Document gb4dQZbGMgbB7LYB9e9E2neEQ

Px 9/ x Original Contributions JAMA The Journal of the American Medical Association Apr* 18. 1&86 Vol 255, No. 15 Health Effects of Long-term Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Richard E. Hoffman, MD; Paul A. Stehr-Green, DrPH; Karen B. Webb, MD; R. Gregory Evans, PhD; Alan P. Knufsen, MD; Wayne F. Schramm, MA; Jeff L. Staake, MPA; Bruce B. Gibson; Karen K. Steinberg, PhD in 1971, sludge wastes contaminated with 2 ,3 ,7 ,8-tetrachlorodibenzop-dioxin were mixed with waste oil and sprayed on a dirt road at the Quail Run Mobile Home Park in Gray Summit, Mo. We performed a comprehensive examination of 154 exposed and 155 unexposed persons in the area. There were no consistent differences between the two groups on medical history, physical examination, serum and urinary chemistry studies, and neurologic tests. Results of liver function tests suggested possible subclinical effects. The exposed group had an increased frequency of anergy (11.8% vs 1.1%) and relative anergy (35.3% vs 11.8% ). The exposed group also had non-statistically significant increased frequencies-of abnormal T-cell subset test results (10.4% vs 6.8% ), a T 4 /T 8 ratio of less than 1.0 (8.1% vs 6.4% ), and an abnormality in the functional T-cell. test results (12.6.%. vs 8.5% ). These findings suggest that long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin is associated with depressed cell-mediated immunity, although the effects have not resulted in an excess of clinical illness in the exposed group. Further studies are indicated to elucidate the pathophysiology and (JAMAclinical significance of these immunologic findings. 1986;255:2031-2038) THERE is considerable controversy hexachlorophene production facility about whether long-term exposure to in Verona, Mo, and mixed with waste (2T,3C,D7D,8),- tleiktreacthhlaotrowdhiibcehnzooc-cpur-rdeidoxaint nine residential sites in Missouri, is aoconilnd. tTrchoolims momneixrcrtuiearsliedawerneatasisaslpo,rfareyeaecsdrteefraontrioMdnuaisslt, hazardous to humans. souri near St Louis.' As of February sluIdnge w19a7s1t,es wTeCreDDta-ckoenntamfrionmateda c1o98n6t,amtwinenatteyd-ewigahsttesitoeils hraeldatbeedentocothne firmed as having at least one part TCDD per billion parts soil (ppb), a From the Center tor Environmental Health, Cen concentration in residential soil at ters for Disease Control, Atlanta (Drs Hoffman, Stehr-Green. and Steinberg); St Louis University School ot Medicine (Drs Webb, Evans, and Knutsen); and the Missouri Department ot H eallh. Je ffe r son City (Messrs Schramm, Staake, and Gibson). Use ol trade nam e^is lor ideniiltcalion only and , cewelrxuhpldiiocmeshduitrtiehpn-uagrhtehdliiuutcmcistaihorneneaaelasxtohcpntoiasvoubitfrlifeeeic/st'ioawSlcisenorcneecsobindneo does not consliiuie endorsement by the Public gun at any residential site until 1982, Health Service or by the US Department of Health and Human Services. Reprint requests to Division ot Environmental ethxeproesuwreastothleeveplsoteonftTiaCl DfDor ahbuomvean1 Hazards and Heallh Effects, Center tor Environmen tal H ealth, Centers lor Disease Control, Atlanta, GA 30333 (Dr Hotlman), prepsbidfeonrti1a1l osirtems.ore years at the nine WowhletaavhThsseeehlrnssbeeel(eQTreunecCpustaDeimditdDloeenfRao2twsu,riu2ana0rsls0teMuddsdpoiipytstbehbcibol)ee.evricnteeHharaueoaMdnsmteieiahsTnstiCPogausahDonrreDiikyrl. etsppbSoattTrtMwrstcsmnraehtehiuoaunioperaioCtaersxnseeaaeeemremnnhbntntrDnntesdreef)sgeeicscepdcpm,itnddDerioolenhabdsnloatint,timesaohnlecyeehslgthtsi(1btretoirwinrpwatttestP9riuitlfchoehhooaozcloae8ehraroeldueatefesmfrv3dsooeseluirgs,lemse1thatsldwdepdsheeheolr3ittoEocstetmolncasih2iwmeteftlg3l,tuPlsagseietse.eils29earhashebdoitAcaauI1nrthmsi,meitnoetsynspenbao'esb;vutaof-psprpmdwstyoaeonprofAuwtnolblulaenaeedafipa3l1nltsognhdasse)rnerh1olntee.ievptkptiocedccaneniohmsmetpme,rohonIeiefclUebs1ni/ntltooyosytoowl,eeT(hSteb1cbfbarb2iceowrocoi0eCgiii(lae,titdotfEltlfto2E0nlaehheiehyDeaefnn0tasdnsPftuddehphi0DhJstggohvpdrAyiepaoerofmilononebasrtlrbemv)mh1msprlogutahroooaeloe1ahepnludcbtenmeaiisae.eilddhnnebe5gslssst.t, samples. METHODS eewRmlsuaiotAgsninminbtyhMclaesotioennbbdtsdoeiilidttevwhepirdaeaHeuterdontatimlhcAieewepxrpheapProtoiealwsrreee1kidrs9neu7f1lot2tto'hr0dae7nsadTihtsxCotMtuDuhodsaeDryeyh.Qm1oau9WolnaRdridees3l JAM A. April 18. 