Polychlorinated biphenyls (PCBs) have been the target of many epidemiological studies because of their toxic potential and widespread prevalence in the environment. Advances in analytic techniques have made it possible to distinguish routinely among the 209 different congeners, which vary widely in their biological properties. We propose here a classification system for the most commonly detected congeners. Group 1 (potentially estrogenic, weak phenobarbital inducers); Group 2 (potentially antiestrogenic and immunotoxic, dioxinlike); and Group 3 (phenobarbital, CYP1A and CYP2B inducers, biologically persistent). Group 2 is further subdivided according to non- and mono-ortho substituted vs. di-ortho substituted, in analogy with toxicity of dioxin congeners

Camann, D

Gammon, M

Stellman, S D

Wolff, M S

English

PubMed

Wolff, Mary S.

Camann, David

Gammon, Marilie

Stellman, Steven D.

Columbia University Academic Commons

CorrespondenceProposed PCB CongenerGroupings forEpidemiological StudiesHealth effects related to polychlorinatedbiphenyls (PCBs), which include 209 possi-ble congeners exhibiting a variety of chlo-rine substitution patterns (Fig. 1), are thesubject of numerous research investigations.Individual members of this family evokediverse responses in experimental modelsand in humans. Certain PCB congenersmimic hormones and are neurotoxic (1-3).Others produce a dioxinlike response,which has been attributed to steric homolo-gy with 2,3,7,8-tetrachlorodibenzodioxin(TCDD) (4,5). Epidemiologic studies havetended to report health effects expressed asthe total of individual PCB congener levelsor as the concentration relative to a com-mericial PCB mixture (e.g., Aroclor 1248,1254, or 1260). However, as congener-spe-cific analyses of serum, adipose tissue, andother media become routinely available, itis highly desirable to organize risk analysisalong biologically plausible lines, therebyavoiding misclassification of exposure andstrengthening the toxicologic associations.One approach to interpreting PCBs inenvironmental materials is to group thedioxinlike PCB congeners together. Withthis method, a single index is computed asthe sum of the congener concentrationsweighted by their toxic equivalents relativeto TCDD (4,6). However, analogousschema for estrogenic, neurotoxic, andcytochrome P450-inducing PCBs are notavailable at this time.As a means of evaluating hormonaleffects, Wolff and Toniolo (7) proposed aclassification system based on structural,biological, and pharmacokinetic considera-tions. They assigned PCB congeners tothree groups: estrogenic/neurotoxic, antie-strogenic (dioxinlike), and enzyme-induc-ing [phenobarbital (PB)-type cytochromeP450]. The desirability of developing sucha system has been raised recently withrespect to a number of ongoing researchinvestigations that are attempting to relateexposure to organochlorines, includingPCBs, with breast cancer risk (8). One ofthese studies, in which we are co-investiga-Figure 1. Polychlorinated biphenyls. Positions2,3,4,5,6 and 2',3',4',5',6' are substituted with H- orCU. Positions 2, 2', 6, and 6' bear ortho-substituents.Table 1. Majora PCB peaks occurring in house dust or human samplesHumans and house dust Human only Dust onlyChlorobiphenyl Chlorobiphenyl Chlorobiphenylsubstitution substitution substitutionBZ#C Ring Id Ring 2 BZ# Ring 1 Ring 2 BZ# Ring 1 Ring 2Group 1 (potentially estrogenic)Group 1A (weak phenobarbital inducers, estrogenic, not persistent)44 25 23 31 25 449 25 24 70 25 3452 25 25Group 1 B (weak phenobarbital inducers, persistent)101 25 245 174 236 2345187 2356? 245 177 2356? 234201 2356? 2345Group 2 (potentially antiestrogenic and immunotoxic, dioxinlike)Group 2A: non-ortho and mono-ortho substituted (moderately persistent)66 34 24 126 34 34574 4 245 156 34 234577 34 34 167 345 245105 34 234 169 345 345118 34 245Group 2B: di-ortho substituted (limited dioxin acitvity, persistent)128 234 234138 234 245170 234 2345Group 3 (phenobarbital, CYP1A and CYP2B inducers, biologically persistent)99 245 24 183 2346 245153 245 245180 2345 245196 2345 2346203 23456 245aEither 2% or more by weight of 65 congeners in dust and high percentage in humans, or demonstratedactivity in one of the three groupings and present at 1% or more of 65 congeners in dust or commonlydetected in humans.bFrom Vorhees (9).CBZ# is congener number as designated by Ballschmitter and Zell (10).dRing 1 structure signifies biological activity for class 1 and 2.tors, is determining levels of PCBs inhouse dust as well as blood, providing anopportunity to assess exposure using inter-nal and external measurements. As a start-ing point for discussion and initial classifi-cation, we suggest one possible set of PCBfunctional