsIncreased liver and small intestinal porphyrinsIncreased liver porphynns and increasedALAS synthesis

Increased liver porphynns

Increased mortality to microbial infection

Decrease formation of splenic PFCs inresponse to SRBCs

Altered graft vs. host responseReduction in splenic and thymic gamma globulinReduction in tetanus antitoxin-producing cellsReduction in gamma globulin-producing cellsReduction in antibody production to SRBCs

Aroclor 1254

Clophen A50Aroclor 1248 > 1254 > 1260Aroclor 1242Phenoclor DP6, Clophen A60,and Aroclor 1260

Aroclor 1248

Aroclor 1254Aroclor 1260Kanechlors 300. 400. and 500Aroclor 1254Aroclor 1248Aroclor 1242Kanechlor 400Aroclor 1254Aroclor 1254

Aroclor 1248Aroclor 1242Aroclor 1248

Porphyria

Aroclor 1242Aroclor 1254Aroclor 1242Aroclor 1242Aroctors 1232, 1248,1254, and 1260

Aroclors 1242 and 1016

Immunotoxicity

Aroclors 1042 and 1016

Aroclor 1242

Aroclor 1016Aroclor 1254Clophen A60 and Aroclor 1260Aroclor 1260Aroclor 1254Kanechlor 400Aroclor 1254

Rat

Rabbit

Monkey

RatRatQuail, ratsQuailRat

Rat

Mouse

Mouse

MouseRabbitGuinea pigGuinea pigMonkey

Ref.

5151242961785511107567

14

Rat

Monkey

MinkRat

Monkey

367287238602525822733. 22855, 124,178, 505,515

1110710

106, 107602359358204, 478

191

332, 333,546

332

498525569568553227554

97

TABLE 4 (continued)Toxicity of Commercial PCBs

Response

Modulation of several nonspecific andspecific immune parameters

Reduction in antibody production to SRBCs

Modulation of T-cell functionReduced NK cell activity

Increased liver weight and/or hepatomegaly

Diverse indices of fatty liver

Increased thyroid activityEnlarged thyroid, decreased serum T4>and altered cellular morphology

Enlarged thyroidDecreased serum progesteroneThyroid atrophyDecreased T, synthesisHypothyroidism and decreased serum T

and/or T, levelsIncreased length of estrusElevated serum corticosteroneNo effects on serum hydrocortisone levelsSuppression of serum adrenal cortex hormones

PCB mixture

Aroclor 1254

Aroclors 1232, 1016, 1242.1248. 1254, and 1260

Kanechlor 500Aroclor 1254

Hepatoxicity

Several Aroclors

Phenoctor DP6Aroclor 1254Phenoctor DP6, Clophen A60,and Aroclor 1260

Phenoctor DP6, Clophen A60,and Aroclor 1260

Aroclors 1221, 1242, and 1254Clophen A60, Aroclor 1260Kanechtors 300, 400, and 500Aroclor 1248, 1254

Kanechlors 300, 400, and 500Aroclors 1221, 1242, and 1254Kanechlor 400Clophen A50Clophen A50Aroclors 1242, 1248. 1254,

and 1260

Aroclors 1248Kanechlor 400

Endocrine Effects

Aroctor 1254Aroclor 1254

Aroclor 1254Aroclor 1248Aroclor 1254Aroclors 1254 and 1242Aroclor 1254

Clophen A60Aroclor 1254Aroclor 1254Aroclors 1254, 1242, and 1016

Species

Monkey

Mouse

MouseRat

Rabbit

RatRat

RatMonkeyGuillemotRatRat

MouseMouseMonkeyRat

Ref.

555, 556

140. 335

530165,505

Rat

RatMouseMouse

12, 55.124, 178,199, 225,266, 274,275, 286,287, 413,463, 505

380, 381466538

567

RabbitGuinea pigRatMonkey

MouseMouseMonkeyMinkRatRat

MonkeyRat

305, 525568,56923810, 13, 14,557, 558

237286, 30422728155, 13111, 199,266, 275,286

10, 14288

54133-135

274, 27552257487122,201,355

399466331123

98

TABLE 4 (continued)Toxicity of Commercial PCBs

Response

Low estrogen levelsMultiple steroid and thyroid hormone abnormalitiesEstrogenic activity

PCS mixture Species

Clophen A30 MonkeyAroclor 1254 Ring doveAroclor 1221 and other PCB mixtures Rat

Neurotoxicity

Developmental neurotoxicity (review)Neurobehavioral toxicity (review)Decreased brain calecholaminesIncreased locomotbr activity and retardedlearning activity

Delayed spatial alternation deficitsDecreased brain catecholamine levelsCentral nervous system toxicityIncreased behavioral toxicity due to prenatal exposure

Impaired discrimination reversal learningAltered serotonin levels in the brainImpaired neurobehavioral activity afterperinatal exposure

Increased hyperactivity

Aroclors 1254 and 1260Aroclor 1248

Aroclor 1248Aroclors 1016 and 1260Aroclors 1254Clophen A30Fenclor 42Aroclor 1248Aroclors 1254 and 1260Aroclor 1254

Aroclor 1248

Thymtc atrophy and thymus toxicity

Thymic Atrophy and Thymus Toxicity

Clophen A60 and Aroclor 1260Aroclor 1254Aroclor 1254

Alopecia, edema, distinctive hair follicles,and hair loss

Hyperkeratosis and other lesions on the earHair loss and other skin lesionsLost fingernailsMeibomian cysts, skin hyperkeratosisFingernail toss and exuberant nail beds

Neoplastic nodules, hepatocellular carcinomaNeoplastic nodules, hepatocellular carcinoma,gastric adenocarcinoma, and intestinal metaplasia

Adenofibrosis, neopiastic nodulesNeoplastic nodules

Neoplastic nodules, hepatocellular carcinoma,and/or adenofibrosis

Neoplastic nodules, hepatocellular carcinoma

Dermal Toxicity

Aroclor 1248

Aroclor 1254Aroclor 1254Aroclor 1254Kanechlor 400Aroclor 1254

Carcinogenicity

Aroclor 1260Aroclor 1254

Aroclor 1260Clophen A30Kanechlor 400Clophen A60Kanechlor 400Kanechlor 500

Monkey

Guinea pigYorkshire pigRat

Monkey

RatMonkeyMonkeyMonkeyMonkey

Ref.

370349155. 179

MonkeyRatMonkey

MonkeyMacaqueMouseRatRatMonkeyRatRat

550474483, 48489.90

3244857326. 327406475483402

89,90

569356505

10, 14,52,53

60258553227557, 558

RatRat

RatRat

Rat

Mouse

287, 394367, 386,572428473288473238237

99

1242. 1248. and 1254 (20 ppm), but no effectswere observed for Aroclors 1221 or 1268.328

Moreover, based on other parameters measuredin this study, the most toxic mixtures were Aroclors1242. 1248. and 1254. These data showed thatboth the high and low chlorinated PCB mixturesexhibited the lowest toxicity. Shaeffer and co-workers1"3 used male Wistar rats as a model fordetermining the effects of chronic feeding of 100ppm of Clophens A30 and A60. After 800 days,the incidence of hepatocellular carcinomas in theClophen A60, Clop^hen A30, and control rats was61. 3, and 2%, respectively. The results of thisstudy illustrated the significant differences be-tween the hepatocarcinogenicity of the most po-tent higher chlorinated Clophen A60 (60% Cl byweight) vs. the lower chlorinated Clophen A30(42% Cl by weight) PCB mixture. These data,coupled with other studies on PCB-induced carci-nogenicity, suggest that the higher chlorinatedPCB mixtures such as Aroclor 1260 and ClophenA60 are more carcinogenic than lower chlori-nated mixtures.237-238-287-367394-428473 This also wasobserved for PCB-induced immunotoxicity in micein which the order of potency was Aroclor 1260> 1254 > 1248 > 1242 > 1016 > 1232.140 Incontrast, PCB-induced lethality (Table 4) was notconsistently dependent on the degree of chlorina-tion of the commercial PCB. The toxicities ofcommercial PCBs are due to the individual con-geners in these mixtures, and it is possible thatone or more structural subclasses of PCBs con-tribute to the different toxic responses elicited byPCB mixtures. The identification of these struc-tural subclasses is discussed in Section V of thisreview. However, it is clear that there is no con-sistent structure-dependent effect of the commer-cial PCB mixtures for all induced toxicities andthis suggests that more than one structural sub-class of PCB congeners is responsible for theseresponses. This conclusion is important for devel-oping schemes for congener-specific hazard andrisk assessment of PCBs (see Section VI).

B. Carcinogenicity of CommercialMixtures

Several studies have reported that after a singleor repeated administration of commercial PCBsto laboratory rodents they develop an increased

incidence of liver lesions, including neoplasticnodules and hepatocellular carcinomas. Theseresponses were primarily observed in studies withAroclor 1260 and Clophen A60 in rats.287394473 Inaddition, Aroclor 1254 increased the incidence ofintestinal metaplasia in F344 rats and this mayhave led to glandular adenocarcinoma in thestomachs of these animals. The evidence for themutagenicity and genotoxicity of PCBs has beenextensively reviewed.452495 In most studies. PCBmixtures and congeners are nonmutagenic usingthe Ames test for bacterial mutagenesis. and thereare only limited data supporting the genotoxicaction of these mixtures. A recent study384 showedthat after multiple administrations of high dosesof Aroclor 1254 (500 mg/kg) no PCB-DNA ad-ducts were reported in the liver, lung, or kidneyDNA using the highly sensitive 32P-postlabelingassay for detecting DNA adducts. There havebeen extensive studies on activities of PCBs ascancer promoters using several different experi-mental protocols and both long- and short-termassays that measure the formation of tumors orputative preneoplastic lesions such as nodules orpapillomas. The results in Table 5 summarize theresults of promotion studies with PCB mixtures.In all of these studies, the animals were initiatedwith a carcinogen followed by repeated or con-tinuous (dietary) administration of the promoter(i.e., PCB mixture). The results show that afterinitiation with a variety of carcinogens, PCBspromoted hepatocellular carcinomas and neoplas-tic nodules in the rat, and similar effects wereobserved in mouse skin and lung. In addition,PCB mixtures also promoted the formation ofenzyme-altered foci in rats and chickens initiatedwith different carcinogens. The enzyme-alteredfoci that are typically characterized in short-terminitiation/promotion bioassays for PCBs exhib-ited decreased ATPase or increased y-glutamyltranspeptidase (GOT) activities. The results ob-tained for PCB mixtures are similar to those re-ported for other tumor promoters, includingphenobarbital, TCDD, and other halogenated aro-matic compounds.198-262-420-429-481

Aroclor 1254 also inhibited aflatoxin B1 -me-diated carcinogenesis in rainbow trout, and it washypothesized that this was related to altered me-tabolism and decreased DNA binding by thecarcinogen.490-491 The effects of PCB mixturesand selected congeners also have been investi-

100

TABLESPCB Mixtures as Promoters: Formation of Tumors or Preneoplastic Lesions

Response

ncreased incidence of^eoatoceiluiar carcinoma

'ncreased formation ofneoplastic nodules (liver)

Increased incidence ofskin tumors

increased incidence ofputative hepaticpreneoplastic lesions

increased incidence oflung tumors

PCB mixture

Aroclor 1254Kanechlor 400

Kanechlor 500Kanechlor 500

Kanechlor 500

Aroclor 1254

Aroclor 1254Phenoclor DP6Clophen A30 + A50

Clophen A50Clophen CAroclor 1254

Species

S-D ratsDonryu rats

Wistar ratsdd mice

F344 rats

HRS/J hairlessmice

S-D ratsS-D ratsS-D rats

S-D ratsChickenSwiss mice

Carcinogen

Diethylnitrosamme3'-Methyl-4-dimethyl-ammoazo-benzene

Diethylnitrosamine(i- Hexachlorocyciofiexaneisomers

2-Acetylaminofluorene

/V'-Methyl-/V-nitrosoguanidine

DiethylnitrosamineAflatoxin B1Diethylnitrosamine

Benzo[a]pyreneDiethylnitrosamine/V-Nitrosodiethylamine

Ref.

427289

392. 393237

540

424

419416397. 39814414510822. 23. 60

gated-1::: using the resistant hepatocyte model.510

The PCBs used in these studies included Aroclor1254 and a reconstituted mixture of PCBs, and noinitiating activity was observed for these mixturesat the doses used in this study. The antitumoractivity of Aroclor 1254 in rats inoculated withWalker 256 carcinosarcoma cells also has beenreported.:8° Depending on the timing of the treat-ment with PCBs and the number of tumor cellsused in the study, Aroclor 1254 inhibited tumorgrowth, increased the latency period for tumordevelopment, increased the host survival time,and caused tumor regression (if administered af-ter the tumors were established). It also has beenreported that Aroclor 1254 did not promote car-cinogen-initiated rumors in a two-stage mouse(CD-1) skin tumorigenesis assay.68 In a subse-quent study.69 treatment of CD-1 mice with Aroclor1254 18 h prior to application of 7,12-dimethyl-benzanthracene resulted in decreased papillomaformation (note: TPA was used as a promoter inthis experiment). Thus, although the resultsstrongly support the promoting activity of severalcommercial PCB mixtures, these same mixturesalso inhibited carcinogen-induced tumor or pre-neoplastic cell formation in certain animal mod-els.