19 8 6 -- Voi 2 55, No. 15 2,3,7,S-TeVachlorodibenzo-p-Droxin-- Hoffman el al 2031 - esipfwbawnotnhltuedeerrordroiQenev9ayleu5lni.ed2aadd0Wuhbil7ocaliieealnunRislnstalteuetsdtowhrtnh,ieeevoiomstdilhtbasddeuptntusudartsd.aiedienlndIyivsgnn.e1tlwroot5ptahhh4calreioaressttlceiiewpncrpteueigtfeprearirsetramiioosntanibidflnllsaoo,igentroahsmdfni(n7tteadhht4lteiieet%golwhsreineee)e lhlritaoonoornduFmlTgigyovCeehrisrDldysuatDiihnzateeelqasdQauncwuidmovamhmoiahololbapebihRdanliaerultdielnsihtvo.onoenhoFmdotihpevmgfoaoereopttrsecuansoopritkfm,xaiantpwwmlhdoeeeiostxihnutmspetpoohsokuisssbmeguuieohrlripeert sLfahocoueuislsdomeilresstariomnppeolalecisthawnoefarrteehacreo. elIlnepcnateorkdnsefrioonfmtthhreeoaS1d5t 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tifttsSooepwrrnfimahpwdorwlptpmfo4sndccw(p1hifpsrthhomphaSronimeiuaaeerxn3fhtottiaoerptaoo)anreu5osetielaafeeagoegkreeihamsestoasboo.phlilearuhnasned%tmWnthabrasen3truo;xrnnpsmithrtesrtthmusmeoscwd3emmderrntieneoittlioejibs%eeittttloterevldapsns9lostCessdrcesea;ftmsn,dyetreeciihqnsebttueiasat%o,ecorohrias)atnMertep2siiudre,hie,etyptfxpuystesnrrxhe(tef"velcaarlefhcweilgdiix6rworieveux5ere,s,et,)mieaspedcmdfpIJxaocnateeariohudapuord.40i1aaoaoepmoaet,nogneonoqopplswdplstdt0rnsoeelm%n2lmnxfWistlttorxeosehtmtsp4rduosdlasaeb%eoolyemhasihedspaersetemppeaic0ernritwuanvffiieosleuerreeuticniaroeprdhnztouooadonrio%rrwdicgtnettneesferggidepotlhtrrprdicaseisesoeanslrrffococelxlsahxteohegaedteyruuaeileoeesgeo,oiddthpttorawihtuiocfeddaatvnstaaoeia:naorteumderxrtptlirrdwotpflohanhclinuragedhmareaenednnireeaodxtyseturetaocabsfidarfceaeTbeisnmiapd-rrereenaledpeguprsrmd;satnnccytitlsiltrr,auasyleprspCemrihsdrmhruentouphhneirtapt3crtocnieosueaigoeesitneosrieseodoessdeb)nehDcelaal(re.onxaimnncldcsekesxfoytpre7sidw.dte0steerrdspae(slcliniueinptfeit2lenisDagdifas%nrtisader.gsa.hfnrdyuutoopgasdiexs6sfedi2nlegtrimrtpktnagbdc.nuBongrhefenreitrrsvfsauocaoep,a1iya%g1ttefevoih1nmgyaoeob,enioerafoerDthepmtmnqninreordaorfrtelmessrveTneyurrsneDdbwtdylo,)aotdcieuhaasltaftrefTeogdsryhe.rohcixiyapsositehmafoxateurinee"tdeTrnrhrg(ureHfs;,ertaentespaeftuuecxueJsnpanarpoa(hdd1etMiai.oHnipOyftinnorpngoseeswhtoc"naPlcipcnochrscrddrveitfp,iroos1mtntmertxdsaohasl,daaTidnenieyhsbileseaec2oaou"aeeirrpargsoaydttm1enbnraes,ildaulormath.mmsr.ceTrwnpdrdsecmaclaiured4oeoeOspnvedrsaktndntwlfnoeasniecdscohnFf5hsdstinnkufsrofse(sundnppdtesujniuedyochdtoceriorlsue1ep>pthn2eniipuoubehdxnlps1)aefatrcsalisrnferillura8M2oleaeooistpuadioslnireupfsnaafnteea3utsosnaccigwud)tn;%fprseitcfroDr;sarrgnowdrssereehphrnerosenh1nttuanatiaolartswonrthaethsidiuorreyiasTiu9teeentnuedemlgtaieleinefcmgcegngbshshteiehoootscmfolere8xnasoslb1nsotroHetssrrgiitydiiiyhsddydnye2eek3s2aererees-f-srt2.,-r;r.tft 1 nieeaabpnxnnxieancTcpdearrgitarmobeigu.tcs--aooiysuisnffteprioaatenaluhtognimnweoartdsvniosnterhttwurcuerheaomdenalgnyarulteefeitmxociatvpuirhenbneonxededsdaoreumpetfdahrodaianefrnptetrteipothierohdcosgenaiiwsytpnaiai.atbvastissuvenottuTetah'cnshaeaniteianrondxsetbtttipainioeggotwdgenweesiinenontaoodhsssfff 2 0 3 2 JAM A. April 18. 1986-- Vol 255. No. 15 2.3,7,8-TelrachlorodibenzO 'p-D ioxin-- Hoffman el al ewdvtmtebtsahniwumii3fetrraawsuMafNsifwot1p(mamabe>Tabchhhatfnxehoadehposiaeoesxwaenvthni5tsnfennneeneeeareeixde1oephanarseesoruerlfesvuacidirlQ4anraeslraadEgrdtredi,soenieesdouvureg5yvdeNcsnirietletewPeallsoatcivtxcoulxgcysa-hoelsopleeeiyarya,nsdtiattuaotcuftmeyetrtcte,)cnheimipyrtaxdus'snoi.etnenzesswsnniebusvnaowrdomalngnioaeepedoilsfpery,iedwafbt,gaoerldistalcbriluletisosseananaoAosemanoiaoeyteleaaitsanlhaoaee)xosonbdsercalgrymsocsrfstiru,rrsgtdangrl.lcniarenoifeetpudeyniitotonkotswoetr'alsemvar;endegocaiisatedolseWedcdoaosdfsinsrsnnvoetv1rvatdlouetndriioswraeftsliwpyhupwisxlhredwcedote9olcyohveeunrarcednttbllreeehocrepeplys<le!d8eiieiiaasrtmcofgrsaeluefseediutdf,huwagotvtfntiu.emcuaa4cedosolrieofifs1iphirrnnpiseodremrsgsneoao.eoogldoraadeavrrisamrQtrero5erungstelcriFset(tglcliehgmnnnessgetrtereaeei)sngdWmhdipseaaraomdesedutnstosrotspco2evsgs.tecvtnstreassgrhamyaswpevwiiiaaniufc,eaoariamewoeiraesnfbldot(eutrbnAldestpaeiaoSoyendyoadrrlaahuwwloireeoiol,pceieenseyrdroiiruaoaviatanftdssDlaadngsresngpenceteisx-renohxihseeupltrsmwematanhloestodaetrdotRpaircdeipssslcsspimtriaaawsiog.errlsasn,ntncafnimloeuoleeedsnhweneeaooagiunistvnyfboiagmctftiaiaxarxfsoehmolivnrtogyuslvtssen`ehbnireceesaoslreeeranli,rnTtw`tp,dofaeuleetsore.ecaeQ.woirlelgedeextedrps0otlacildorwdeisetrybCecrommfbaieegsnmnxt,5c)Prtaetluelottoaros(pouyhse.drFaxethDenau.ysaaiQh.chago.esHnicfnaaebe,sonforsarsenxvcdatppsetoeinsouyctgefefoiDoidreAgidueeufnwaeddsedheoamelegippvaocrknderdnirpcathncCse)-el,tmpmrslteoneinturreneha.caio.idahiisiRbool1iosoldswerotfdenselvodonirnitnsntfsrneifebeiiy3eie-avfeParfronamiesduornaisanFeduvfcieegdaexdeo7ict'fooclnafRaiTnvgocusnetrugcitxrei"aipebtroouooipmaneofgrrhdoadpovephiirtssdseaCuosndnprrnijannarraredodoineenefehsnietitnenaeueatnfdgomouoDtudrfnxi.aaaeodunspiajrdrotetsnnstccotnnmitibbanaessulil(ugttetmueasanhmaraDniasteLtoeatccheheexbrggttnleoomitecscrsiriialt'Itidtieieiddg'yesseendddyssfhseeen!oee;ossstf,frsltttl,. RESULTS Group Characteristics gutttoihrsveoTaea;uthsg,puie;ss;otdehrwsaeeotexpfar;repeoprexfcrasepouctsomesisc;esipieoydtdlnaoeerabdsal,abaciwhnnlceoedoTrowbadaibniutclphdneidr.eeraax1esllpcessooprhsshveoeeaorcwdtl Table 1.-- G roup C h a ra c te ris tic s \ C haracteristic Age. mean No. ol years + SO .1; Sex, % -v . \F :v : '" ? - * ' i:. ^ Race. % While, non-Hispanic Other HoiEngsheed Index o l eoctoeconomicJevel, mean score Subject's educational level, % completing high school Tobacco use, <K> Ever used _ -. - - -. - "' .C urrent ireenTiil;;.'.'-' - ' 7 ` Alcohol use. % Ever used Current users Pesticide use Mean No. of cans of insect ropetlant used per y e a r'. Using professional home interior services in past ' 5 yr Herbicide use, % employing professional lawn services in past 5 yr Wood preservative use in past 5 yr, % Use of pesticides, herbicides, o r wood preservatives at home during past 5 yr, % History of occupational chemical exposure, % with ex- posure .