groupings (see Table 1) basedon existing literature (1-8,11-13) andstructure-activity considerations.Mary S. WolffMount Sinai School of MedicineNew York, New YorkDavid CamannSouthwest Research InstituteSan Antonio, TexasMarilie GammonColumbia School of Public HealthNew York, New YorkSteven D. StellmanAmerican Health FoundationNew York, New YorkThe authors acknowledge supportfrom NIH,grant CAIES66572.REFERENCES1. Korach KS, Sarver P, Chae K, McLachlan JA,McKinney JD. Estrogen receptor-binding activ-ity of polychlorinated biphenyls: conformation-ally restricted structural probes. Mol Pharmacol33:120-126 (1988).2. Safe SH. Polychlorinated biphenyls, dibenzo-p-dioxins, dibenzofurans, and related compounds:environmental mechanistic considerations whichsupport the development of toxic equivalencyfactors. Crit Rev Toxicol 21:51-88 (1990).3. Seegel RF, Schantz SL. Neurochemical andbehavioral sequelae of exposure to dioxins andPCBs. In: Dioxins and health (Schecter A, ed).New York:Plenum Press, 1994;409-434.4. Safe SH. Toxicology, structure-function rela-tionship, and human and environmental healthimpacts of polychlorinated biphenyls: progressand problems. Environ Health Perspect100:259-268 (1993).5. Kutz FW, Barnes DG, Bottimore DP, Greim H,Bretthauer EW. The international toxicity equiv-alency factor (I-TEF) methods of risk assessmentfor complex mixtures ofdioxins and related com-pounds. Chemosphere 20:751-757 (1990).6. Ahlborg UG, Becking GC, Birnbaum LS,Brouwer A, Derks HJGM, Feeley M, Golor G,Hanber A, Larsen JC, Liem AKD. Toxic equiv-alency factors for dioxin-like PCBs.Chemosphere 28:1049-1067 (1994).Environmental Health Perspectives * Volume 105, Number 1, January 1997 13Correspondence7. Wolff MS, Toniolo PG. Environmentalorganochlorine exposure as a potential etiologicfactor in breast cancer. Environ Health Perspect103(suppl 7):141-145 (1995).8. Timing of environmental exposures in breastcancer and northeast/mid-Atlantic breast cancerprograms, NIEHS, 25-26 September 1996.9. Vorhees DJ. Multimedia human exposure topolychlorinated biphenyls [PhD dissertation].Harvard School of Public Health, Boston, MA,1996.10. Ballschmitter K Zell M. Analysis of polychlori-nated biphenyls by glass capillary gas chro-matography. Fresenius Z Anal Chem 302:20-31 (1980).11. McFarland VA, Clarke JU. Environmentaloccurrence, abundance, and potential toxicityof polychlorinated biphenyl congeners: consid-erations for a congener-specific analysis.Environ Health Perspect 81:225-239 (1989).12. Connor K, Safe S, Jefcoate CR, Larsen M.Structure dependent induction of CPYP2B bypolychlorinated biphenyl congeners in femaleSprague-Dawley rats. Biochem Pharmacol50:1913-1920 (1995).13. Harper N, Connor K, Steinberg M, Safe S.Immunosuppressive activity of polychlorinatedbiphenyl mixtures and congeners: nonadditive(antagonistic) interactions. Fundam ApplToxicol 27:131-139 (1995).DDT/DDE and Infant ExposureThe article by L6pez-Carrillo et al. (1),which discusses the public health implica-tions of using DDT in Mexico, is a wel-come contribution to the literature. DDTis a public health concern not only in thecountries still using the chemical but also inthose countries that have restricted, phasedout, or banned use of the chemical.Presently, it is difficult to conclude if DDTcontributes to breast cancer incidence, andthe lack of complete confidence in ourunderstanding of the relationship betweenthis xenoestrogen and breast cancer shouldnot prevent us from finding alternatives toDDT that have less public health impact.L6pez-Carrillo et al. (1) base their concernfor DDT primarily on the possible increaseof breast cancer with exposure. Althoughthis endpoint is of concern, toxicologicalendpoints that deserve equal attention per-tain to infant exposure.Teratology studies by Eriksson et al.(2-4) have investigated neurological anddevelopmental endpoints in neonatal mice.Although work is still required to elicit thenature of low-dose DDT damage to thecentral nervous system in neonates, theresults of their work suggest that 1) theneonatal period of brain development maybe similar to other perinatal periods inwhich the brain is susceptible to xenobioticcompounds and 2) susceptibility to dam-age by DDT and similar-acting com-pounds may be greatest during the heightof rapid brain growth and during the rapiddevelopment of muscarinic acetylcholinereceptors in the cerebral cortex (2-5).Although a direct comparison betweenthe 10-day-old mice used in these studiesand 10-day-old humans cannot be made,the sequence of events of brain develop-ment between humans and rodents is quitesimilar (6,7) That is, nerve production,myelin formation, receptor development,etc., are events that occur in the sameorder in rodents and humans (7). At day10, mice are in their last stages of neuronproduction for the hippocampus and cere-bellum (8). Antimitotic drugs are muchmore toxic if exposure occurs earlier indevelopment when more neurons are beingproduced (9,10). However, the first 2weeks of postnatal life in the rodent are aperiod of rapid development of synapticconnections, transmitter systems, andmyelination. During this stage of braindevelopment, exposure to teratogens leadsto disruption of some or all of these events,resulting in permanent injury. For exam-ple, metals such as lead, cadmium, andorganotin can injure the brain at this stage,as can hypothyroidism (11). The applica-bility of these teratology study results tothe human situation will continue tobecome clearer as future findings delineateeffects at developmental time points whenmice are more sensitive and when thedevelopment of rodent and human neu-rosystems are similar.It was with the consideration of thispreviously described experimental workthat a breast milk study was initiated in thestate of Washington to access a populationof concern consisting primarily of low-income Hispanics. We conducted thisstudy to 1) determine actual levels ofDDTand DDE in breast milk of mothers resid-ing in the Yakima River basin; 2) assess therelative impact of fish consumption on thetotal DDT/DDE body burden; and 3)determine if total DDT and DDE levelsreceived by breast-feeding infants were ele-vated to potentially deleterious levels. Fishcollected from the Yakima River between1989 and 1991 had DDT and DDE levelsamong the highest recorded in the UnitedStates (12). We were concerned that moth-ers who frequently consumed Yakima Riverbottom-feeding fish could have breast milkDDT and DDE concentrations sufficientlyhigh to expose their infants to potentiallydeleterious levels of these compounds.Among the 36 individuals sampled (12individuals for each of three cohorts: fishconsumers, Mexico-born nonconsumers,and U.S.-born nonconsumers); results indi-cated that fish consumption did not signifi-cantly increase DDT/ DDE breast milkconcentrations. However, as has beenreported elsewhere, subjects born in Mexicohad significantly elevated levels of DDTand DDE (p < 0.01) in breast milk com-pared to levels found in subjects born in theUnited States (1, 13,14).For each cohort sampled, an infantDDT intake level was determined usingthe breast milk value that included two-thirds of that particular cohort. For a 5-kginfant consuming 1 kg breast milk daily,infant DDT intake levels for the cohortswere in the range of 0.7-3.5 x 10-3mg/kg/day. These results do not includetwo outliers from the Mexico-born non-consumer cohort who had DDT/DDE lev-els greater than two standard deviationsfrom the mean. Our infant exposure valuesderived from the cohort data (excludingoutliers) were more than two orders ofmagnitude below the administered doseused by Eriksson et al. (2-4). The twowomen (considered outliers) had DDTbreast milk levels that correspond to theelevated levels observed in women living inMexico. These DDT breast milk levelswould expose breast-feeding infants eachday to levels that are less than two ordersof magnitude from the one-time adminis-tered dose given to neonatal mice.Although DDT may contribute to anincrease in breast cancer, exposure to DDTmay also produce neurological and devel-opmental endpoints of significance thatrequire consideration. The study conduct-ed in Washington State and data on breastmilk DDT levels obtained from women inMexico indicate that infants may beexposed to potentially deleterious levels ofthese compounds through breast milk.With DDT in our environment, variouspopulations can still be exposed to suffi-ciently elevated DDT levels in the UnitedStates that warrant concern. Also, due tothe influx of Mexico-born women into theUnited States, their U.S.-born infants maybe a population of concern. Futureresearch in this area should consider thefeasibility of detecting these neurologicaland developmental outcomes in individu-als that have been previously exposed asinfants, and not just for those living inareas where DDT is still in use but also incountries or areas where use has beenbanned or severly restricted.Koenraad MarienOffice of Environmental HealthAssessment ServicesState ofWashington Department of HealthOlympia, WashingtonREFERENCES1. Lopez-Carrillio L, Torres-Arreola L, Torres-14 Volume 105, Number 1, January 1997 * Environmental Health Perspectives

Proposed PCB congener groupings for epidemiological studies

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Proposed PCB congener groupings for epidemiological studies.

Proposed PCB congener groupings for epidemiological studies.

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