Smith and co-workers506 have reported a syn-ergistic interaction between Aroclor 1254 and ironin Ah-responsive C57BL/10ScSn mice in the

development of hepatocellular carcinomas, whereasthe toxic effects were significantly lower in theless Ah-responsive DBA/2 mice. Due to limita-tion in the number of animals and toxicity to theanimals used in this study, the role of iron statusand the Ah-locus requires further investigation.Using this same model system, it was reportedthat Aroclor 1254 (+ iron overload)-induced car-cinomas were not accompanied by H-ras muta-tions, which are frequently observed in hepatomasinduced by other carcinogens.443 The mutations ofprotooncogenes or tumor-suppressor genes andtheir role in PCB-induced carcinogenesis are un-known and should be investigated further.

C. Biochemical Changes Induced byPCB Mixtures

The results in Table 6 summarize the bio-chemical changes observed in laboratory animalsafter exposure to PCB mixtures. The induction ofhepatic cytochrome P450 and diverse P450-de-pendent monooxygenases is a sensitive indicatorof PCB exposure that has been observed in mul-tiple species, including rats (see References 11-13, 15, 16, 18, 28, 74, 104-107, 154. 177, 205,210, 219. 225, 235, 240-245, 267, 318, 334.336, 344, 379-382, 395,414,417, 507, 529,546,551, 587. 597), rat hepatoma cells in cul-

101

TABLE 6PCB Mixture-Induced Biochemical Effects

Responses PCB mixture

Induction of P450-Dependent Enzymes or Isozymes

Induction of O- and N-dealkylase activity

Induced P450 levels ,

Decreased barbituate sleeping timesInduction of diverse hydroxylases

Induction of AHH activity

Increased ALA synthetase

Decreased ALA dehydrataseIncreased epoxide hydrolase

Increased glucuronosyl transferaseInduction of c-Ha-ras, c-raf, c-yes, c-erbA.and c-erbB protooncogene mRNA levels

Increased serum liptds and HMG CoA reductaseIncreased indices of hepatic lipoperoxidation

HypocholesterolemiaIncreased fatty acid desaturationModulation of plasma lipoproteinsInduction of lung pepsinogen isozymesDecreased uroporphyrinogen decarboxylase

Increased aldehyde hydrogenaseInhibition of citrate cleavage enzymeBinding to the cytosolic Ah-receptor

Increased serum cholesterol and lipids

Increased serum SGPT, SGOTDecreased hepatic vitamin A

Aroclors 1248, 1254, and 1260Aroclors 1016, 1221, 1232, 1242, 1248,

1254, and 1260Aroclor 1242Clophen A50Aroclors 1248, 1254, and 1262Aroclor 1254Aroclor 1254Clophen A50

Aroclor 1254Aroclors 1016, 1221, 1232, 1242, 1248,

1254, and 1260Aroclor 1242Clophen A50

Aroclor 1242Aroclors 1016, 1232, 1242, 1248,

1254, and 1260Aroclor 1254

Other Biochemical Responses

Aroclor 1254Aroclor 1242Aroclor 1254Clophen A50Aroclor 1254Clophen A50Clophen A50

Clophen A50

Aroclor 1248Aroclor 1254Aroclor 1254Kanecntor 400Aroclor 1242Aroclor 1254Aroclor 1254Aroclor 1254Aroclor 1254

Others

Clophen A50Aroclors 1248, 1254, and 1262Clophen A50Clophen A50

Species

Rat

Rat

Guinea pigMouseRat

RatMinkQuailRat

Ref.

11154

107414126019,225414116465,466154

107414115359219

334

RatQuailRatRat

RatRat

RatRat

RatRat. pigeonChickHamsterQuailRatRatRatRat

Rat

RatMink

2035920414334414260

258, 259150, 268,416

3758020323435950733429548

551355112, 115

102

ture 1)l J7l-47--5-»8.55: mjce :o.&o.61.78.232.255.336.466 rab_bits.:L488 monkeys.239 ferrets.3'8 quail.1 ".MSJSMMmink," "'5 guinea pig,''6 kestrel.'59 herring gulls,'74

cockerels,2" barn owls/3 1 4 3 2 insects,24 andfish 1.157.158.,75.206.2l2.224.253.353.383.570The pCB-induCCd

microsomal enzymes from different speciesincrease the oxidative metabolism of diverse sub-strates such as benzo[a]pyrene and related poly-nuclear aromatic hydrocarbons (PAHs). aflatoxin,nitrosamines and other carcinogens, and various;V- and 0-alkyl-substituted compounds (dealkyla-tion). Direct hydroxylation and epoxidation ofmany other xenobiotics and drugs also have beenobserved. Inducers of hepatic drug-metabolizingenzyme activities were traditionally divided intotwo main classes typified by phenobarbital (PB)and 3-methylcholanthrene (MC).136'137-509 Pretreat-ment of rats with PB-type inducers enhancesnumerous hepatic drug-metabolizing enzymeactivities, including several cytochrome P-450-dependent monooxygenases (such as dimethyl-aminoantipyrine [DMAP], ethylmorphine andrelated /V-dealkylases, biphenyl-4-hydroxylase,aldrin epoxidase, and several <9-dealkylases in-cluding pentoxyresorufin O-dealkylase). In con-trast, MC and MC-type inducers enhance hepaticmicrosomal benzo[a]pyrene hydroxylase (aryl hy-drocarbon hydroxylase [AHH]), ethoxyresorufinO-deethylase (EROD), and several other cyto-chrome P450-dependent monooxygenases. Thecommercial PCBs, typified by Aroclor 1254, in-duce both MC and PB-inducible monooxygenaseand were initially classified as "mixed-type"inducers.16 Subsequent studies in several labora-tories have demonstrated that the mixed-type in-duction pattern observed for PCB mixtures inrodents was due to the induction of both PB(CYP2A1, CYP2B1, CYP2B2)- and MC(CYP2A1, CYP1A1, CYPlA2)-inducible P450isozymes.86-413-444-*46-543-545 In contrast to rodents,PB does not induce P450 isozymes in fish andonly CYPIA1 is induced by PCB mixtures.518

PCBs also induce P450 isozymes that regulatesteroid metabolism in some species180-186-265 andinhibit various adrenal steroid hydroxylases in theguinea pig.18S~187 There are other reports indicat-ing that commercial PCBs repress the constitutiveexpression of pulmonary P450 isozymes.488-559"561

Borlakoglu and co-workers79-81 also have reportedthe induction of lauric acid hydroxylase activity

by Aroclor 1254 in both rat and pigeon liver,suggesting that PCBs induce CYP4A1.

PCBs induce other enzymes associated withdrug metabolism and these include glutathione S-transferases. epoxide hydrolase, and glucuronosyltransferases. Moreover. Table 6 summarizes ahost of other biochemical responses reportedlyinduced by various commercial PCBs. including5-aminolevulinic acid synthetase (ALAS); c-Ha-ras, c-raf, c-yes, c-erbA, and c-erbB protoonco-gene mRNA levels; various serum lipids andlipoproteins; HMG-CoA reductase. hepaticlipoperoxidation, fatty acid desaturases. lung pep-sinogen isozymes, and aldehyde dehydrogenaseactivities. PCBs also cause a decrease in ALAdehydratase and uroporphyrinogen decarboxylaseactivities and these responses are associated withdevelopment of PCB-induced porphyria.

Thus, commercial PCBs elicit a large numberof toxic and biochemical responses in multiplespecies and target organs. Because these indus-trial compounds are complex mixtures, the in-duced responses must be due to contributions ofindividual PCB congeners and their possible non-additive (synergistic or antagonist) responses.Extensive research on the structure-activity rela-tionship (SARs) among various structural classesof PCBs has been carried out in order to identifythe individual compounds responsible for PCB(mixture)-induced effects. Characterization of theeffects of individual PCB congeners and theirrelative potencies also is important for develop-ment of procedures for the risk and hazard assess-ment of this class of pollutants because the PCBcomposition of environmental residues does notresemble that of the commercial products.

V. PCB CONGENERS AND DERIVEDMETABOLITES: STRUCTURE-FUNCTIONRELATIONSHIPS

A. Characterization of Ah-ReceptorAgonists

1. Coplanar PCBs

Structure-induction studies in several labora-tories demonstrated that three congeners, namely,3,3',4,4'-tetrachlorobiphenyl(tetraCB),3,3/,4,4',5-

103

pentaCB. and 3.3',4,4',5,5'-hexaCB (Figure 2).resembled TCDD or MC as inducers of CYP1A1and CYP1A2 gene expression and several associ-ated enzyme activities in a variety of species (Table7). In addition. 3,4,4',5-tetraCB also exhibitedcomparable activity.471 These compounds are allsubstituted in both para and at least two metapositions, and the removal of any one of thesesubstituents or the addition of one or more ortho-chlorine groups results in a significant loss of"MC-type" activity. The data summarized in Table7 demonstrate that the coplanar PCBs present inrelatively low concentrations in the commercialAroclors must contribute to the induction ofCYP1A1 by these mixtures. 3,3',4,4',5-PentaCBalso suppresses the expression of the constitutivemale-specific rat hepatic CYP2C11,59"93 and thereis evidence that both 3,3',4,4',5-pentaCB and3,3'.4,4'-tetraCB induce CYP4A1-dependent ac-tivities.79-230 However, the induction of w- andw-1 fatty acid hydroxylase activity (i.e., CYP4A1)is not specific for coplanar PCBs because2,2',4,4',5,5'-hexaCB also induced this response.79

Coplanar PCBs also induce epoxide hydrolaseand glutathione transferase activities and theseinduction responses also were observed for otherstructural classes of PCBs. A recent report27 sug-gested that the induction of the glutathione S-transferase P-form (GST-P, 7-7) may be specificfor coplanar PCBs.

Cl

Cl Cl Cl

Cl

3,3' ,4,4'- tetraCB 3,4,4',5-tetraCB

Cl Cl Cl

3,3',4,4',5 - pentaCB 3,3',4,4',5,5'- hexaCB

FIGURE 2. Structures of coplanar PCB congenersand 2,3,7,8-TCDD.

The induction of CYP1AI gene expressionby TCDD, MC, and related compounds has beenextensively investigated196578"580 and the resultsare consistent with the role of the Ah-receptor inmediating this response. The chemical inducerinitially binds to the cytosolic Ah-receptor; theresulting receptor complex undergoes transfor-mation, nuclear translocation, and binding tospecific genomic sequences (dioxin responsiveelements [DREs]) prior to the induction of genetranscription. Thus, the liganded Ah-receptor com-plex acts as a nuclear transcriptional enhancer forthe induction of CYP1A1 gene expression. Thecoplanar PCBs competitively bind with relativelyhigh affinity to the cytosolic Ah-receptor48 andthis interaction is consistent with the subsequentinduction of CYP1A1 gene expression by thesecongeners. Extensive genetic studies and struc-ture-toxicity relationships with TCDD and relatedPCDDs and PCDFs support a role for theAh-receptor in mediating many of the toxic andcarcinogenic responses elicited by these com-pounds. iw.422.423.448js7»-58o Moreover, many of theseresponses, including the wasting syndrome, thy-mic atrophy, neurotoxicity, hepatotoxicity andporphyria, reproductive and developmental toxic-ity, dermal toxicity, immunotoxicity, endocrineeffects, decreased vitamin A levels, antiestro-genicity, altered lipid metabolism, and carcinoge-nicity, also are observed in animals treated withmany of the commercial PCB mixtures (Tables 4through 6). The results summarized in Table 7show that the coplanar PCBs also elicit the samepattern of Ah-receptor-mediated responses in di-verse species, suggesting that this structural classof PCB congeners contributes to the toxicitiesinduced by commercial PCB mixtures. Moreover,the relative potencies of the coplanar PCBs forseveral responses in genetically inbred mice seg-regated with their Ah-responsiveness.435 49M97 Forexample, 3,3',4,4'-tetraCB (100 mg/kg) inhibitedthe splenic plaque-forming cell (PFC) response tosheep red blood cells (SRBCs) and induced he-patic P450 levels in Ah-responsive C57BL/6 mice,whereas at the same dose no effects were ob-served in the less-responsive DBA/2 mice.497 Thedifferential induction activity of coplanar PCBsalso was observed for AHH induction in the ge-netically inbred C57BL/6 and DBA/2 mice.435