* : ./>. - - ` Difference (rom unexposed group, P C .0 1 . Exposed (n<=154) 2 6 .5 + 16.1 Unexposed (n=155) 2 8 .5 + 15.7 v-f.v. 4e.7--.- v 4 5 .2 5V:*" ~V VX"1.54V'- 100.0 0.0 5 1.8 *1 1 .4 * 48.7* 47.4 31.8 * , 98.1 1.9 <-.* 4 S . j i n . i < - 64.5 v; 7 ,* 5 2.9 57.8 48.7 65.2 53.6 1.6+2.1 - * 29.2 ' f - j : 1-3+ 1.S :' ,7 . - 31.6 3.9 71 79.2 5.2 14.2 80.7 2 5.3 ' - 2 9 . 7 . - .- ghtsvitmnrhiriegcivaoTeacenotudahseilpi;lfverniseriacitcandeanriflndnadsowc.enetrohraxsnaisfbsodt,totasirioohctfcmhfronoteyrwerwetreooehisnvfftefhceeooerpmrmrc,lhapeacbsetaalthmoenspityectawiamccHteaohiieetlorsensontla,ritlwcdisenta,lohtgelohoalocsdyertf t(hrhPeoleuca.stOeephdlao)r.ltdtoicE(iPdpsou<acnc.i0ato1stei')co,onwenadolhumiccaihanctdiioslneisvnaoelvcle,iorleesaevcnoledyl nomic levels were lower in the yy6cdomp(thrhlnrleiamhoeenxee.iaaauv7ssoprsanapPrdldimectyibenokrrtoddoaeairs3sbglasrvriele)tmea.eewe1tene4fd(i1mnrsirtdnc6iac.i,nesade7isegQidphnoafQ%epTanrtifiodatud1nohracnhuit)m9nasueorrhaiyt7itiorptneQlieneeo48siltyef.cra;.feuRe9ifeR2eritpaoaiyntuhtnspr.uhicraeh8nielsacnnae3ntetuors.pRrhtbp61kifrissmMnaenuae1r..)r9rcfrr5n.eeaoee(ytke4ed1a7irsr(xseTO9c.(nci%Seiamp7wdippdhhnpD1roeTaaTeea)neeassn)rnr1dsChuwentct9clihydemiiDthei3a8eicmcvusenne3.Dibiae9ingppn,emn,derdwrdaarwwsaoater3tntinewnaauenhha.araoott4ddnnpyoeesessstff tpiwnQnhaaeugatreaittkoiiilntcnhiRo.pearuayngFnmpatoalsroratdrtygyeetea,h-ndfveoaeaounttridramwQhe6ou(i9r2osak9tfio(le%4trdhR5y)%eiuninor)eftxehoswxpnetaaoocsmsteroeekiiddal gfapowrarrneuvaeoosrdetemiuksrdki4ap.d.e.g9newhPecahtaedhi4orce.tfih3aniicryomiopetnhhuaeaeoaerrnmnstomsseiroanofmainabmt3pni.lot7tlyehehreemeh3woos.ut2amibitnmsieyeeleexefdasppohrrroaoassrpmwaekeodnnesrf Medical History There were no statistically signifi cant differences between the two groups in the number of reports of any physician-diagnosed medical con dition, including those for which we sought medical records, except for a gspkraiernatitcepirrpoabnflrteesmqisun"entahcnyed ca"aomtethognoerrgiemseix"spcooethslleeadr snteaotuisstidcaislelyasesisg."nifNicoanptrceodnodmitiinoanntwaors reported in these categories. No cases of chlnracne, porphyria cutanea tarda (PCT), lymphfifma, sarcoma, or cancer of the liver were reported. Six persons r(tewpoorteedxphoasveidng vhsad fcoaunrceru.nAelxtphoosuegdh). there were two cases of immunodefi- JAM A. April 18. 19 8 6 -- Vol 2 55, No. 15 2 ,3 .7 ,8 -T e lra ch lo ro d ib e n zo -p -D io xin -- H oflm an el al 2 0 3 3 Table 2. -- R esults of S e le cte d C linical C hem istry T ests Exposed Group Unexposed Group - Urinary analytes o-Glucaric acid, m m ole/m ole1of cre a tin g Uroporphyrin, n o /g of creatine Serum analytes Triglycerides. m g/dL Total cholesterol, m g/dL Total bilirubin, m g /d L Aspartate aminotransferase, units /L Alanine aminotransferase,''mg/dL 7-G!utamyl transferase, u n its /L Alkaline phosphatase, unrts/L- 1 0-Glucuronidase, units/L 5 '-Nucleotidase, unrts/L Glutathione S-transferase, units/L Alanine aminopeptidase, unrts/L Mean (SD) ' 3.7 (2.3) 9.6 (4,4)1 S7.0 (65.8) 192.2 (37.3)1 0.4 (0 .2 )t 37.6 (9.3) 16.4 (10.9) 30.0 (68.3) 146.0 (100.6) 2.6 (1.9) 7.4 (3.0) 10.0 (1.6) 105.1 (2 8.2 ) N % Abnorm al* 153 3 .3 v > 153 16.31 141 7.8 142 3.5 142 0.7 145 23.9 134 6.0 140 3.6 140 31.9 142 4.9g 140 5.0 142 2.1 140 7.9 M ean (SD) 3.8 (4.1) 8,4 (4.4) 108.3 (97.2) 201.2 (42.2) 0.5 (0.4) 36.4 (6.4) 15.2 (8.5) 20.1 (23.4) 126.8 (60.0) 2.3 (1.2) 7.2 (2.3) 9.9 (1.6) 96.7 (23.0) N % Abnorm al 1 4 8 .r146 4.1 7.5 146 . 148 148 142 135 141 143 142 147 147 146 9.5 4.7 2.7 17.9 3.0 3.6 23.1 1.4 2.7 4.1 4.1 'Above laboratory specific normal ranges, except (or 0-glucuronidase, 5 '-nucleotidase. glutalhione S-transferase, and alanine aminopeptidase, for which more than 2 SDs from the unexposed group mean was defined as abnormally elevated. tS ig n ifica n ily.d iffe re n t from unexposed group (P < .0 5 ). with analysis of covariance adjusted for sex, age, socioeconom ic status, and current alcohol consumption. 1 Significantly differenl from unexposed group (P C .0 5 ), w ith logistic regression adjusting for sex, age, and socioeconom ic status. gDifferenl from unexposed group (P = .0 5 ), w ith logistic regression, as above. Table 3 .-- R ela tio nsh ip o( Y ears E xposure W ith S erum Liver F unction T e s ts Outcom e Aspartate aminotransferase (P *= 0 .2 3 ; P < .0 1 ) Alanine aminotransferase (H I = 0.20; P c . O l) 7-Glutamyl transferase (fl* = 0 .1 2 ; P < .0 5 ) Alkaline phosphatase ( f l I =0.26; P C .01) Alanine aminopeptidase ( f t 1= 0 .1 6 ; P < .O l) 0-Glueurntdis ( *= 0 .'IS; P < 5'-Nucleotidase (fl*= 0 .0 7 ; P > .iO ) Glutathione S-transferase (P*=0.09; P > .0 5 ) Tolal bilirubin (fl*= 0 .0 9 ; P < .0 5 ) D uration of R esidence, yr 0 .8 3 5 t 1.3721 10.155t 6 .6 9 6 t 3.5621 0.131 0.197 -0 .0 4 6 ' -0.005 'B ased on analyses of exposed group. tE slim a le d coefficient significantly different From zero; P < ,0 5 . tEstim ated coefficient significantly different from zero: P < .0 1 . E stim ated Sim ple R egression C o e ffic ie n ts ' Age, yr 0.102 0.120 1.038 -1 .4 7 9 1 -0 .2 4 4 0.025 0.04 i t -0.0 2 0 0.001 Sex (1=M , 2=F) -7 .7 6 5 1 -7 .3 4 1 1 -2 8 ,6 9 3 -3 9 .7 4 9 1 -1 3 .7 1 6 1 -0.8621 ' -0 .5 7 6 0 .7 0 9 1 --0 .1 3 0 t H ollingshead Index (Range, 11-77) 0.053 -0.0 8 3 0.686 0.520 0 .5 0 4 1 ' 0.031t " * 0.009 0.008 -0 .0 0 2 C urrent Alcohol C onsum ption (1=Yes, 0=No) -1.3 7 8 -2.2 0 0 23.756 -3 3 .0 6 7 1 1.520 -v-a-r-4 -0 .2 4 4 ^ ' 0.206 0.308 0.021 taecrcexoeilesscnptnofosci(r.srcydemosdmreoedprpagorrrreebotsdeyuudplwt)s,brietyohvftieheoxnweuposroneseiemodfiwmnieunrmtndheeoievdloiiduncgnauoiclt dsatthuhbeceeNrohsroeftxroiodepranqisofasufs,edeefrdnvaeenetcnaarydcnsleedcoshfdpuiwerlrndaeeeertgrpxhenerpnsao,ofndowscuuesiydncpthtdooigvnucrbetotoaecnutndowgpmeisesoeoneeuirsinns, TocttaorahlmnFe"tmossple,ryianlitssfntwyohcamroernmepdoatapfsontermie1doe4evnsdiasnslwl.eeetslenhf'rc-'eereienep(x1towph)roaetsnseehuddamsngsibgrydonnmstueifopspisr. fpeeertsi(s2tSe.n6%t sevvser1e8.h1e%a;daPcch.OesS()26a.0n%d (v2s) 1n4if.2ic%an;tP<d.i0ff5e)r;etnhceesse spteartsiissttiecdallywhsiegn aFD(sSwpbw(8caltea=iea.eoas4cfrn.srft%a0tceueciuo7mrc)esosn,)e.ivbepentsNasroaaceaos3ofngoerunl.fset2lvrdse,d%teeidnrindwdfes;uffmechemtPoxhihrorbno=,rebeyros.nnp0soasnctes6eunheiytscl)hdge(scf9b-hehw.re1otopsmeet%rolrprwmtoecooeogmeiheptorieoadeoctvoenflaeiarcsrcdbdtloyagioPanoslr3prcnOtoo.cdhrr9lmuMoaee%eeprsovsrsiSsecss;f. lwetiianoacnesh. ngosrtodautifpifsetrriecepanolcretsiinniggnthpifericopalornnocpgeeo. drtiTionhnfeerocef Physical Examination There was a statistically significant sinpcerceifaicsedinertmhaeteitxipso(sgerdougrpoinupg olefsnioonns oifvPucrtsaCaohll2mTse;rePowxdaracelimr.lfiOfeneianrldn)aaei.annattiNygcooenomnsoo.tciswchaeeedssrreiesitnpeofsaoftruhcttneohicsdgleioeportainhanncedptnr.ih,evNyi1odso6r Hematology, Urinary, and Serum Chemistry Findings eccPodPonociccfuuyTtf..intne00haetrt5l5eser))((nce,,i74noc,,a1eu3wmn0snt0edh00etr/iea/nVemcn(uu5wesm.ta5haammn%eibtatmmiespnsoetvlbirvvsuwclcssaoteh5eoln63i.ld9tyt,,e%09ga00crgs;bea00ieglln//lPocconuouufcidldfo.miiOfmmccfcaoyemmlennrt)le.;;tl 2 0 3 4 JAMA, April 18. 19 8 6 -- Vo! 255, No. 15 2.3.7.8-Tetrachlorodiben20-p-Dioxin-- Hotfman et al Table 4. -- Delayed-Type H ypersensitivity Skin Test Results Exposed Unexposed Total Adtills H Children SI . 35 16 Mean No. o f P o s itiv e A ntigens > . 2.3* 2.5 1.9* A ve ra g e In d u ra tio n , . m m . - 10.1 11.0 8.1 % % R elative . - A n e r g i c ': / , , . A n e rg ic * ------r Mean No. of P ositive. A ntigens - 11.8 35.3 93 3.1 11.45 12.5 28.6 ' 50.05 . 71:_- - , . T : . ? : * ; 22 2.9 A ve ra g e In d u ra tio n , %_ I. A n e rg ic 12.9 1.1 13.3 ' : * " 1.4 ; ' 11.4 0.0 ` Defined as no positive reactions to any of the seven standard antigens, t Defined as a positive reaction to one or none of the seven antigens. * Different from unexposed group; PC.OS; analysis of covariance adjusted for age, sex, and socioeconom ic status, and date o l examination. Ditferenl from unexposed group; P < .0 5 ; logistic regression adjusted for age, sex, and socioeconomic status. i'OIder than 19 years of age. % R elative A n e rg ic ,, ... 11.8 % 1.1.3- ' 13.7 We compared the groups for the prev anloernmceal oraf ngteestandrefsouultnsd othuetsiedxepostehde group to have a statistically signifi cant increased prevalence of elevated wPc>r1h<eT0ai.ht,s0e0ee50d)0.be/lxcpopuoreodvseamcdleemlnlgc; ercoo5uou.p3fn%tehle(advdveasftienadne0d.7ui%rnais; gFnracar.myOul)roofpaoncrdrpehaaytirninsei;glne1vi6fei.lc3sa%n(>tl1yv3s hfi7igg.5hp%eerr; OptionPre<p.hv0ys5r)8in.m4s e/(ta9gn.6plefeirgvegplreaormfgruoarfmincarorefyatciurnereao). Nrino ppaartttiecrinpaonrt 'healedvaateudrilneavreyl poofrtpohtayl urinary porphyrins indicative of ei ther latent (>400 /ig/dL) or overt PCT. ramCaetteegrosriocfalthceomurpianrailsyosniss, oinf calulldpinag mseidcirmosecnotp, icshoawneadlysnios doifffertehneceusrbinee btweWteweeneeftnohuegnrtdowuonpogmrsoieguanpnissf.icfaonrtadniyffesreernucme analyte except for serum cholesterol, creatine, and bilirubin. For these, twhaes sviaglnuieficfaonrtlythheiguhneerxtphoasnedthgartofuopr the exposed group for each of these variables. In the exposed group, the ncpuorroropmnoairdltliayosneelwoefvaaspteagdrrteicavitapelarunettshs aownf iti^hn-gtalhube upnreesxepnotssed thgerourpesu(JltPs=.0f5o)r. Tsealbelceted2 serAusmshliopwidns ianndTalibvleer 3fu, nmctuioltnivatersitast.e ysrueegarrrroessgsoaiftoenrfeaosnridaedlryotssteces oinufsTitnhCgeDnpDuamrskhboeawrseodaf aarelalanstitinaoetnissahtmiicpianlolwypitehpstiiAgdnSaiTsfei,c, aAanLntdT,aplGoksGaitlTiinvPee, phosphatase. Immune Studies Evaluation of DTH skin test results revealed decreased responses in ex posed participants compared with unexposed. For the entire study group, 22 (16.7%) of 132 exposed pwaitrhtic1i1pa(n8.t1s%w) eorfe13a6neurngeicxpcoosmedpasruebd jects. Fifty (37.9%) of 132 exposed subjects compared with 27 (19.9%) of 136 unexposed