104

TABLE 7Biochemical and Toxic Responses Elicited by the Coplanar PCBs, 3,3',4,4 -TetraCB, 3,3',4,4',5-PentaCB, and 3,3',4,4',5,5'-HexaCB

Response

Induction of CYP1A1 and CYP1A2gene espression and associatedmonooxygenase enzyme activities

Suppression of constitutiveCYP2C11 gene expression

Induction of CYP4A1-dependentactivities

Induction of glutathioneS-transferases

Induction of epoxide hydrolaseBinding to the rat cytosolicAh-receptor

Inhibition of uroporphyrinogendecarboxylase activity

Induction of ALAS activityHypothyroidism and decreasedserum thyroid hormone levels

Decreased hepatic or plasmavitamin A levels

Thymic atrophy and toxicityto thymic cells

Kepatotoxicity, includinghepatomegaly, fatty liver

Reproductive and/ordevelopmental toxicity

Neurobehavioral andneurotoxic responses

Dermal toxicityBody weight lossPorphyria (accumulation of octa-and heptacarboxyporphyrins)

Immunosuppressive activitiesTumor promoter activity

Embryolethality (fish)

3,3',4,4'-TetraCB

109. 115. 148, 181,190, 197. 256. 323,365, 388. 389. 407.413, 421. 437, 471,501.518. 548, 597,598

79

648

276, 277, 319. 499,500. 528

277513,564

35, 36, 97, 98, 100,129,378,425,514

25, 323, 388, 389,599

599

114, 115, 512

130, 162, 163,549

352323276, 358, 470, 499.501

132,348, 496, 497117, 118, 337,468,469

571

3,3',4,4',5-PentaCB 3,3',4,4',5,5'-HexaCB

115. 148. 159, 323,376. 403. 404, 407.413. 437. 471. 501.548. 563, 594-597,599

230

27

48

129

25, 323, 599

599

110, 113, 115,346,348

323501

348173

571

110. 115. 148. 188, 190192. 216. 253, 301. 303.323. 342, 360. 407. 413.421, 437, 471. 501. 526.548. 597, 599

592. 593

27, 302

48

276, 277

277277

25, 72, 299, 300, 323,351,599

72, 299, 300, 599

115,345

72, 32372, 193, 276, 470. 499,501

278, 279, 348

Note: Numbers in columns are References.

2. Monoortho Coplanar PCBs

The results of extensive structure-function stud-ies showed that the monoortho coplanar deriva-tives of the 4 coplanar PCBs (Figure 3) constitutea second major structural class of compounds thatexhibit Ah-receptor agonist activities. This groupof PCBs includes several congeners that have beenidentified in commercial PCB mixtures and envi-

ronmental extracts: 2,3,3',4,4'-pentaCB, 2,3',4,4',5-pentaCB, and 2,3,3',4,4',5-hexaCB. The monoorthocoplanar PCBs resemble Aroclor 1254 as inducersof hepatic drug-metabolizing enzyme activities andCYP1A1, CYP1A2, CYP2B1, CYP2B2, andCYP2A1 gene expression. Similar results have beenobtained for some of the analogous brominatedbiphenyls.413-435-436 Thus, the introduction of a singleortho chloro-substituent to the coplanar PCBs did

105

1

CI2,3,3'A4'-

Penta CBs

CI ' CL Ci CI CL Ci .CI

Hexa- &Hepta CBs

2,3,3'.4,4',5- 2,3',4,4',5,5'- 2,3,3' ,

C. <• C.

2,$,Z'AA',S,S'-FIGURE 3. Structures of monoortho coplanar PCBs.

not eliminate the "MC-type" induction pattern, butresulted in a series of compounds exhibiting "mixed-type" activity. The monoortho coplanar PCBs alsocompetitively bound to the rat cytosolic Ah-recep-tor,48 and the major difference between the copla-nar and monoortho coplanar PCBs as Ah-receptorligands and CYP1A1 inducers was their potency(Table 8).

Because monoortho coplanar PCBs competi-tively bind to the Ah-receptor, these compoundsalso should elicit the biochemical and toxicresponses comparable to other Ah-receptor ago-nists. The results in Table 9 summarize the bio-chemical and toxic responses observed for themonoortho coplanar PCBs, including inductionof CYP1A1 and CYP1A2 gene expression, in-duction of epoxide hydrolase, inhibition of bodyweight gain, immunosuppressive effects, thymicatrophy, hepatotoxicity, tumor promoter activity,antiestrogenicity, and reproductive and develop-mental toxicity. All of these responses were ob-served for the coplanar PCBs, TCDD, and relatedtoxic halogenated aromatics and appear to bemediated through the Ah-receptor. Moreover, stud-ies with genetically inbred C57BL/6 and DBA/2mice also support a role for the Ah-receptor in theinduction and immunosuppressive responses elic-

ited by monoortho coplanar PCBs.412-435'496-497

These data suggest that these same responses alsocaused by commercial PCB mixtures (Tables 4through 6) are due, in part, to the individual co-planar and monoortho coplanar PCBs present inthese mixtures. Moreover, because some of themonoortho coplanar PCBs are present in rela-tively high concentrations in commercial mix-tures and environmental extracts, this class ofPCBs may contribute significantly to the TCDD-like activity of PCB mixtures.

3. Other Structural Classes of PCBs

The activity of other structural classes of PCBsas Ah-receptor agonists also was investigated bydetermining their activity as inducers of CYP1 Aland CYPIAI.40^11413 The 13 possible diortho-substituted coplanar PCBs were synthesized andevaluated as inducers in rodents and most of thesecompounds, including 2,3,4,4',5,6-hexaCB,2,2',3,3',4,4'-hexaCB, 2,3',4,4',5',6-hexaCB,2,3,3',4,4',6-hexaCB, 2,2',3,3',4,4',5-heptaCB,2,2',3,4,4',5,5'-heptaCB,2,3,3',4,4',5,6-heptaCB,2,3,3',4,4',5',6-heptaCB, and 2,3,3',4,4',5,5',6-octaCB, induced AHH activity and/or the CYP1 Al

106

TABLE 8PCBs: Summary of Structure-Induction/Binding Relationships456

Cytochrome P450 induction(% of control)' Relative activity

PCB structures

Coplanar RGBs" (3)Mono-ort/7o coplanars (8)Di-o/tno coplanars (12)2.2'.4,4',5,5'-Hexa-chlorobiphenyl ,

2,3.7,8-TCDD

P450C

P450d

4100-18002400-750900-250

No induction

3500

P450b

P450e

No induction4700-26006300-1000

7300

No induction

AHH Induction (%)In vivo"

Inactive

In vitroc

100-10.3-2.4 x 10-5

InactiveInactive

400

Receptorbinding4

100-356-1.5<0.3'<0.3(

2500

Male Long-Evans rats (dose: 500 nmol/kg).Male Wistar rats (dose: 300 nmol/kg).Rat hepatoma H4II-E cells.Determined by the competitive displacement of [3H]TCDD bound to male Wistar rat hepatic cytosol.3.3',4,4'-Tetra-, 3,3',4,4',5-penta-. and 3.3'4',5,5'-hexachlorobiphenyl.Represents nonspecific binding to the Ah-receptor, although this congener binds to other proteins.59

isozyme.409""1-413 The activities of the diorthocoplanar PCBs as CYP1A1 inducers have beenreported in other studiesI8J89522 and the resultsconfirm that, with the possible exception of2,2',4,4',5,5'-hexaCB, the diortho coplanar PCBsexhibit weak Ah-receptor agonist activity.Moreover, limited studies have shown that someof these congeners cause porphyria in rats(2,2',3.4.4'.5'-hexaCB and 2,2',3.3'.4,4'-hexaCB)522 and inhibit the splenic PFC responseto SRBCs in C57BL/6 mice (2,3',4,4'.5',6-hexaCB).141 It also has been reported that copla-nar and monoortho coplanar PCB congeners inwhich one para-substituent has been removed(e.g., 3,3',4.5,5'-pentaCB, 2,3,3'.4,5'-pentaCB, and2,3,3',4,5,5'-hexaCB) exhibited some weak Ah-receptor agonist activity. 141.405.589 Because thepotencies of these compounds and the diorthocoplanar PCBs are weak compared to the copla-nar and monoortho coplanar PCBs, it is unlikelythat they play a major role in the "TCDD-like"activity of the commercial PCBs and environ-mental PCB residues.453

B. "PB-Like" PCBs and Their Role inPCB-lnduced Toxicity

The "mixed-type" monooxygenase inductionactivity exhibited by commercial PCBs indicatesthat some of the observed responses must be due to

congeners that exhibit "PB-like" activity. Themonoortho and diortho coplanar PCBs constitutetwo structural classes of PCBs that exhibit "PB-like" induction activity, and 2,2',4,4',5,5'-hexaCBis a congener that has been utilized as a prototypi-cal "PB-type" inducer.190200-413421 2,2',4,4',5,5'-HexaCB and the structurally related 2,2',4,4'-tetraCB are both substituted in at least two orthoand the two para positions and induce CYP2B1and CYP2B2 in rat liver.413 In addition, many ofthe PB-type PCBs induce CYP3A isozymes, whichare prototypically induced by glucocorticoids suchas dexamethasone.476 Many of the most active "PB-type" inducers contain at least two ortho and twopara chlorine substituents;l46 however, no compre-hensive structure-activity rules have been devel-oped for "PB-type" inducers inasmuch as conge-ners with a variety of chlorine substitution patternsin the ortho-, para-, and mew-position exhibit "PB-type" induction activities. Rodman and co-work-ers436 also have reported that several tri- andtetraortho-substituted PCB congeners, which in-duced benzphetamine /V-demethylase activity andP450 levels in cultured chick embryo hepatocytes,also induce EROD activity and cause the accumu-lation of uroporphyrin. The latter two effects occurat relatively high dose levels and may representexamples of Ah-receptor-independent responsesthat also are elicited by Ah-receptor agonists atmuch lower concentrations.436 The only unambigu-ous structure-induction relationship for PCBs as

107

TABLE 9Biochemical and Toxic Responses Elicited by the Monoortho Coplanar PCBs

Response

Induction of CYP1A1 and CYP1A2gene expression and associatedmonooxygenase activities

Induction of epoxide hydrolase

Inhibition of body weight gain

Immunosuppressive effects

Thymic atrophy

Hepatoxicity including hepatomegaly,fatty liver

Tumor promoter activity

Reproductive and developmental toxicityincluding embryolethality (fish)

Antiestrogenicity in MCF-7human breast cancer cells

Congener

2',3.4,4'.5-pentaCB2,3,4.4',5-pentaCB2,3,3',4,4'-pentaCB

2,3',4.4',5-pentaCB2,3,3',4,4'.5-hexaCB

2,3',4.4'.5.5'-hexaCB2,3,3',4,4',5'-hexaCB2,3,3',4,4',5,5'-heptaCB

2,3,3',4,4'-pentaCB2,3',4,4',5-pentaCB2',3,4,4',5-pentaCB2,3,3',4,4',5-hexaCB2,3,3',4,4',5'-hexaCB

2,3,3',4,4',5-hexaCB

2,3,3',4,4'-pentaCB2,3,3',4,4',5-hexaCB2,3,3',4,4',5'-hexaCB2,3,4,4',5-pentaCB

2,3,3',4,4'-pentaCB

2,3,3',4,4'-pentaCB2,3,4,4',5-pentaCB

2,3',4,4',5-pentaCB2,3,3',4,4'-pentaCB2,3,3',4,4',5-hexaCB2,3,3',4,4',5'-hexaCB

2,3,3',4,4',5-hexaCB,2,3,3',4,4'-pentaCB,2,3,4,4',5-pentaCB

Ref.

323, 407. 413,407, 412. 413,148, 173. 323,

471, 599323, 407, 413,148, 323,407,563

148, 407. 413,323, 407, 413,138, 407,408,

435. 471437, 471407, 413, 435,

435, 471, 504413, 435, 471,

471435, 437, 471413, 435, 471

All eight congeners noted above 413

323, 590323323323323

141,496

25,323,413,43525, 323, 413, 435323, 413323

590, 599

173118

34, 57157175, 110, 113110, 113

310

"PR-type" inducers is that the coplanar 3,3',4,4'-tetraCB, 3,3',4,4',5-pentaCB, and 3,3',4,4',5,5'-hexaCB congeners do not induce the "PB-like"drug-metabolizing enzyme activity.