subjects demonstrated relative anergy. "MFeotrhotdhse" sreecatsioonn,s wdeispceursfsoerdmeidn stthae tistical analyses of the DTH tests read only by readers 3 and 4. As presented in Table 4, six (11.8%) of 51 exposed subjects were anergic com pared with one (1.1%) of 93 unex posed subjects. This difference was statistically significant (P<,05). In aandedritgiyonw, atshseignfriefiqcuaenntlcyy inocfreraesleadtivine the exposed group (35.3% vs 11.8%; Pc.Ol). The exposed group had a smaller mean number of positive antigens (2.3 vs 3.1; P<-05) and smaller mean total induration, al though the latter was not statistically significant (10.1 mm vs 12.9 mm; P>.05). There was no significant difference between exposure groups in the prev tarielcelianptcaievnetolsyf waahnnoeerrhggaicidc (nt(ho2rneerseopevcvsisf2icezredore)or)pmaoarr titis on physical examination. No apnaenrtgsicreoprorrteeldativuesliynganaergmicedpicaarttiiocni containing a corticosteroid. No partic inpoasnutppgarevsesiaonhissetcoornydoafryretcoencatnicmemr uor cthaenrcaepry.chemotherapy or radiation The results of T-cell surface marker analyses showed statistically significaanndt Tdielcrceealslsed(Pp<er.0ce5n) taing"etsheoieTxp3TosTe4d. gobrTeottwuhpee.enTb-ucteglrtlhosueupmbsseeat(nsTawnbualems cboe5mr).poafBre-aacbcelhlel cnbftslsyohpoeuuumsueIostsnnnnpeedtstdxthhseovpoesxtioctowobrsytnieeooytdubdremeestTghalbyrns-rneocimetwogreuietnglpaploeish.mfdfniofciiupnrtacoeanronacngoncttleldt-lcliiyTnyfuosnlargapmcaatretetnweeriidvaadviapsitesteuhtyrreeaeartrndaoiaesdnfl, cytotoxic T lymphocytes (Table 5). slEytximmppoushleaodtpiroionnldifivwridaittuhiavlesphhyartdeoshpceoommnsapegasgrlaubttlioe aopfenlwyeainoidarmnTcdkesh,eapncnwbahcpognoleeoenertdecrocdsyc5iuotntenapaemnanatstliivaawsstbaoctogiieilntgetcitihnpcevwarnrileoteAleayeyafs(,bnsePsanenpoi<ndtogtahfdrs.n0remitr5ttcfieaeihtyc)cwtsl.ietaappoonTnoiatnmtounhngu.xsrsetmmiseoctudubonipeixtfTnores ccgarttluieeorrgvtpseneeeetaaosss)irtdreentaedereounsdrfmeuferrpldbTtgeea.sqey-r.brcucoIseFeenvlinnnloe(tcr,raasyagutdttwhoehbhdefeipeistarooionpefafnxetounhrputlagaahonltytnsyedoiesoadinpnsetts,exhdhrgpeaacwrrobteoesenisluernaotdpae a6sotiPcisnc(trnm8hhhter.neto8ca.learos1emnl%.tautenw%0ih-esllsus)5eeetesit,ttnsndadui)havce.asbi(etnsaet1risTfvtxlsT2eerule6itp.hvlyte4t6sin.aoiore4cq%/tttenTos%aruixteevenrlSedepdlxe)evsnyi,iopsfstfmrcsfuauaoaaie8enbmeslnntrd.prtes5inecedeodau%rt(nosspr2ingoirutooagt6a)g,yefminln-f.nrrct7aostAaiiap%lfpialatuelbcillhbaubsctpin(Thespann1snvori-ona0taoosnrtcesa.untrlhr4mestg1mmt%alosl4ahnvlwaa.lew1ihhlllneate%iiijhaarrTnttv.ssoOyddoyoettst-; JAM A, April 18, 19 8 6 -- Voi 2 55, No. 15 2,3,7.8-Tetrachlorodibenzo-p-Doxn-- Hoffman et al 2 0 3 5 Table 5 .-- Results o f In V itro Immune Tests P aram eter Total lymphocyte count t Non-T-cell co un t! T-cell subset populations T3, ce lls/e u mm T3,% . . . . T4, cells/cu mm T4. % T8, ce lls /c u mm T8, % T l 1, c e lls /c u mm T l 1, % T4 /T 8 ralio Lymphocyte proliferative responses, cpm Phytohemagglutinin Concanavalin A Pokeweed mitogen Tetanus toxoid Allogeneic T-celf cyloioxicity, % activity Serum immunoglobulin G, m g /d L H M ean E xp o sed (SO) (n=135) 2,465 (724) ~ ' S40.'(289)t 1.69B (519) *72.2 (7 .5)f 1,021 (353) 43.5 (0.8)! 592 (223) 24.8 (6.2) 1.801 (550) 77.8 (6.6)* 1.9 (0.8) 46.882 (15,112) 44,679 (18,104) 38,370 (10,696)! 25,062 (17,535) 25.5 (14.1) 1,042 (212) % Abnorm al* High, 0.0; low, 2.0 `" H ig h , 6.4; low, 0.8 ` 1.5 NC 0.7 . NC 1.5 NC 2.4 NC 8.2 , 3.0 3.0 High, 3,0; low, O.O'I 3.0 5.9 High, 0.8; low, 0.8 M ean U ne xp o sed (SO) (n=142) 2,311 (634) ' 455' (190) ' % Abnorm al High. 0.0; low, 0,7 Z High, 4 .3 ; low, O-O/'r- 1,673 (493) , 74.2 (7.4) . ' . 1,033 (346), ' 45.9. . ( 7 . 6 ) A 578 (198) 25.8 (5.7) 1,795 (493) 79.6 (6.0) ' " 1.9 (0.6) 1.4 0.0 0.0 _ ,, - '7 . 2.1 'n .- - / '- 6.3 49.256 (17,878) 43,630 (16,901) 34.921 (12.855) 23,975 (15,038) 27.6 (14.7) 1,034 (189) 3.5 2.9 High, 1.4; tow, 5.6 0.7 4.2 High. 0.7; low, 0.0 'D efined as less than 2 SDs below mean in the unexposed group for all param eters except for: total lym phocytes i 2 SDs from the un ex posed group mean, non-T-cefls 2 SDs from ihe unexposed group mean, T 4 / T 8 ratio of less than 1,0, tetanus toxoid stimulation index of less than 3.0, pokeweed mitogen 2 SDs from the unexposed group mean, and immunoglobulin G level greater than 1,483 m g /d t and less than 568 m g /d t (laboratory-norm al range). !N = 152 for exposed and N = 1S 1 for unexposed. ! Significantly different from unexposed group (P C .05) with analysis of covariance adjusting tor sex. age, and socioeconomic status. Not calculated. ''Significantly different from unexposed group (P c.O S ), Fisher's exact two-tailed test. TJN= 129 for exposed and N= 139 for unexposed. gcoromuppa.red with none in the unexposed sustoutsreTptedphosrse,eetmovswsaieulvaulaetnadiavtdelaeyerfdztfiheeatecthtetephroPeoetOfgeranMesptssiSssaoyilctocoinhiatmaotmillmoosongucdionceraooleslf