Inspection of the data for the structurally di-verse PCBs that resemble PB as inducers indi-cates that, with the exception of hepatomegalyand some hepatotoxic effects,72-193-300 these com-pounds do not cause most of the putative Ah-receptor-mediated responses observed in experi-mental animals after exposure to the coplanar and

monoortho coplanar PCBs and the commercialmixtures, although reproductive toxicity of othercongeners has been reported.447 One major excep-tion to this observation is associated with PCB-induced tumor-promoter activity. Several com-pounds, including 2,2',5,5'-tetraCB,468 2,2',4,5'-tetraCB, and 2,2',4,4',5,5'-hexaCB, which inducePB-like activity, also promote the formation ofenzyme-altered preneoplastic focal lesions in ro-dents. '17a 18-317 These results suggest that "PB-type"PCBs and possibly other structural classes of PCBs

108

may be important contributors to the activity ofthe commercial mixtures as tumor promoters andthis is an area of PCB structure-function relation-ships that requires further investigation.

C. PCBs That Induce Neurotoxicity

Several studies have reported that 3.3'.4,4'-tetraCB causes neurotoxic and neurobehavioralchanges in rodents, including a permanent motordisturbance or ''spinning syndrome" and otherchanges in neuromuscular activity130549550 and al-teration in cholinergic muscarinic receptors.162163

Exposure of the non-human primate, Macacanemestrina, to Aroclor 1016 resulted in decreaseddopamine levels in specific regions of the brain,including the caudate, hypothalamus, substantianigra. and putamen.485 Gas chromatographic analy-sis of brain samples identified only three conge-ners, 2,4,4'-tnCB (Figure 4), 2,2',4,4'-tetraCB, and2.2',5,5'-tetraCB, and these congeners also persistin other organs/tissues. Subsequent studies havedemonstrated that these compounds and other ortho-substituted PCBs (but not the coplanar PCB conge-ners) caused a concentration-dependent decreasein dopamine levels in PC-12 pheochromocytomacells.486-489 Thus, these results define a new struc-tural class of PCBs, other than Ah-receptor ago-nists, that elicit neurotoxic responses. It has beenhypothesized that these compounds may play arole in the neurobehavioral deficits in infants asso-ciated with in utero exposure to PCBs; however,this in an area of research requiring further study tovalidate or invalidate this hypothesis.

D. Toxic and Biochemical ResponsesAssociated with PCB Metabolites

The metabolism of PCBs has been exten-sively reviewed451 -480-50--5- and a summary of themajor metabolic pathways is shown in Figure 5.PCBs are metabolized either directly or via areneoxide intermediates into phenolic metabolites,which can be hydroxylated further or conjugatedto form catechols and phenolic conjugates, re-spectively. The highly unstable arene oxides alsoreact to form dihydrodiols, glutathione conju-gates, and covalently bound protein, RNA, andDNA adducts. Because oxidative metabolism ofxenobiotics is a major route for the detoxicationand ultimate elimination of the more hydrophilicmetabolites, initial studies on PCBs focused pri-marily on the toxicity and genotoxicity associ-ated with the formation and subsequent reactionsof arene oxide intermediates. Several reports haveshown that in vivo and in vitro metabolic activa-tion of PCBs resulted in the formation of pro-tein, RNA, and DNA adducts and increased DNArepair in mammalian cells.366-480-492-493'586-588 How-ever, the PCBs that are readily metabolized andform arene oxide intermediates are the lowerchlorinated congeners, or those compounds thatcontain two adjacent unsubstituted carbon at-oms. With the exception of 3,3',4,4'-tetraCB,most of the toxic coplanar and monoortho copla-nar PCB are not readily metabolized. Moreover,treatment of Wistar rats with Aroclor 1254. oneof the more toxic commercial PCBs. did notresult in formation of DNA adducts as deter-mined by 32P-postlabeling.384 Thus, it is unlikely

2,2',4-triCB

OH ,CL i _CI

Cl

3,3',4',5-tetrachloro-4-biphenylol

SOCH3

4,4'-bis(methylsulfonyl)-2,21

I5,5'-tetraCB2,4,6-tetrachloro-

4'-biphenylol

RGURE 4. Examples of PCBs and metabolites that elicit Ah-receptor-independent responses.

109

Cly Clx

Phenols

JP450•

Arene oxideintermediate

protein,

RNA, DNAMacromolecular

adductsepoxide

hydrolaseGlutathioneS-transferases

Dihydrodiolsdehydrogenase.ase/

Glutathione conjugatesmultiple pathways

Catechols

Phenol conjugates

Xiultip

Methyl sulfonyl metabolites

FIGURE 5. Scheme for the metabolism of PCBs.

that metabolic activation plays a major role inPCB-induced toxicity and genotoxicity.

PCBs undergo metabolism to form hydroxymetabolites or their conjugates, which are readilyconjugated and excreted by laboratory animals.The toxicities of several hydroxy-PCB metaboliteshave been evaluated and compared to the effects oftheir parent hydrocarbons.294298516517590599

3,3',4,4'-Tetrachloro-5-biphenylol and 3,3',4',5-tetrachloro-4-biphenylol, the two major rat urinarymetabolites of 3,3',4,4'-tetraCB, were consider-ably less toxic than the parent hydrocarbon anddid not induce Ah-receptor-mediated responses.598

Similar results were observed for the rat urinarymetabolites of 3,3',4,4',5-pentaCB. In a parallelstudy, the chick embryotoxicity of the hydroxy-lated metabolites of 3,3',4,4'-tetraCB were at leasttwo orders of magnitude less toxic than the parenthydrocarbon.294 Thus, it is unlikely that the Ah-receptor-mediated biochemical and toxic responsescaused by the commercial PCB mixtures (Tables4 through 6) and individual congeners are causedby the hydroxylated metabolites.

However, hydroxylated PCBs are not devoidof biological activity. For example, hydroxylatedPCB congeners can act as uncouplers and inhibi-tors of mitochondrial oxidative phosphoryla-tion;153-377'390-391 hydroxylated PCBs competitivelybind to the estrogen receptor and increase mouse

uterine wet weight in vivo;306 hydroxylated PCBsinhibit various P450-dependent enzyme activi-ties;479 and hydroxylated PCBs bind prealbumin,a major serum thyroxine-binding protein.430 It alsohas been reported that hydroxylated PCB metabo-lites are selectively retained in the serum of ratsand this was due to high affinity binding to a thyrox-ine transport protein, transthyretin (TTR).96-100-293

For example, 3,3',4',5-tetrachloro-4-biphenylol(Figure 4), a major metabolite of 3,3',4,4'-tetraCB,exhibited higher TTR binding affinity than thy-roxine, the endogenous hormone. Preliminaryresults indicate that hydroxylated PCBs are presentin serum of wildlife and human samples.293 It hasbeen hypothesized that some PCB-induced toxicresponses may be due to the interaction of hy-droxylated PCBs with TTR and other endogenousreceptors; however, this suggestion requires fur-ther validation.

The metabolism of PCBs also results in theformation of glutathione conjugates, which areexcreted in the bile and undergo microbial C-Slyase cleavage in the intestine. Methylation of theresulting thiols followed by reabsorption andS-oxidation yields methylsulfonyl PCB metabo-lites, which have been identified in human andanimal serum and several organs/tissues (see Refer-ences 41, 63, 65-67, 92-94, 194, 214, 215, 263,357, 426, 448). Using 4,4'-bis(methylsulfonyl)-

110

2.2'.5,5'-tetrachlorobiphenyl (Figure 4) as a model.it has been shown that this metabolite preferen-tially accumulates in the lung and kidney andbinds with high affinity (Kd ~ 10~9 Af) to a consti-tutive protein that resembles uteroglobin.95 339-*40

This compound also binds with high affinity torabbit uteroglobin182 and fatty acid-binding pro-teins in chicken liver and intestinal mucosa.3:o

Methylsulfonyl PCB metabolites and related bind-ing proteins have been identified in humans.215 339

Methylsulfonyl PCB metabolites also inhibit in-duced AHH activity both in vivo and in vi'rro.290"292-338

Thus, hydroxylated and methylsulfonyl PCB me-tabolites are biologically active and bind to en-dogenous proteins; however, the lexicological sig-nificance of these interactions has not been delin-eated.

E. PCB Interactions

Because PCBs in commercial products andenvironmental samples are complex mixtures ofisomers and congeners, their toxic interactionsmay be important determinants in the resultingtoxicity of the mixtures. Several studies have in-vestigated the interactions between individual PCBcongeners and mixtures with other Ah-receptoragonists such as TCDD. and these studies serve asmodels for assessing the environmental interac-tions of PCBs with other halogenated aromatichydrocarbons (HAHs) such as PCDDs and PCDFs.Denomme and co-workers reported that Aroclor1254 and several PCB congeners significantlyincreased hepatic cytosolic Ah-receptor levels inrats.147 For example, 8 days after administrationof Aroclor 1254 or 2,2',4,4',5,5'-hexaCB, therewas an approximately two- or threefold increasein cytosolic Ah-receptor levels, which remainedelevated for the 14-day duration of this study.Comparable results were noted in C57BL/6 mice.50

It was suggested that the 2,2',4,4',5,5'-hexaCB-induced receptor levels may synergistically en-hance the biochemical and toxic responses elic-ited by Ah-receptor agonists such as TCDD orcoplanar PCB congeners. Cotreatment of C57BL/6or DBA/2 mice with different concentrations ofTCDD and 2,2',4,4',5,5'-hexaCB (500 mol/kg)resulted in a marked enhancement of TCDD-induced hepatic microsomal AHH and EROD ac-

tivity at low doses of TCDD (1 nmol/kg) but notat higher doses (100 and 500 nmol/kg).50 Thesynergistic induction response also was noted inDBA/2 mice for several doses of TCDD (10. 25.80, 200. 500, and 5000 nmol/kg); however, theincreased monooxygenase activity was <100% atall doses. 2,2'.4,4'.5.5'-HexaCB did not enhanceTCDD-induced thymic atrophy or body weightloss in mice, and the only'significant interactiveeffect was protection of DBA/2 mice from TCDD-induced body weight loss. The interaction of2,2',4,4',5,5'-hexaCB with 3,3',4,4',5-pentaCB and2,3,3',4,4',5-hexaCB also was investigated in themale Wistar rat.322 The interactive effects betweenthe PCB congeners on toxicity and EROD induc-tion were minimal, and similar results were re-ported for the interaction of 2,2',4,4',5,5'-hexaCBand 1,2,3,7,8-pentachlorodibenzo-p-dioxin.'42

Nonadditive (synergistic) interactions of 2,2',5,5'-and 3,3',4,4'-tetraCB as promoters of hepatic pre-neoplastic lesions in rats also have been reported;468

however, the nature and significance of these in-teractions require further confirmation by dose-response studies.

It also has been reported that individual PCBcongeners and commercial mixtures exhibit Ah-receptor antagonist activity .49-7!-140-141-209 Davis andSafe140 showed that Aroclors 1260, 1254, 1248,1242, 1016, and 1232 caused a dose-dependentinhibition of the splenic PFC response to SRBCsin C57BL/6 mice, and the EDjo values for thisimmunosuppressive effect varied from 104 to 464mg/kg. These data indicate that the commercialPCBs were relatively weak Ah-receptor agonistsfor this response inasmuch as the correspondingED50 value for TCDD was 0.77 u,g/kg. The inter-action of the commercial PCBs with TCDD (1.2Hg/kg) showed that Aroclors 1232, 1252, 1248,1254, and 1260 significantly inhibited TCDD-induced immunotoxicity in C57BL/6 mice (Table10). Table 11 summarizes the results obtained forthe interactions of Aroclor 1254 and TCDD forseveral effects in C57BL/6 mice; it is evident thatthe percentage of maximum antagonism is re-sponse-dependent and ratios of Aroclor 1254 toTCDD, <20,000:1 and >1670:1, are required toobserve partial antagonism. Analytical studies ofextracts from human tissues and environmentalextracts have shown that the ratios of PCBs toPCDDs plus PCDFs is in the range required for

111

TABLE 10Effects of Commercial Aroclors, TCDD, and Commercial Arodors plus TCDD on the PFCResponse to SRBCs in C57BL6 Mice140

Treatment (dose)

Control (corn oil)3

TCDD (1.2ug)Aroclor 1232 (25 mg/kg)Aroclor 1232 (25 mg/kg)

+ TCDD (1.2 jig)Aroclor 1242 (25 mg/kg)Aroclor 1242 (25 mg/kg

+ TCDD (1.2 vig)Aroclor 1248 (25 mg/kg)Aroclor 1248 (25 mg/kg)

+ TCDD (1.2 ug)Aroclor 1254 (25 mg/kg)Aroclor 1254 (25 mg/kg)

+ TCDD (1.2ug)Aroclor 1260 (25 mg/kg)Aroclor 1260 (25 mg/kg)

-i-TCDD(1.2ug)

Plaque-forming cells/spleen (x 105)

1.12 ±0.170.30 ± 0.081.09 ±0.100.34 ±0.10

0.94 + 0.150.49 ± 0.04"

1.04 ±0.010.54±0.14C

1.02 + 0.070.63 ± 0.05"

0.95 + 0.140.71 ± 0.28b

Plaque-forming cells/10s viable cells

912 + 221180 + 35960 + 126244 + 63

725 + 75440 + 96"

741 + 191427±110b

802184459 + 86"

756 + 112459 + 93"

Control group contained nine animals; all other groups contained four animals; the treatments did not affect thespleen cell viability.Significantly different (p <0.01) from animals treated with TCDD alone.Significantly different (p <0.05) from animals treated with TCDD alone.