geaospatwispaleglcanihitntrncbxhonysavnarrdoradcsssp,radieegsoeoeuenitenomssvdrsscdpngssfsgmiisvtioeeueoddseaieabardmdmegreutdstneaaenfirta.stoeeotnnhoQtgaltwmnnriwsupyrerftu(uesiepiootbpie.saoewmaotsup.erdthnifsntthlpiruebFhacTtysso)ilRelhraa(utnauhprheounlertmaleilierietftneemnoynorphehrfafedntdstrmetigabshuupsw)serytileutwgumvromwy,omhtabninsehewoaieoitrgiaeatrxeteiubfrehiroeinxpitpesvlloctnmhynppaol,aieauy.nmttoeasronphiearwoskravrdCtedseeenaeeededxomttphdTbrigrpiundoaiigeaCwcereogfsntrnfetonoftrushoDeneteeenemueoderbrllxorrrDsdyydplees,-t, Neuroehavioral and Neurosensory Tests emfonrecAaenthsbsetetaottwrivseoetsecicnaawblualgylsraordyuseipgmssnouinfbiinscttearsnaatttgegdordfeifgoftanehtlryee W(34e.c7hsvlesr 41A.1d,ultrawIntseclolirgeesn;cePcS.0c1a)le. cTsegwlfetttmfsgtdiDsahmtonehhoaihohrcnrirnheimeoniruacrmroaegeaooeFcfpregenogtekrfunluhlespeorripneieeserte/sieppeldeterlehsirnaraescreyxxra.ssen/oerngopp)hsiinIwooeslwfnn(txrtioonsdaodfcfioohAemecissbeeotnesesntaereehaa,r.rtetdthstesteddtc/hcdelheitaacydahieeltowendneuiteinsenemgutongi(tTidar,ebjynse1trhrnnrotfPeecipretuto3shosaoaeoenhciBhOtac.lu.rtcwurelx(nwt7etdoirt,o1impaMigpplt,hioermem1svdedlfrgostsoesneela.fSsoiiwrhi6yshceecsannugrlguieaoreo1oekepisgndinptre1tcnorvilsnihinmsdeend.nsateirsfs1svegggissinscyogito;eoecnrtrntsretdhn8amnsnnhaoPotsohtioes.i,nefonuteu9egfenfactitonor;ssbtppcehhad.gisr.teyttfnOfaostsleceseteylhahPtttnfyhr.xoah,sheodlteTT<tpr,m,b)timroiwewtgehorft.nuthated0oasfsaoustteeewioewgnataohnhe5irtrniroersrfnhlkdhdnodeeeeee)-./f COMMENT urinsTckhesretraferinotmcyurrlroeennggtal-yrtedrimnexgistestxhpeosscuiherneeatilfttihoc TatpcrhoodaCiundnsDntetasdDd.msitntAuiognadlnattythdthheoeeduasgdmnohicdafaifraniteclharaueegslcc.etoridmeunaTseitttrhnaoionetfvisgnoeedfr,esTpsTfyiaaagCbcrnDtstloeiiucnrrigs1- pfilenoovrdseeilcd,saottghcerieooytuehcppaosrtnowovthmeidreieecencxooapmnoindspesadirgeahdabtunledcinaettuxoionctneehpaxetl mpreaeardstoiiccnaispl athmeisionttoitvrhaieetsisntgupdryoin.vidHdioevwideeuvvaeildrs,enthctoee othpaertataives;eltfh-eserleecwtieorne fbewiassigwnaisficannott cdpiriafefnve-ardelienancgcenesosobefedt1w4emseynemdtphicteaolgmrsoc,uo4pn7sdpiitnhioytnhssie, TsmrerntatsclpiihttveeanooCiouaosfsiaWtdsnndlpDtemdsetee.teodyecDttno^nhthbTwcfc)psseeaooehttseatacouhtnfihsesuargff,dessetrtusnihieitioabesnesciouremltfeadidxteeindposhcepiineaifavcaxloccrtxtatiinnpuheaaet1dpbtlytog4elsfulosolliersuhyyn,sdarieneclsedoaldabltdtsciatinrahumonoigsntoegstmrgwsripitoryvsemoethpaotksehucxuisaomnonorpeatnporsfseounycueae.fswwsdtcnbtsiidhmniaemdemlceoese/soels"esmierffndcaiwcutaanTouirihhtnbcncidmihnhtaaoaallihieeyee-t-l 2 0 3 6 JAMA, April 18. 1986 -- Voi 2 55, No. 15 2,3,7.8-Tetrachlorodibenzo-p-Dioxin-- Hoffman et al dwmeiaptlhlestticuoodnriteiscoafhlavTteh-dybemepeiencntdhdeyenpmtleictairoaentarospanhidny rsDpeTjleeHcetnioarnne,sdpanolydnmsiepnshc,renaroesddeedusc."seu'd"sDceaeplpltroibegsirlsaietfdyt some other mechanism(s) to which pmouriTortolhitgfeeeesrntsas,itgiwnvaeiefrieTcra-nencsoecptlelo-sndeosnefepsiettnhtivodeee.npinotckreBewa-ecseeeddll mitogen, and the greater mean num ThwluoenCawpesDexarDptiaoctisshssemoaducn.inicacrTttloehehsadeuorsm.,mawweliathnheenthzvyeaexmrlupeeoinsaucforcrerteiavstiehttdyoe Two findings indicated possible itno iannfiemctaiol nsthuadviees.a"lsIonbveietnroresptuordtieeds geopplrlhyaxeefaramtpsvervetsoeacdepessaeldehleclledildoolulnyricnlgtprmyahgoterpeeebtrdhnshsoe.aoiee"ropmnnraprIaipstmermnetsioidilusnoaaloeinlndttfdMhedsrseititatomusrsuitefosdeidionpotioyeounc,sbsgroy1as0eiohtewl.nof1tsr1eaetevorTnrsasaxedCtttiiictsiDomohudnDnaugesTs-t, gTfbureConrDuctpDoiofnimsnaaonuyndn-chTnlae-uvacmeerlblasebnru.tienfsfeutchgtgeeosnetxsBpot-chseealdtl fDcidhneheaTrgSomvaHltetosouitgnvdrsrieseihceetsaosrrsslpwaefostuneipsnnldtosredenexsaesspdcensrsa.oei1empts1tat"uorraseriemlbseTsdssuhiettdebaoalyngubmpdetlcenapuhsthhttatfaeoouvornpemlnelrpooanoswunlooyiss-tf ocrosGalssheeatuerfliGvaraggnibugenthrcTrcilimieeeselsnPnistrsnae,isoilicdtiinefcoeamevaanaltnemlltehlsyclihkasneieeannoholfsdoiefietanpigphtuxftfeoefniaeprveptiitoraeQfntoiseilplatcedueniohranvdnaacxynoeziuseilrsytecgmp--.mirunRhbmorTeAeaeuuosfmuhrtSnppfaleteToetsohciarae,oftvaspn,snniat:yhgdAremunyiaLatarri((nhafrTiot2Iidnyees),) The Multitest CMI system was used vainisvsoetshsbeiencgparuceesselelunilttarswtimuasdmyruenapesorfutaendcwtiatooyn bionef immune abnormalities observed in dtnhiodet wceoxenpfsoiinssedtdenegvtriwdoueitnphceitnhtehtshaetisrpessptyuocrdhtyos,lowngaoirs dppcaeoonurrppctiehhoyyuorrsiiflnnyaplbletaevetcertaelasurtsnimoe.nuEtshsateirrnbleyetwohinraetsesurunpbroircneleaitnverdiiy ssoktuairnnedtxaeprsedtsri,zieewndhceiacthnhdaartretehclieraibtrielceaa.d'l9i'"tnogIetonfswtuhares cinagTl shs.terensesuerxopbleahianveidortahletiemstms uwneerefinadd cpparalottdesurtcnaegoeafs tchhoefarfiaPvcCetTeproirsaptrihecydrthiinsotsru."igbhSutitmiotino ing valid data, were subject to exam ministered in this study because larly, although the multivariate re rtinheeesrultfesorufrororr.praeWgrtueilcaiprexacnrltuesadrdeedeardstbhyebetcwDaoTusoHef wpprrooerdvkiueocrutssioenxeppooirsdeedhmatinoodlToligCniDcg Dosfdtuu2dr,ii4ne,g5s -ttrhoie-f gression analyses suggest a dosermeulasttedbeeffveicetwoefdT' cCaDuDti,outhsleysebreecsauulstes there was evidence that they were not chlorophenol attributed complaints of years of residence in Quail Run is a measuring DTH responses properly. asthenia, irritability, insomnia, and crude measure of TCDD dose. It does Although we might have introduced easy fatigability to exposure." In the not take into account the concentra .bwismaieamprseoprlbeetysasnesotnefltteioatchtllineynogttsehtauetdhnsyaaomnt gretarhoneeudvpeofnm,indwitsihnuegbinss TompriCelomDttDoesrmtyiunpdleoMyrsasio,smfsaoeniunndrtdi,imvrcieedhncuatenaanllgtseiplsel,enxrpesscooshsnerwadolenirttiyoec ntatihnaoetneinydodefasivToriisCdl.uDoNafDle'rsvieieicsrioadtnhnetdenalccetethsseww, fiwatrhseeqtcfuhoeeenlnttclateyhmaaosittf cdlautdaedfoirn atlhle paanrtailcyispeasn. tsWewecraenniont trhepeoerxtepdoswedithgrionucpr,e"asbeudt fwreequweenrceynboyt osuf bTjCecDtiDvedoasned,avtahielraebfloereto, ubse.st index predict the direction and magnitude able to confirm these findings by The skin condition chloracne has of the potential bias because the true neurobehavioral testing. long been associated with exposure to crulanutedexespdoosfaerdaenpnearogrttyikcfnioporawnntth.seIwnehxotphoweseeddreesaiegnxnd ceaannrsdeufrucionlngadttuthceetnqtoiuofanlfiutsythuoorufeldDfTiebHled sgksitviunedntieetssot, measurements. TsTeaatvsnCCriAiadDDmPlteDDtCianhn.lTcogeuiasa2gonts,hf3hdsa,oec7btcl,huih8inauhne-itTmedcepaeeadavtalnnrittdalwo,i"cevtsihontetuhxlrcwoeidcrde,ieoeixdfsseprfe,iofoboafumesesdnuencedtrzmssbeouoo-ncptntohhoo-f tTthhhaCeelDroegDlieik.ns"ealnItihteodohhoaidsshtyobodrefyreonocaafarscsbshiegolronntrsiefadiccsnatuenhc,tahtthee"axnisf fcpehoclsotusrraefcrnoetmo,,isToCtrhDeDadclviisenrircseeaml ohmteeaa.rltHkheernceoeff, acmleannutWecinrneieggtyyio.ndbaTestnephhrdreeveescedsraxeesdplaeaosntsicevoediefnllc-gamrarnenoeaeeudrsrpiegagdyytoe,dfipnribenitovmdhtaihe rparrocstephetfeexhrteefshsosepreerpuudemsocooolrlustitatonsnedcsscntds.stsaheie,tourTechgonhgtrsorhehre,aainoucsrdpuassodmyit(,puseeoa,toilggipnnewatn,hdinycoem.eemtvrcaxddeiyalraotetwtleryegrnielohgriemaotenynbhttmdaipeoaivmteuneieilxgttrtstylmhhpirsymsdaeealu)aiintt.psrniicasonohFeoTnirneoterCeDdid,kwtvrteiTDiegcirnbtoHsooiDsyecrytf, dioxin is a potent inducer of certain hepatic microsomal enzymes, esper dally aryl hydrocarbon hydroxylase." gSleurcuumroneildeavsaetiomnsayofbeGGeTviPdenanced 0ofhepatic enzyme induction, as can dHeecpraeatiscedmiscerrousmombaillireunbzyinmevaalcuteisv.i"t-y*0 smhnta-uegsdalyusau,rlarsorenimocbeedneaitncffioedifrn.e1"dun4ir1crieneIcantwrlyyastehaxesfcsoreuespntsrideoednsebbnoeytf tween the exposed and unexposed groups in the levels of u-glucaric acid, but the mean serum bilirubin level of the exposed group was significantly TCDD exposure."" The Quail Run ecisTfpaiepmnlothxlmlhoCuiuneelgttyodDdonreehisrytnisnbdDiicas,cssgtiac,alintsnlaiilhnntotteleyuheosf.ecedfetteuxaxwrycepaelsd.1aovtesmoy5ssnDuiss4dgileenbwoted-ssiefntaanpaexstcspcsirpieeuthoamdeogltndrosohgtteeforhieesdcnaoceisiegcrhtpxnlnapalaaptoeebabchnrhodrkysaatesitestsiucionstcthnrhifooTcinieepeeorsC.artyvttoDhWnherooarotDtiynosesftft CONCLUSIONS The findings in this report suggest JAM A. April 18, 1986-- Vol 255. No. 15 2.3,7,8'Tetrachlorodibenzo-p-D ioxin -- Hoffman et al 2 0 3 7 armdiptmmhebeoupaapssmnyoeutrnreuerthcsenlssesoaeeutnvodopaoenfbfp-TDtanrCcTdsceorilDsvHgrmisenmDniroiricsafneeewailscixlptaalcapiyosneononstndsa;sdussedeiirspnsaqioefrguacfvonenieilatroenodoteswnceneiegdndcTsoee.dCvfwsiiEDttimhrtoixDhnoer repeated infections, the abnormalities eforuedndsuinbctlhinisicastl.udIny tshheoufludtubree,coitnwsidill btlkaaiidbvimmhdennvieedeevdoemmuifrerwimuetlauugionxrlofinnppspctuneeohonw,brtecscfotohrelufatidduosinndnouyeniwcetnvcbpcttaaecttiebaoolilrlwrouruinemntndrefaiiaodrciticislenneneialeprdnoeelaeaorwisscningbaeofaditmsouvcsleitatfpevhrooenriavnerrdtdsTneihagurrdCdtoetaoipoDsclolraaseseenDhmtlsrlisitows.tuvnuohoueildndneatlIildhnnyyiygrs wiLh known TCDD body burden. SosgaWRKRHHlclfostoeoyeraesTlitidibteemnrihpsihskrserer,etltepniyerry.aktkte,,nssaPeraFM,Mtc,ruuhaLe.MHDDitldMlukhRly,eD,ot,eoEeihSfr,nraMnM,easAianaCrcnP,Dndtnkdhewhd,neDyDSrto,BKihPetu,sSaeWMaaitlMDtmndorteDbpepoewbWaerh,nrlresirtRaaoekieeCaprllruoe,nltd.ai,ogsFerJH,dGPhKla,i.onmo,htReaicwCHiMorarNlahaeenlenuc,iD,.rnc,npkdDii,ogsnMnlWfi,,RaPoaEDvtPwhetoMhhibrh,DndelkMiDbeDas,BedcleF,c,drogrmaoC,,CDKnerrMoPbadinaeMmnnaauteriadhurtyucySbrhyaeltl,,, u27amiIaiQstc4anSAlbbpPPs4HTi3indnf1tjnoRpmR13m5isylyel9nnHetiilpo:i:3drgi:9or4u2eds2uxeac,o1orm11m11e1aagsx981e675o4:em3c18a:2ej1ls.nAiioc4ibo737M226n1pespJ.2l0rd.s..b.n..ncukh7.iv5p.ps.stt...m7ddn7l2.x5.iautsscio7aDist;rctd.hioHDl1-J0eIT.6R1id,AlTSUpl3oHcaasenHoSn.NNeiis,cn1SahemHo9of.m--tnae4lno-hnatentzeo17rfr2S6ctbJ8ePrh2ciPeishuaresc(ei(oeaddesmlur9ihlFa8cn.l29oSlb5eysaanc6yuTnsmnytleedlhoozutirf5i.pdo'94uaiEt;mrte0lnrmns1foefltsuemyraz1T7ygTnurrrlGiaRt.T.ipennpeNlim.dpcS9odolunbceoehlo.0snugatonaejepsul.ttp8Heroinspromelve0xi-iPaathcostxnwen)loRato4rschtnJirwlorr:oiiiPNanhmu,RhaAorilsi2,atdnnCli;aetrhnzgoIhciB1angrn1rrisenosiBoM8,stbadlt1eaia,ofpocNe,ei)