TABLE 11Aroclor 1254 as a 2,3,7,8-TCDD Antagonist in C57BU6 Mice — Summary19140209

Response

AHH inductionEROD inductionThymic atrophyImmunotoxicityTeratogenicity

% Maximumantagonism

2023

010080

PCB-mediated antagonism of TCDD-induced re-sponses in laboratory animal studies; however,the significance of PCB to PCDD plus PCDFinteractions in wildlife species and humans isunknown.

Individual PCB congeners that inhibit TCDD-induced responses also have been identified.71-141-369

2.2',4,4'.5,5'-HexaCB at high doses (400 to 1000pnol/kg) partially inhibited TCDD-induced ERODactivity, immunotoxicity, and teratogenicity inC57BL/6 mice. For example, the results sum-marized in Table 1271 demonstrate that 2,2',4,4',5,5'-hexaCB completely protected C57BL/6 mice from

Antagonist/agonist window

1,667-10.000/11,667-10,000/1

No antagonism observed1,340-20,160/1

+12,100/1

TCDD-induced inhibition of the PFC response toSRBCs, and comparable protection was observedfor TCDD-induced teratogenicity. The mechanismof these interactions was unclear because no bind-ing was observed between [125I2],4,4'-diiodo-2,2',5,5'-tetrachlorobiphenyl (an analog of2,2',4,4',5,5'-hexaCB) and the cytosolic Ah-recep-tor or any other cytosolic protein. Davis and Safe141

also identified other PCB congeners that inhibitedTCDD-induced immunotoxicity; however, thesecongeners were considerably less active thanAroclor 1254 or 2,2',4,4',5,5'-hexaCB as partialantagonists. The nonadditive (antagonistic) PCB/

112

TABLE 12Effects of TCOD, 2,2 ,4,4',5,5 -HexaCB and TCDD + 2,2',4,4 ,5,5 -HexaCB on the Splenic PFCResponse in C57BL/6J Mice Treated with SRBCs71

Treatment(dose, nmol/kg)

Corn oilTCDD (0.0037)HexaCB (100)HexaCB (400)HexaCB (1000)HexaCB (100)+ TCDD (0.0037)

HexaCB (400) '+ TCDD (0.0037)

HexaCB (1000)+ TCDD (0.0037)

Spleen cellularity(x 107)

12.6 ±3.413.3 ±2.415.1 ±3.717r6± 1.9

13.1 ±2.715.4 ±3.7

12.3 + 2.7

13.8 ± 1.7

PFCs/spleen

1.36 + 0.140.37 + 0.061.46 + 0.171 .56 ± 0.081 .42 ± 0.070.37 + 0.08

1.14 + 0.04

1 .36 + 0.08

PFCs/10* viablespleen cells

1127 + 213284 + 48995 + 88979+ 192

1117 + 277244 ± 60

936 ± 144

995 + 93

%ofControl

10025

879922

83

88

TCDD interactions in mice suggest that in com-plex mixtures of PCBs, PCDDs, and PCDFs, theformer compounds may suppress the activity ofother Ah-receptor agonists in the mixture.

The nonadditive interactions of other complexmixtures of PCBs have not been extensively inves-tigated. Reconstituted PCB mixtures of individualPCB congeners that have been identified in humanmilk samples have been investigated and thesemixtures exhibit many of the same partial Ah-receptor agonist and antagonist activities reportedfor the PCB mixtures.140208 The potential interac-tions within these mixtures using a TEF approachare discussed in Section VI of this review.

The toxicity of Clophen A50, Aroclor 1254,and fractions of the commercial PCBs containingnonortho-. monoortho-, di-tetraortho-substitutedPCBs and tricyclic impurities (e.g., PCDFs) wasinvestigated in mink.281 The commercial prod-ucts, monoortho and nonortho PCB fractions,caused reproductive impairment; the resultsshowed that both fractions exhibited comparabletoxic potencies and indicated that the monoorthoPCBs, which are less toxic than the coplanar PCBs,are important contributors to the toxicity of themixture due to their relatively high concentra-tions. The authors also report that in cotreatmentstudies the diortho- to tetraortho-substituted PCBfraction enhanced the reproductive toxicity of boththe nonortho- and monoortho-substituted PCBfractions. The effects of commercial PCBs andthe different fractions on several other responsesin mink also were investigated and these included

effects on blood parameters,156 steroid hormoneexcretion,343 P450 induction,"' vitamin A levels,-3

liver histology,64 and morphology of the reproduc-tive organs.56 The relative potencies of the indi-vidual fractions and the commercial mixtures werehighly variable and response-specific. For example,elevation of serum enzymes indicative of liverdamage appeared to be associated with the nonorthoPCB fraction, but this activity was enhanced bycotreatment with the di- to tetraortho PCB fraction.Decreased vitamin A levels were due primarily tothe nonortho and monoortho PCB fractions.223

These data are at variance with the reported an-tagonism of TCDD-induced responses by Aroclorsand 2,2',4,4',5,5'-hexaCB in mice; therefore, theinteractive effects of nonortho- and monoortho-substituted with di- to tetraortho-substituted PCBfractions should be investigated further in otherlaboratory animals to determine the species andresponse specificity of these interactions.

VI. DEVELOPMENT AND VALIDATIONOF THE TOXIC EQUIVALENCY FACTOR(TEF) APPROACH FOR THE RISKASSESSMENT OF PCBs

A. Background — Derivation of TEFs forPCDDs and PCDFs

PCDDs and PCDFs are routinely detected ascomplex mixtures of isomers and congeners inalmost every component of the global ecosys-

113

tern. \M.2t> 1.454.455.5 39 These compounds are not in-tentionally produced but are formed as byproductsof numerous industrial processes including thesynthesis of diverse chlorinated aromatics. par-ticularly the chlorinated phenols and their derivedproducts, production and smelting of metallic ores,pulp and paper production, and combustion ofmunicipal and industrial wastes.454 Despite thecomplex composition of many PCDD/PCDF-con-taining wastes, the congeners that persist in theenvironment and bioconcentrate in the food chainare the lateral 2,3,7,8-substituted congeners:TCDD (or 2.3,'7,8-tetraCDD), 1,2,3,7,8-pentaCDD, 1,2.3.6,7,8-hexaCDD, 1,2,3,7,8,9-hexaCDD, 1,2,3,4,7,8-hexaCDD, 1.2,3,4,6,7,8-heptaCDD, octaCDD, 2,3,7,8-tetrachlorodibenzo-furan (tetraCDF), 1.2,3,7,8-pentaCDF, 2,3,4,7,8-pentaCDF, 1.2,3,4,7,8-hexaCDF, 1,2,3,6,7,8-hexaCDF. 1,2,3,7,8,9-hexaCDF, 2,3,4,6,7,8-hexaCDF, 1,2,3,4,6,7,8-heptaCDF, 1,2,3,4,7,8,9-heptaCDF, and octaCDF. The relative and abso-lute concentrations of these congeners in pollutionsources and environmental matrices are highlyvariable. For example, octaCDD is the dominantcongener that persists in all human serum andadipose tissue samples, whereas this compound isa minor component in PCDD/PCDF extracts fromfish.454

Risk assessment of PCDDs/PCDFs initiallyfocused on one congener, TCDD, which is themost toxic member of this class of compounds.However, with the improvement of analyticalmethodologies, it was demonstrated that in manyindustrial and environmental samples TCDD waspresent in relatively low concentrations. More-over, based on structure-toxicity relation-ships, W.«2.«3.448.453.578-580 which wefe developed

for the PCDDs and PCDFs, it was recognized thatin addition to TCDD many of the 2,3,7,8-substi-tuted PCDDs and PCDFs also were highly toxicand were major contributors to the overall toxic -ity of these mixtures.

Based on structure-activity, genetic, and mo-lecular biology studies, it is generally acceptedthat most of the toxic responses elicited by thePCDDs, PCDFs, coplanar and monoortho planarPCBs are mediated through the Ah-receptor. Twoof the hallmarks of receptor-mediated responsesare (1) the stereoselective interaction between the

receptor and the diverse ligands and (2) the rankorder correlation between structure-binding andstructure-toxicity relationships for most of theseligands. Thus, based on these mechanistic consid-erations, a TEF approach has been adopted bymost regulatory agencies for the risk assessmentof PCDDs and'PCDFs.2-55162 3l6385453 All the rel-evant individual congeners have been assigned aTEF value, which is the fractional toxicity of thecongener relative to a standard toxin, i.e., TCDD.Thus, if the ED50 values for the immunosuppres-sive activity of TCDD and 1,2,3,7,8-pentaCDDwere 1.0 and 2.0 ^ig/kg, respectively, then theTEF for the latter compound would be the ratioEDjo (TCDD):ED50( 1,2,3,7,8-pentaCDD) or 0.5.The relative potencies or TEF values have beendetermined for several different Ah-receptor-me-diated responses and, for every congener, the TEFvalues are highly response- and species-depen-dent.453 For example, the TEFs for 2,3,7,8-TCDFobtained from in vivo and in vitro studies variedfrom 0.17 to 0.016 and 0.43 to 0.006, respec-tively. Regulatory agencies have chosen singleTEF values for all the 2,3,7,8-substituted PCDD/PCDF congeners (Table 13) and the selectioncriteria include the relative importance of dataobtained for specific responses (e.g., carcinoge-nicity; reproductive and developmental toxicity)and for chronic studies since these effects and theduration of exposure are important endpoints thatare used for protecting human and environmentalhealth. It should be noted that proposed TEFs areinterim values that should be reviewed and re-vised as new data become available.

There are reports indicating that the single-value TEF approach for PCDDs and PCDFs canbe successfully used to predict the toxicity ofcomplex mixtures of PCDFs and PCDDs/PCDFsin laboratory animals.152-453 Thus, despite the rangeof experimental TEFs, the TEF values used forrisk management can be utilized to predict theAh-receptor-mediated toxicity of PCDF/PCDDmixtures, suggesting that nonadditive interactiveeffects are minimal. The major application of theTEF approach has been the conversion of quanti-tative analytical data for PCDD/PCDF mixturesinto TCDD or toxic equivalents (TEQ), where[PCDFJ and [PCDDJ represent the concentra-tions of the individual congeners, TEF, is their

114

TABLE 13Proposed TEFs for the 2,3,7,8-Substituted PCDDs and PCDFs453

Relative potency ranges

Congener

PCDDs2.3.7,8-TCDD1.2,3,7.8-PentaCDD1.2,3,4,7.8-HexaCDD1,2.3,6.7,8-HexaCDD1.2.3,7.8.9-HexaCDD1,2,3,4.6,7,8-HeptaCDDOCDD

PCDFs2,3,7,8-2.3,4,7,1,2,3,7,1.2.3.4,2,3,4.6,1.2.3.6.1.2.3.7.1,2,3,4,1,2,3.4,OCDF

TCDF8-PentaCDF8-PentaCDF7.8-HexaCDF7,8-HexaCDF7,8-HexaCDF8.9-HexaCDF6,7,8-HeptaCDF7,8,9-HeptaCDF

In vivotoxicities

0.59-0.0530.24-0.0130.16-0.01520.14-0.016

0.0076>0.0013

0.17-0.0160.8-0.120.9-0.018

0.18-0.0380.097-0.017

0.220.20

' Recommended by Safe.4530 Currently used TEFs.385

corresponding TEF and n is the number of conge-ners. Thus, the

TEQ = ZilPCDF, x TEF,l) + I.((PCDD, x TEF,]n)

concentrations of a complex mixture of PCDDsand PCDFs in a sample can be reduced to a singleTEQ value that represents the calculated concen-tration of TCDD equivalents in that sample. TheTEQs for PCDDs/PCDFs have been determinedfor several types of mixtures, including extractsfrom industrial and combustion processes, fishand wildlife samples, various food products, andhuman serum and adipose tissue. For example,based on the analysis of food products and theirconsumption, the daily human dietary intake ofTEQs in Germany was estimated as 41.7 (milkand milk products), 39.0 (meat, meat products,and eggs), 33.9 (fish and fish products), 6.3 (veg-etables and vegetable oils), and 9.4 (miscella-neous food products) pg/person.57 The estimatedtotal daily intake was 130 pg/person and only