iRpk3aighLraidxnty9nine:9usbKettnfHoayscalhBl2n:RLS1id:Siltoei-AcFur7mrlarpdiigeenpDtoc2h2:2yK,owataRul!ghotefce41trtoERos,pose.9AhhAnsAerhoiItvgeec3gehs;4ipi,o:rtKyoini3tltn1nKysreaears:mkeeen,ir.c5niovnoeaYaiN7.moMcn1smvsipiv.lnnttlu6atSTuegstuern.erLh2,rfehteaoSpehiooee,-somt8bdyeyLmmaniwaayyr:1laa,rMieseyniuerfra3sp-try.lchnkgotC,ca4rsttaeoootrlCu,bB7re1NtPig,DAuMetSgNn6unMfispgboad1gh6ph9bsuPhNopno-etFr1rpm2cdrTe,rci9ip-Ha5rreircrafeCrIorrnhoei.of,of3eioiogaaoe8igV53HethaseelizbloatnSEm,nSle8i,muiiccenapnhs3c;em,stqdonneRnons,r767r-Ute,eMdrhholsHs;hcHGt.o-hgeueitaTina4,.3toaosd2aepulytrtFv8moSerniai1lIiiYaLorB:eziHitNtaru,lncertm-r2DmiAollrmy9rooc3totnsri,Tciate(dbrran8ehIoe,n8.Sonex,ngrAfSse-fmltmnlu7eC-Kefua1olGiPeogidoemeearP3(Lbthl1npcrd,r(;trufuDauTlnfAditr1iea58u,3tP9Lieearuuouobroianeemvsrnop9dnr.i.h3-b8doeDtUgp:rmlcotlneloxatreoWta8eohhn:oyt1TsseoleneaaeHenD2sptnstni5lnrd)up;ymgasoalD1nrig)ntucirn5e7,zs:aPl;g,iriseedmonl)yic1yifSac-n7ervcoottaJiG:Rpe,,aHgvfeH2yine6heSa1e:nMeyedvcttitamap1hn4ce7e:Be:src1ss4oyybe11trhsa7iina9s9yo.lnpeslit9li1sor,99,acee:tCoNtT4ucl8venii1.rutoce8eih7o8a8iaxtqlne3iep2onatrAee4hdoaoeepmt2na6lJ3dn3leTAryt--L;ght:l-:seff.,l-:;-;: References c2B2CBEnEDapAtsAFsaAPTa1otCpUam1ti5deaz1ICh9a,iilhninaisin35llof9oaCl3ni*ts4oItlsrt2:2ore.2pl:2s22selh22i2o9t2i72eathDiS71ors1mocn:nt-,vm9181oele17Di6vl45eihdvd12371:e0Mike2nnBrx948laeu.gr7eeg.6m.51r.v.nnS..s-Ai5Maeme....iid,9o..iD;auin.Tn.w.sges4t1em8atsi2ng5ennlt,Cu-FRlyVedVCCyt.ceHcn1CRteaKoin/toKHe42---JsoA.ePy1ssl6eoreil1rae-1lyodAlaSeoxe9fdo4sah1dtuabeeoccnle.e19naJddnaa9d5niiwsnresrixs:t1sr9Sen-uornenoa4tttr8rr7caiu8bueikSeIeil1ds,aAtbriz.emh7prvgskAnabcidtp6k4rnengo1mrs0ssl.a.iJse,9ismyiPnv8shJiiioiteas.Izeg;el3etpdl;tfGicimmucn8sTeec5tRGm;o2DudAeciiieuCnnsnDonl0r6KJmhotaenn1dnug3Ap1en6mEeun,uCcrWebE-g-sm1l,se,lA:ncS:R9,riW.pg:7tJplCorK1tMfiouR3M:le1f,cKaeeMps8uMsje7'1Rei,-rDaNuHC6poe9SFrNno2nSn,yrCsLe4Tdeh5Ai31l,rTo8iun0xereiP5GlAchmolg,out,au,s;easm1Vis9iannel,P:iudCR-o3silpic1nhoftoes2urinos-snK.cn3aHtPetdPaCNi3e;msiAxe1to-r7tpobuLgxee9yroreonbciub9why1tui:eet:mis9at6esdnrhll0esrpause,di:6:rafue4gcnslleeu2Alztliy,8nC2ob:-itisurdat7pbinnda.orsAn5Ordtn'kJ2s4.imosu,csMRsny3cmN1rshsehtriilI4effAzhDe9Ts;eihMencattegceo-ea9mJoeeo5nte.(nkyEokpar9Nre6ol:1aPnathyLs48hud,Anr2nrmslrMibl-t.poiEtJ8r,m9srngilJ14mda:neWa:sornlcop,Asp,nmbiZ17eiM8Mt,ARahs2yo,JcapehlenJ,oI-muiL.5rpe5anC.i:cSi7Tn.dpitfedtrtrhCptaDyhnsz:nn-;1rn;tieilide5utiCz-tiap,uv8J4CheltivBpecpru9kiolnooesDDfh)soeai1spl2:isvceMnadTi8r(rP.emlztl5outnxspt1wtknm9at.ttebaos'eavmeeish0ir,e1esyto7stilht8ndcFgtol.Jytiellgi,sacaiPanicly5rd.y-eeeirMaati3nsGpBam)egBblzna2glphiid-eptnnr:yyauE,iucJavg5runh1u.yroamhpinnio:Mapcai2ezeelHpmtegAy2onk.iusonzc(ot.odBlacstAsy,ddtsp0idTTnei2acieWiIidrs3vylBamam,muotuNcmn:er.MJieah4cdeCo.iihlhyan6cnliarfS7vBfDr8asyoDeoeAstaoxtaJiaf9dyDyoRoeItsCoou,o-cssninmwtg:eastLonil8mt2m2Ce.tilSpperuoche,crnDeic,dseebyo-d-r5G,cereeriifJxsist7mJ.tnYe.reenCend4)tdlsg1merreae1Leu0ylc(ECdna1AstJ.ts9scpaseohtiuuyCtr9ecC0tayh9kz,rrcleee7eottmuhxharrned8ntaae.ale7shaeolioiaall4knnonnaolesmmp5y)iennloolndile-l6np:-elf,;n::-l,-,n-f;t;t-f; Je11hIb158HnUJnSpetmDwMDSi41tcDsebDe(tthtnAif9ni:e25eii:neiTya9eae0cfto5fouey3oooyor4ici44i8a4i0:nf4g333pf3iMz33t8e3333lp:rltCxo7oni9s7nrnpnfpo2sn34re2ep12:hl09iz78uy6n52c3a1430ee22aeo7-xxeusea..d..Dcd.p7bgse;.oo...A.y.t,..mm4t...aa-71rari-AAoiAaillns.,t5irrle5Ldnbn14sdan;DsrpCCas3I:cHTvHsuEMuseMEE-SBeRtAF3b7ggoyrge.0disositsr-a1Sie2esseotrro)e6lui052s.ic.fese0nuese.aifen9naae8doaisionDiipamteixu7rpa.58pnpnth.noornisDi8nitmn4CrmclwnaCaCorsnhC.Dtuotni-3voorccosocontelCd2.uLtSetznhet3igy-ehereo.ofcybyniiysimeiepysti:isuiyNG1gnrcnniovne2niniainanuripoo,i,ii.mrrtilflM4vmclitRJtt4notKncuuicmyytn,c.eftrxuaeooY1o(o1.CtPt1eir8iiJ1ieipt,sinleETLa,t2iyreicrt9of9n9snnd:a>oJ,hrn9msBy,aneAraA1,o8o,Ca88MSlpannH,Den38.MyneMMrm,il8tn00e0UrnMrRHniFoeLdDJao1aCinyrwa,Ml..a9riaa,l,,cci7Jpc,entiPPt;sfPvWtmdleeeCsSn,un6eDrDB2ahsiiipipae,psApdeKs,,siabr,t,,ut8,.taioxgs9iapthstppSppeohr-lOn)r,pverntMe.itc-nl:wciyeegS.UoUlhUTrthTcTue1oapttoe1cJPt2o1Mi2ikimllsehcLcniieore1pdrAnrnnno9nlkaptSuiSGiS0i82eroemthiieiselse3Cec7uhngaosdsrcep87Sna3Mldln,iraeJr3rayerl71eeca.cdofd-u1R-ethE-EDEtlbttBanncr-21yJs;9ii2pxrintSku9nlzfrfoe1,1vCfnsBenieimnnaaDfa,,.hJ,9172deaohce8idEhnco:tce1uanvnnnvv590clH5le8piaHSMrl.3GMa,Ciuy3ob,i,nors1l.;.elit.3iaien;aMco3mCic6lotrrrsrrat2Hx9ceeoCtCo4cosPotehrSio2oswooTTi.oTgf5rl7tarih,m-liAtoCoabutoa.ol0ifndbaenPwinndd8ml0l5OOlOioirnmgnum:soutrshmiHnf3mi:;mbmmuef5rIPnhib,31,.cE,trlfopleceu6gtmotae6Taiyleeaa:7ae,oeaiJhnnie.ueemm.aLn1nr4gnlriltoc4DoDgDnAlzasmnponngnrrtta7liA-cCrare-xfnimziLason5eptat-ttalrrer3tA:AoaunroJiD:acaoa1aaed7iynyoyencoDascA7iMuonMCncmtc:f8lll-nM1drMdidsddozho7laJp,ntdnet.Meoy.tehdeefeaA,.sH,llaeeHRPi,PPe-fte:raolcsnnnedneredsdo,emrrerrsleeeuGh,eemrltKpia1if1ts11iolaeloo1ejaocptateoltausl9a9nt99al9afatototyFiFiFiolhrdlfx877ne8etnecttafrr7ntamaaetrweoarEoEEsee2i14ohikiaL2achlcecc8lillddntl-dnr:.:;-l;;::r;r:l::.,;::, 2 0 3 8 JAMA. April 18. 1 9 8 6 -- Voi 2 5 5 , No. 15 2.3,7,8-Telrachlorodibenzo-p-D ioxin-- Hoffman et al