In vitrotoxicities

0.64-0.070.13-0.050.5-0.0050.0090.0030.0006

0.43-0.0060.67-0.110.13-0.0030.2-0.0130.1-0.015

0.048-0.037

TEF

1.0'0.50.10.10.10.010.001

0.10.50.1a/0.05b

0.10.10.10.1O.WO.OI"O.I'/O.OI"0.001

15% of this total was due to TCDD alone. Thedaily intake of PCDDs/PCDFs was estimated as 2pg/kg/day (TEQs). This value is within the 1- to10-pg/kg/day range of acceptable daily intakesrecommended by most regulatory agencies, withthe exception of the U.S. Environmental Protec-tion Agency (EPA), which has utilized a value of0.006 pg/kg/day. The significant differences be-tween the U.S. EPA and other regulatory agen-cies are based on their calculation methods andassumptions.415494 For example, the U.S. EPAassumes that TCDD is a complete carcinogen297

and their threshold limit value of 0.006 is derivedfrom the linearized dose model, which assumesno threshold for the response and protects theexposed population from one additional cancerper 106 individuals. In contrast, most other regu-latory agencies use the same carcinogenicitydata,297 but utilize a safety factor approach inwhich it is assumed that TCDD is a promoter andthat there is a threshold for this response. Thedisparity between the U.S. EPA value of 0.006

115

pg/kg and the current intake of 2 pg/kg/day ofTEQs is of concern and is currently being reevalu-ated by the agency.73-168

B. Development of TEFs for Coplanarand Monoortho Coplanar PCBs

The results summarized in Tables 1 through 9demonstrate that the coplanar and monoortho co-planar PCBs are Ah-receptor agonists. Thus, anycalculation of TEQs for industrial, environmental,food, or human samples is incomplete unless theestimated "TCDD-like" activities of other Ah-receptor agonists, such as PCBs. are included.Safe453 has previously reviewed the QSAR studiesfor the coplanar PCBs and an updated summary ofthese data are given in Table 14. In some of thesestudies, the comparison of the toxic and biochemi-cal potencies of the coplanar PCBs with TCDD isnot given. In other reports,85 only the TEFs or acomparison of the maximal effects doses437 wereprovided and not the ED50/EC50 values. The re-sults show that, with few exceptions, 3,3',4,4',5-pentaCB is the most active PCB congener in everyassay system: however, the response-specific TEFvalues are highly variable (Table 15). In short-term (14-day) studies, the TEFs for body weightloss, thymic atrophy, and AHH and EROD induc-tion in the rat varied from 0.093 to 0.015.323 Thesedata were determined from the ratios of the ED50(TCDD)/ED50 (3.3'.4,4',5-pentaCB) for the differ-ent responses. Preliminary data reported by VanBirgelen and co-workers563 calculated TEF valuesby comparing the ratios of the no observed effectlevels (NOELs) and lowest observed effects lev-els (LOELs) for TCDD and 3,3',4,4',5-pentaCBbased on their modulation of thyroid hormonelevels, liver and thymus weights, body weightgain, and induction of EROD activity. In this study,the compounds were administered in the diet for 3months and preliminary results indicate that theTEFs varied from 0.6 to 0.06 and were higher thanobserved in the 14-day study. The inhibition of thesplenic PFC response to SRBCs348 and trinitro-phenyl-lipopolysaccharide (TNP-LPS)217 antigensby 3,3',4,4',5-pentaCB has been determined inC57BL/6 and DBA/2 mice and the TEF values forimmunotoxicity varied between 0.08 and 0.77. In

contrast, the TEF for 3,3'.4.4',5-pentaCB-inducedteratogenicity was approximately 0.07 to 0.04.348

Several studies have reported the induction ef-fects of 3,3'.4.4',5-pentaCB in chick embryos andchick embryo hepatocytes;*5 "591 the TEFs variedfrom 0.1 to 0.017 and this range was lower thanthe corresponding induction-derived TEFs (0.32to 0.40) in rat hepatoma H4II-E cells. Flodstromand co-workers1^3 estimated that the TEF for tu-mor-promoter activity using the rat liver modelwas 0.1. With the exception of the low TEF ob-served for early life stage mortality in rainbowtrout (i.e., 0.003), the TEFs for 3,3',4,4',5-pentaCBvaried between 0.77 to 0.015, and the mean valuefor the TEFs summarized in Table 15 was 0.19 ±0.22. However, based on the tumor promotion-and teratogenicity-derived TEFs, the value of 0.1proposed by Safe453 represents a reasonable TEFfor 3,3',4,4',5-pentaCB.

The biochemical and toxic potencies and thederived TEF values for 3,3',4,4'-tetraCB and3,3',4,4',5,5'-hexaCB are summarized in Tables14 and 15, and the range of experimentally de-rived TEF values varied from 7.0 x lO'6 to 0.13and 5.9 x 10^ to 1.1, respectively. These varia-tions were not totally unexpected for 3,3',4,4'-tetraCB because this congener is rapidly metabo-lized in rats and many of the lowest TEFs wereobserved in this species.323 The results of a 4-week feeding study in female B6C3F1 mice usinga single dose of 3,3',4,4'-tetraCB also indicatedthat the induction-derived TEF was <0.00001.148

In contrast, the TEF values for inhibition of thesplenic PFC response to SRBCs in C57BL/6mice348 were considerably higher (0.13 to 0.03)than TEFs derived from 14-day studies in the rat.Sargent and co-workers469 also compared the tu-mor-promoting potencies of 3,3',4,4'-tetraCB andTCDD in the rat liver model and the TEF for thisresponse was 0.029. The mean of the 14 TEFs inTable 15 is 0.029, and the value for tumor promo-tion is 0.018 ± 0.034. Several of the 3,3',4,4'-tetraCB-induced responses summarized in Table14 were not used in these calculations due to thelack of data for TCDD. However, TEFs can beestimated for both 3,3',4,4'-tetraCB and3,3',4,4',5,5'-hexaCB by calculating the ED50(3,3',4,4',5-pentaCB)/ED50(3,3',4,4'-tetraCB) ra-tios and multiplying this ratio by 0.1 (i.e., the TEF

116

TABLE 14Comparative Toxic and Biochemical Potencies of 3,3 ,4,4'-TetraCB, 3,3 ,4,4 ,5-PentaCB, and 3,3 ,4,4 ,5,5 -HexaCB

Response

Body weight loss3

Thymic atrophy8

Hepatic EROD induction8

Hepatic AHH induction8

Cytosolic Ah-receptor binding"Immunotoxicity8

LDM8

Hepatic EROD induction8

Hepatic EROD induction"

Hepatic AHH induction"

AHH induction"EROD induction"Inhibition of lymphoiddevelopment8

Early life stage mortalityLDM values

Inhibition of bursal lymphoiddevelopment

Inhibition of lymphoiddevelopment in mouse-thymi

Teratogenicity

or ECSO valuesSpecies

Rat (W)Rat (W)Rat (W)Rat (W)Rat (W)

Mouse (C57BL76)Mouse (C57BL76)Mouse (C57BL/6)Mouse (C57BL76)Mouse (DBA/2)Mouse (DBA/2)Chick embryoChick embryoChick embryohepatocytes

Chick embryohepatocytes

H4II-E cellsH4II-E cellsChick embryo

Rainbow trout (ER)

Chick embryo

Fetal mouse(C57BL/6)

3,3',4,4 -TetraCB

>1.46 x 105

>1.46 x 10s

>1.46 x 105

-1.46 x 105

12.6 x 10"

5.728.2————8.461.750.67

0.35

10.225.814.6

1348 x 103

50

58.4-87.6

3,3 ,4,4 ,5-PentaCB

1.08x 103

3.10 x 102

39.23593.9 x 10"

1.71.08.0

1269723.070.0970.39

0.41

0.0780.0811.31

74 x 103

4

0.65

261-522

3,3 ,4,4',5,5 -HexaCB*,

5.41 x 103

3.21 x 103

236181

Insoluble

0.72.7

15206971

17314.4—

—

21.88.70

108.3

—

300

72.1-108

TCDD

16.129.00.971.29

3.2 x 10J

0.770.771.41.5

11.29.7

0.025

0.007

00310.026

240

0.064

<20

Ref.

32332332332348

348348217217217217110,110,591

591

471471110,

571

25

25

209,

113113

113

348

In micrograms per kilogram.In micrograms per liter.

TABLE 15Response-Specific TEF Values

Response

Rat: 14-day studyBody weight loss, thymic atrophy,ana AHH and EROD induction

Rat: 3-month studySeveral responses in which LOELsand NOELs were compared

Mouse: immunotoxicity and teratogenicityInhibition of the SRBC-inducedresponse '

Inhibition of the TNP-LPS-inducedresponse

TeratogenicityInhibition of thymus lymphoiddevelopment

Chick embryosAHH inductionEROD induction

Rat hepatoma H4II-E cellsAHH inductionEROD induction

Rainbow troutEarly life-stage mortality

Tumor-promoting activity

for 3,3 ,4,4 ,5-PentaCB, 3,3 ,4,4 -TetraCB, and 3,3 ,4,4,5,5 -HexaCB

3,3,4,4,5-PentaCB 3,3',4,4'-TetraCB 3,3',4,4',5,5'-HexaCB Ref.

0.015. 0.093.0.07. 0.025

0.06-0.6

0.45, 0.77

0.09. 0.08, 0.16,0.14

0.07-0.04 (est.)0.098

0.0170.06, 0.1

0.400.32

0.003

0.1 (est.)

1 x 10-1. 2 < 10-". 3 x 10-3. 9 x 10-3.9 x 1Q-6. 7 x 10-6 7 x 1Q-3. 4 x 1Q-3

Not available Not available

323

563

217. 3480.13,0.03 1.1.0.29

Not available 0.09, 0.05, 0.16, 0.14

Not available Not available1.1 x 10-3-7.3 x 10-4 8.9 x 10-*-5.9 x 10-*

0.020.037, 0.02

3.0 x 10-31.0 x 10-3

1.8 x 10-1

Not available

<0.10 x 10-3

1.4 x 10-33.0 x 10-3

Not available

Not available

85, 110. 113, 591

471

571

173

for 3,3'.4,4',5-pentaCB). This calculation givesthe following estimated TEFs for 3,3',4,4'-tetraCB:0.036 (LD50 — chick embryos); 0.0055 (ERODinduction — chick embryos); 0.009 (inhibition oflymphoid development — chick embryos); 0.008(inhibition of bursal lymphoid development —chick embryos). The mean of these four TEFswas 0.014; the combined mean for all the dataderived from dose-response studies was 0.017 ±0.030. The selection of a single TEF for 3,3',4,4'-tetraCB is problematic due to the unusually widespecies- and response-specific variations in theTEFs, and therefore the 0.01 value proposed bySafe may be useful as an interim TEF.453

A similar approach can be taken for calculat-ing the mean TEF for 3,3',4,4',5,5'-hexaCB basedon the data summarized in Table 14. A TEF of 0.13is a mean of 14 responses and this value decreasesto 0.053 ± 0.089 if the unusually high immunotoxicTEF (1.1) in C57BL/6 mice is deleted from thiscalculation. In addition, estimation of TEFs for

3,3',4,4',5,5'-hexaCB relative to 3,3',4,4',5-pentaCB, as noted above, gave values of 0.0018(LD50 — chick embryos); 0.0067 (EROD induc-tion — chick embryos); 0.0012 (inhibition of lym-phoid development — chick embryos); 0.0013(inhibition of bursal lymphoid development —chick embryos). The mean TEF for these responseswas 0.0012. Thus, the TEFs for 3,3',4,4',5,5'-hexaCB range from 0.00059 to 1.1; Safe453 as-signed a TEF of 0.05, which is lower than theaverage of the responses noted in Tables 14 and 15but higher than the 0.0012 value obtained for theeffects in chick embryos. The induction-derivedTEF from 4-week feeding studies with femaleB6C3F1 mice was <0.05.148 The assignment of afinal TEF value for 3,3',4,4',5,5'-hexaCB must awaitresults of additional studies; however, the proposedTEF of 0.05 may be useful on an interim basis.453

The relative potencies and TEFs for severalmonoortho coplanar PCBs are summarized inTable 16. For risk management of this structural

118

class of PCBs. TEFs should be determined for themajor congeners present in the commercial mixturesand environmental samples, namely, 2,3.3',4,4'-pentaCB, 2.3',4,4'.5-pentaCB. and 2.3,3',4,4',5-hexaCB. Safe453 proposed a TEF of 0.001 for all themonoortho coplanar PCBs; however, this valuemay be too high based on the results summarizedin Table 16. Mean TEFs of 0.00098 ± 0.002.0.000088 ± 0.000096, and 0.00040 ± 0.00043were observed, respectively, for 2,3,3',4,4'-pentaCB (10 responses), 2,3',4,4',5-pentaCB (11responses), and 2,3,3'.4,4',5-hexaCB (14 responses).The induction-derived TEFs for 2,3,3',4,4'-pentaCB, 2,3,3',4,4',5-hexaCB, and 2,3,3',4,4',5'-hexaCB administered (as a single dose) 5 days perweek by gavage to female B6C3F1 mice for 4weeks were estimated as <0.00005, <0.0005, and0.001, respectively.148 The results from these long-term studies were within the range of values sum-marized in Table 17; the induction-derived TEFfor 2,3,3',4,4',5-hexaCB was similar to the 0.0004mean value, whereas the induction-derived TEFsfor 2.3,3'.4.4'-pentaCB and 2,3,3',4,4',5-hexaCBwere lower and higher, respectively, than the meanTEFs of 0.00098 and 0.00029 (Table 17). Basedon the data summarized in Table 17, the follow-ing respective interim TEFs are proposed for themonoortho coplanar PCBs: 0.001, 0.0001, and0.0004 for the 2,3,3',4.4'-pentaCB, 2,3',4,4',5-pentaCB, and 2,3.3',4.4',5-hexaCB congeners.In addition, the respective mean TEFs for2.3,3'.4,4'.5'-hexaCB, 2'.3,4,4',5-pentaCB, and2.3,4,4'.5-pentaCB are 0.00029, 0.00005, and0.00019; the respective suggested TEFs for thesecompounds are 0.0003, 0.0005, and 0.0002.

C. Application of TEFs Derived for PCBs

TEFs for PCDDs/PCDFs have been used ex-tensively to determine TEQs in industrial, com-mercial, and environmental mixtures of thesecompounds. Tanabe and co-workers269"272-331"537

were the first to develop analytical techniques toquantitate coplanar PCBs in various mixtures,and they initially determined PCB-derived TEQsutilizing TEFs derived from the relative potenciesof PCB congener-induced AHH and EROD ac-tivities in rat hepatoma H4II-E cells.471 Their re-sults showed that the TEQs for PCBs in most

extracts from environmental samples or humantissues exceeded the TEQs calculated for thePCDDs/PCDFs in these same extracts. The re-sults in Table 18 summarize the calculation ofTEQ values in human adipose tissue samples basedon the TEF values and the concentrations of indi-vidual PCDDs. PCDFs. and PCBs present in thissample. The data indicate that the TEQs for thePCB fraction are higher than those for the com-bined PCDDs/PCDFs, and comparable resultshave been observed in other studies.30-149-231-350'539

D. Validation and Limitations of theTEF Approach

The potential interactions of different struc-tural classes of PCB congeners may have impor-tant implications for the risk assessment of PCBs,PCDDs, and PCDFs. Previous studies have dem-onstrated that Aroclor 1254 and other PCB con-geners inhibit TCDD-induced enzyme induction,teratogenicity, and immunotoxicity in C57BL/6mice 49.7i.i4o.i4i.209 and it is conceivable that forPCB mixtures the interactions also would de-crease coplanar PCB-induced toxicity. These po-tential inhibitory interactions between differentstructural classes of PCBs would result in overes-timation of the toxicity of PCB mixtures using theTEF approach. Davis and Safe140 reported theeffects of various Aroclors on the inhibition of thesplenic PFC response to SRBCs in C57BL/6 mice.This effect is one of the most sensitive indicatorsof exposure to Ah-receptor agonists. The concen-trations of coplanar and monoortho coplanar PCBsin these mixtures have been reported and are sum-marized in Table 19. Unfortunately, the immuno-toxicity-derived TEFs are available only for3.3',4.4',5-pentaCB (0.45), 3,3',4,4'-tetraCB (0.13),3,3',4,4',5,5'-hexaCB (1.1), and 2,3,3',4,4',5-hexaCB (0.0011) (see Tables 15 and 16); how-ever. these values can be used to estimate theTEQs for these four congeners in Aroclors 1016,1242, 1254, and 1260 because the coplanar andmonoortho coplanar PCBs in these Aroclors havebeen analyzed.271 •482 The TEQs for these Aroclorscan be calculated from the immunotoxicity-de-rived TEFs and the concentrations of the indi-vidual PCBs in these mixtures (i.e., TEQ = I/PCfi,x TEFJn). The results in Table 20 summarize the

119

TABLE 16Biochemical and Toxic Potencies for the Monoortho Coplanar PCBs and Their DerivedTEF Values

Response

Induction of AHH and ERODactivity in rats

Body weight loss and thymicatrophy in rats

Immunotoxicity in 0578176 mice

Lethality (LD^) in chick embryos

Hepatic EROD induction in chick embryo

Hepatic AHH and EROD induction inchick embryo hepatocytes0

Hepatic AHH and EROD induction in rathepatoma H4II-E cells"

Early life stage mortality LDM values inrainbow trout"

Inhibition of lymphoid development inthe fetal mouse

Teratogenicity in C57BL/6N mice

Tumor-promoting activity in female rats

EDso/EC,,, values (TEF) (mg/kg) Ref.

2,3,4,4'.5-PentaCB, 9.8 (7.3 x 10-*); 19.6 (5.0 x JO-*) 3232.3,3',4,4',5'-HexaCB, 2.16 (6.0 x 10^); 2.53 (3.8 x.2,3.3',4.4',5-HexaCB, 2.53 (5.1 x JO-1); 9.0 (J . r x2,3.3',4,4'-PentaCB, 21.2 (6.1 x JO-5)2.3'.4.4',5-PentaCB, 53.8 (2.4 x JO-5); 83.3 (1.2 x JO-5)2',3,4,4',5-PentaCB, 42.4 (3.0 x 70-5); 71.1 (1.4 x JO-5)

2,3,4,4',5-PentaCB, 58.7 (2.7 x J0~*); 65.3 (4.4 x JCM) 3232,3,3',4.4',5'-HexaCB, 79.4 (2.0 x 10~>)\ 81.2 (3.6 x JCM)2,3,3',4,4',5-HexaCB, 65.0 (2.5 x JO"1); 65.0 (2.5 x JO-4)2,3,3',4,4'-PentaCB, 245 (6.6 x JO"5); 336 (8.6 x JO-5)2,3',4,4',5-PentaCB, 366 (4.4 x JO"5); 506 (5.7 x JO-5)2',3.4,4',5-PentaCB, 121 (J.3x JO-4); 911 (3.2 x JO-5)

2,3,3',4,4',5-HexaCB, 0.72 (J .J x JCh3) 141

2,3,3',4,4'-PentaCB, 2.19 (3.8 x JO-")' 1102,3,3',4,4',5'-HexaCB, 2.49 (3.4 x J0-")a

2,3,3',4,4',5-HexaCB, 1.52 (5.6 x JO^)3

2,3',4,4',5-PentaCB, >4.01 (2.1 x 10~t)t

2,3,3',4,4'-PentaCB, 0.15 (1.2x JO-3)4 1102.3',3,4,4',5-HexaCB, 0.20 (8.8 x2,3,3',4,4',5-HexaCB, 0.14 (1.3 x2,3',4,4',5-PentaCB, 2.19 (8.9 x JO-5)'

2,3,3',4,4'-PentaCB, 0.13 (5.4 x JO-5); 0.030 (8.3 x 1Q-4) 5912,3',4,4',5-PentaCB, 0.030 (2.3 x 10-1); 0.098 (2.6 x 10^)2,3,3',4,4',5-HexaCB, 0.54 (J.3 x JO-5); 0.51 (4.9 x 1Q-S)

2,3,3',4,4'-PentaCB, 0.029 (J.J x JO ); 0.039 (6.7x 10-*) 4712,3',4,4',5-PentaCB, 3.75 (8 x JO-6); 2.89 (8.9 x JO-6)2,3,4,4',5-PentaCB, 0.32 (9.8 x JO"5); 0.184 (1.4 x JO-1)2',3,4,4',5-PentaCB, 1.28 (2.4 x JO-5); 0.362 (7.2 x JO"5)2,3,3',4,4',5-HexaCB, 0.74 (4.1 x JO-5); 0.32 (8.1 x JO"5)2,3,3',4,4',5-HexaCB, 0.46 (6 x JO"5); 0.26 (TO")

2,3,3',4,4'-PentaCB, >6970 (<3.4 x JO-5) 5712,3',4,4',5-PentaCB, >6970 (<3.4 x JO-5)

2,3,3',4,4',5-HexaCB (<9.8 x JO"5) 25

2,3,3',4,4',5-HexaCB, 118.5 (3 x JCM) 75

2,3,3',4,4'-PentaCB (< 1.0 x JO ) 173

a Derived from the ratio EDM (3,3',4,4',5-pentaCB)/ED5o(congener) x 0.1.b In milligrams per liter.

120

Table 17Proposed TEFs for Coplanar and Selected Monoortho Coplanar PCBs

Congener

3.3',4.4'.5-PentaCB3,3',4,4'.5,5'-HexaCB3.3'.4.4'-TetraCB2.3.3',4,4'-PentaCB2,3.3',4,4',5-HexaCB2,3'.4,4'.5-PentaCB2.3.3'.4.4'.5'-HexaCB2',3.4,4',5-PentaCB2,3,4,4',5-PentaCB

3 Number of responses.

Relative potency range(in vivo and In vitro)

0.003-00.0059-1

0.000007-00.000034-0

0.0011-0.0.0000089-0

0.0006-0.0.00013-00.00044-0

.77

.1

.13.0012000013.000260000600001400005

Mean TEF(± SD) (n)'

0.190.0530.017

0.000980.0004

0.0000880.000290.000050.00019

±0.22 (21)± 0.089 (13)± 0.030 (19)±0.002 (10)± 0.00043 (14)±0.000096 (11)±0.00019 (7)± 0.000044 (6)±0.00014 (6)

ProposedTEF

0.10.050.010.0010.00040.00010.00030.000050.0002

TABLE 182,3,7,8-TCDD Equivalents in Human Adipose Tissue Samples from the PCDDs, PCDFs, andCoplanar PCBs"1

2,3,7,8-TCDDTEF Concentration Equivalents

Congener (TEF)" (ppt) (ppt)

2,3,7,8-TCDD1,2,3,7,8-PentaCDD1,2,3,4,7,8-HexaCDD1,2,3,6,7,8-HexaCDD1,2,3,7,8,9-HexaCDD1,2,3,4,6,7,8-HeptaCDDOCDD

Total

2,3.7,8-TCDF1,2.3,7.8-PentaCDF2,3,4,7,8-PentaCDF1,2,3,4,7,8-HexaCDF2,3,4,6,7,8-HexaCDF1,2,3,6,7,8-HexaCDF1,2,3,7,8,9-HexaCDF1,2,3,4,6,7,8-HeptaCDF1,2,3,4,7,8,9-HeptaCDFOCDF

Total

3,3',4,4',5-PentaCB3,3',4,4',5,5'-HexaCB3,3',4,4'-TetraCB

1.00.50.10.10.10.010.001

0.10.050.50.10.10.10.10.010.010.001

0.1 (0.1)0.05 (0.05)0.10 (0.02)

3.76.43.9

345.7

33510

3.10.5

11.05.61.45.3

2.9

33090

350

Total

1 Revised TEFs as summarized in Table 17.

3.73.20.393.40.570.330.5112.01

0.310.256.50.560.140.53

0.029

8.09

33.0 (33.0)4.5 (4.5)3.5 (7.0)

41.0 (44.5)

121

TABLE 19Concentrations of Coplanar and Monoortho Coplanar PCBs in Aroclors 1016,1242,1254,and 1260271"2

Cogenersubstitution

3.3',4,4'.5-3.3'.4,4'.5.5'-3.3',4,4'-2.3'.4,4'.5-2.3,3'.4,4'-2.3'.4.4',5.5'-2,3,3',4,4',5-2,3,3',4,4',5'-2',3,4,4',5-2.3,3',4,4',5,5'-

Concentration1016

_———————

1242

170.05

5.20016,2008,600—900—

1254

460.5

60063,90038,3002,10016,200—

1260

8.30.05

2605,700700

2,6008,8001,400

8,1001,100

calculated TEQs and ED50 values for the immuno-toxicity of the commercial PCBs using TEQsderived from only four of the coplanar and mono-ortho coplanar PCBs. The calculated ED50s aremaximum values inasmuch as the contributionsfrom Ah-receptor agonists other than the com-pounds noted above have not been included in thecalculation. In all cases, the calculated ED;o val-ues are significantly lower than the observed ED50values and the ratios of ED50 (observed)/ED'50(calculated) were 1.1,22.5,364, and «= for Aroclors1260, 1254, 1242, and 1016, respectively. Thesevalues represent the degree of overestimation ofPCB-induced immunotoxicity in C57BL/6 miceif the TEF approach is used. The data suggest thatthere are nonadditive (antagonistic) interactionsbetween the PCB congeners in these mixtures,and this is consistent with the results of compa-rable antagonistic interactions between PCBs andTCDD.140-141

Recent studies in this laboratory have inves-tigated the dose-response induction of hepatic mi-crosomal AHH and EROD activities by Aroclors1232, 1242, 1248, 1254, and 1260 in male Wistarrats and the ED50 values were 137, 84, 51,92, and343 mg/kg (for AHH induction) and 678, 346,251, 137, and 442 mg/kg (for EROD induction),respectively.219 Because the induction-derived TEFvalues for the coplanar and monoortho coplanarPCB congeners in rats have been determined(Tables 15 and 16) and their concentrations inAroclors 1242, 1254, and 1260 also are known(Table 19), then the TEQ values can be readilycalculated (Table 21). The results show that, with

one exception, there was less than a twofold dif-ference between the observed vs. calculated ED50values; these data suggest that the interactive ef-fects were minimal for AHH and EROD induc-tion in the rat by the commercial PCBs. Using asimilar approach, it has been shown that therealso were minimal interactive effects for theinduction of AHH and EROD activity by PCBmixtures in rat hepatoma H4II-E cells.241'472 Forseveral coplanar and monoortho coplanar PCBcongeners, it was reported that there was a linearcorrelation between the in v/rro-logEC^ valuesfor EROD/AHH induction in rat hepatoma H4II-Ecells vs. the in v/V0-logED50 values for AHH/EROD induction, thymic atrophy, and inhibitionof body weight gain in the rat;450-45W58 this sug-gests that there are minimal nonadditive interac-tions of PCBs for Ah-receptor-mediated responses,such as thymic atrophy and body weight loss, inrats. Thus, the TEF approach is useful for estimat-ing "TCDD-like" activity in rats and this con-trasts with the results obtained for immunotoxicityin mice, in which the TEF approach significantlyoverestimates the immunotoxicity of PCB mix-tures. The value of TEFs for risk management isdependent on minimal nonadditive interactionsamong the PCBs, PCDDs, and PCDFs. The re-sults obtained in mice and rats for PCB mixturesillustrate that there are significant species- andpossibly response-specific differences in the non-additive antagonist interactions between PCBs andother Ah-receptor agonists. Analysis of the ratdata supports the TEF approach for several re-sponses (AHH and EROD induction, body weight

122

TABLE 20Application of the TEF Approach for Calculating the Immunotoxicity of Aroclors 1016,1242,1254, and 1260 in C57BL/6 Mice: Comparison of Observed140 vs. Calculated EDM Values

_________ AroclorsParameter

TEQs (ng/g) (calculated) (4 congeners only)3

ED50 (mg/kg) (calculated from the TEQs andutilizing EDM (TCDD) = 0.77 ng/kg)

EDM (mg/kg) (observed)EDso (observed)/E0,0 (calculated)

3 3,3',4,4'-Tetra(5B, 3,3',4,4',5-pentaCB, 3,3',4,4',5.5'-hexaCB, 2,3,3',4,4',5-hexaCB: concentrations of individualcongeners shown in Table 19 and the TEF values were derived from References 141 and 348.

1016

-0-0

464

a

1242

6961.1

400364

1254

146.6

5.25

11822.5

1260

52.614.6

1047.1

TABLE 21Application and Validation of the TEF Approach for Predicting the Induction Activities ofAroclors 1242,1254, and 1260 in Male Wistar Rats219

AroclorsParameter

TEQs (jig/g)AHH induction-derivedEROD induction-derived

EDso (mg/kg) (calculated from TEQs and utilizing ED^ [TCDD])AHH induction (EDM [TCDD] = 1.29 ug/kg)EROD induction (EDX [TCDD] = 0.97 ng/kg)

EDM (mg/kg) observedAHH inductionEROD induction

EDM (observedyEDso (calculated)AHH inductionEROD induction

loss, and thymic atrophy); however, it is possiblethat there may be response-specific differenceswithin the same animal species.

Giesy, Tillitt and co-workers have utilized invitro and in vivo studies to investigate the role of"TCDD-like" PCBs, PCDDs, and PCDFs as pos-sible etiologic agents in wildlife toxicity.547-548-582-583

Tillitt and co-workers547 extracted double-breastedcormorant eggs and determined their TEQ valuesfor PCBs in these extracts using the rat hepatomaH4II-E cells as a bioassay. This assay providesTEQ values for mixtures, and the results showedthat there were minimal (nonadditive) interactiveeffects, as noted above.472 In this study, there wasa linear correlation between the PCB-TEQs in spe-

1242

1.412.24

915433

84346

0.090.80

1254

12.359.95

104102

92137

0.881.34

1260

5.452.43

422251

343442

0.8121.76

cific colonies and their reproductive success. Theseresults suggest that this response may be Ah-re-ceptor mediated and that the 'TCDD-like" PCBcongeners may be responsible for the observedreproductive toxicity. However, in a second study,583

the PCB-TEQs in extracts from Lake Michigancninook salmon were determined by high-resolu-tion chemical analysis and there was no correlationbetween the calculated PCB-TEQs and the mortal-ity of eggs and fry from the different clutches.Most of the calculated TEQs were significantlyhigher than the observed total rearing mortality,and this may be analogous to the immunotoxicityin mice in which the calculated TEQs overesti-mated the toxicity due to nonadditive (antagonis-

123

t i c ) interactions. It also is possible that the rearingmortality response is not Ah-receptor mediatedand is due to other classes of toxic chemicals.

Thus, the TEF approach can be used to calcu-late the TEQs of PCBs, PCDDs. and PCDFs inextracts of environmental samples and in com-mercial mixtures. However, the results of labora-tory animal and wildlife studies suggest that thepredictive value of TEQs for PCBs, PCDDs. andPCDFs may be both species- and response-de-pendent because both additive and nonadditiveiantagonistic) interactions have been observed.Therefore, these data would suggest that TEFs forPCBs and other halogenated aromatics, such asPCDDs and PCDFs, should be used with care innsk assessment of these contaminants.

E. Application of TEFs for CarcinogenicPotencies

The development of regulations for PCBs andmany other environmental toxins often utilizesdata from long-term rodent carcinogenesis bioas-says. Many of the current regulations for PCBsare derived from the carcinogenicity of Aroclor1260,394 which is assumed to be a complete car-cinogen. However, because most studies indicatethat the higher chlorinated PCBs are nongeno-toxic452-495 and do not form persistent DNA adductsin v/vo,'84 it is more likely that these mixtures actas cancer promoters, as summarized in Table 5.The relative potencies of PCB mixtures as car-cinogens or promoters have not been extensively

investigated, but the results suggest that the mostactive PCBs are the higher chlorinated mixtures,such as Aroclor 1260 or Clophen A60.473 How-ever, based on the concentrations of the coplanarand monoortho coplanar PCBs in the commercialAroclors and Clophens. the TEQs for Aroclor1260 and Clophen A60 are lower than that ob-served for lower chlorinated mixtures, such asClophen A30 and Aroclors 1242, 1248, and1254.:7156: The carcinogenicity of Aroclor 1260and TCDD has previously been determined infemale Sprague Dawley rats and the results inTable 22 compare the effects of dietary concen-trations of TCDD and Aroclor 1260 on the devel-opment of hepatocellular carcinomas. The dataillustrate a lack of correspondence between thecalculated TEQ values and cancer potency forAroclor 1260 and TCDD. The low TEQ value forAroclor 1260 suggests that at most only a fractionof the carcinogenicity of this mixture is due to the"TCDD-like" congeners and that other structuralclasses of PCBs are major contributors to thisresponse. As noted in Section V.B, PB-type PCBsalso are tumor promoters; these congeners pre-dominate in higher chlorinated PCB mixtures andmay play an important role in the carcinogenicityof Aroclor 1260. This is supported by the resultsof a recent study219 showing that Aroclor 1260was considerably more active than Aroclors 1232,1242. 1248, and 1254 as inducers of CYP2B1-dependent activity in rats and this also corre-sponded to the potencies of these mixtures asrodent carcinogens. The use of TEFs and TEQsfor risk management is limited only to Ah-recep-

TABLE 22Limitations of the TEF Approach for PCB-lnduced Carcinogenicity in Female Sprague-DawleyRats297394

Treatment

Control (com oil)TCDDTCDDAroclor 1260

Concentrationin feed

210 pot2100 ppt100 ppm

TEQ(PPt)

21021001040»

Adenocarcinomas

Male

0000

Female

02/50 (4%)

11/50(22%)24/47 (51%)

a The TEQ of 10.4 ppm was calculated from the concentrations given in Table 19 and the TEFs in Table 17.

124

tor-mediated responses. Therefore, because thedata summarized in Table 22 suggest that devel-opment of PCB-induced hepatocellular carcino-mas in female Sprague-Dawley rats may prima-rily be an Ah-receptor-independent response, theTEFATEQ approach may not be appropriate forrisk management based on this endpoint. Thehigher chlorinated PCBs. such as Aroclors 1254and 1260. are poorly metabolized, and it is likelythat the carcinogenicity of these mixtures is asso-ciated with their activity as rumor promoters. Thus,cancer-based risk assessment of PCB mixturesrequires additional data on the tumor-promotingpotencies of the major congeners present in thesemixtures and environmental samples.

VII. SUMMARY

1. Commercial PCBs and environmental ex-tracts contain complex mixtures of conge-ners that can be identified and quantitatedby chromatographic procedures. The envi-ronmental PCB residues do not resemble thecommercial PCBs, and congener-specificrisk assessment of these mixtures is war-ranted.

2. Occupational exposure to relatively high lev-els of PCBs resulted in a number of adverseresponses, which appear to be reversible.Epidemiological surveys of several occupa-tionally exposed groups did not reveal anyincreased incidence of specific cancers in allstudies. Some reports showed increased in-cidences of cancer at different sites, whereasin other studies no increases were observed.The major adverse human health effects as-sociated with environmental exposure toPCBs may be neurodevelopmental deficitsassociated with in utero exposures. The roleof PCBs or other as yet unidentified chemi-cals as etiologic agents for this responserequires further investigation.

3. Commercial PCB mixtures elicit a broadspectrum of biochemical and toxic responsesand most of these effects are similar to thosecaused by TCDD and other Ah-receptoragonists. Two major structural classes ofPCBs, the coplanar and monoortho coplanar

PCBs. exhibit Ah-receptor agonist activityand appear to be responsible for many of thePCB mixture-induced responses.

4. Other structural classes of PCB also elicitbiochemical and toxic responses. PCBs thatexhibit "PB-like" activity also are tumorpromoters, and these compounds comprisea high percentage of higher chlorinated PCBmixtures. The results -of most studies sug-gest that PCBs are not genotoxic but act astumor promoters in several bioassays. Thus,congener-specific regulation of PCBs basedon their tumor-promoting activity must takeinto account the contributions of the "PB-like" congeners. This is an area of PCB riskassessment that requires further study.

5. Other structural classes of PCBs and PCBmetabolites also exhibit diverse activities,including neurotoxicity, estrogenicity, en-dogenous protein-binding activities, and in-hibition of oxidative phosphorylation. Thetoxicological role of these compounds inPCB-induced toxicity has not been deter-mined yet.

6. Several studies have demonstrated that PCBmixtures and individual congeners inhibitedTCDD-induced responses, and the results ofthese studies suggest that in some animalmodels and for some responses nonadditive(antagonistic) interactions may be impor-tant.

7. TEFs for the coplanar and monoortho copla-nar PCBs have been estimated: 3,3'.4,4',5-pentaCB. 0.1: 3.3',4,4'.5.5'-hexaCB. 0.05:3.3'.4,4'-tetraCB, 0.01; 2,3,3',4,4'-pentaCB.0.001; 2,3',4,4',5-pentaCB, 0.0001:2,3.3',4,4',5-hexaCB, 0.0004. These valuescan be used to calculate TEQs only for Ah-receptor-mediated responses.

8. The calculated TEQs for various environ-mentally derived extracts tended to be higherfor the PCBs than the calculated TEQs forthe PCDDs plus PCDFs.

9. The TEF approach for the risk assessmentof PCBs must be used with considerablecaution. The results of laboratory animaland wildlife studies suggest that the predic-tive value of TEQs for PCBs, PCDDs. andPCDFs may be both species- and response-

125

specific because both additive and nonaddi-tive (antagonistic) interactions have been ob-served with PCB mixtures. Moreover, analy-sis of the rodent carcinogenicity data forAroclor 1260 using the TEF approach sug-gests that this response is primarily Ah-re-ceptor-independent. Thus, risk assessmentof PCB mixtures that uses cancer as an end-point requires more quantitative informa-tion on the PCBs congeners contributing tothe tumor-promoter activity of these mix-tures.

ACKNOWLEDGMENTS

The financial support of the National Insti-tutes of Health (P42-ES04917) and the TexasAgricultural Experiment Station is gratefully ac-knowledged. The author is a Burroughs WellcomeToxicology Scholar. The invaluable assistance ofMrs. Kathy Mooney in the preparation of thismanuscript is greatly appreciated

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