Document L177EgNKOXV0bMwVpJk6dJe7

P' l Telephone: Carol Van Strum 7493 East Five Rivers Road Tidewater, Oregon 97390 (503) 528-7151 Telefax: (503) 528-7105 M a y 14, 1993 To: Dioxin Nerds Re: Dioxins in 2,4-D: M a r c h 2, 1993 S t e p h e n Fu n k m e m o to Jill Bloom, Special Review Branch (EPA) (attached) Please read and supply brainstormsi The attached memo has major implications for both the Agent Orange epidemiologic studies as well as for Vietnam veterans still being re-exposed to 2,4-D. Agent Orange was a 50/50 mix ture of the n-butyl esters of 2,4-D and 2,4,5-T. The attached memo is the latest EPA word on dioxins in 2,4-D. It reports 2.3.7.8- TCDD and 1,2,3,7,8-PCDD levels in two and three (respec tively) of eight samples of technical grade (i.e., purified, not product grade) 2,4-D herbicide, at levels above the EPA "limit of q u a n t i t a t i o n (loq)" of .1 p p b and .5 p p b respectively. It's important to note that the "loq" is not a limit of detection, but a "limit of quantitation required by the Agency and a reflection of the level of toxicological concern." All other dioxin and furans analyzed for were also found, but at levels below the "loq". These data are woefully incomplete. We can't tell which combinations were present in any one sample, or whether all analytes were in all samples. We don't know how many samples contained 2,3,7,8-TCDD at less than 100 ppt. We don't know how many manufacturers were required to conduct the analyses, whether these results are from composite samples, or indeed whether they are compiled from all the submissions or from only one or several. (Each manufacturer was required to conduct analyses of seven samples; the results reported here are for a total of only eight samples.) About the most we can say is that of eight supposedly randomly selected samples of 2,4-D, two contained as high as 130 ppt 2,3,7,8-TCDD; three contained as high as 2600 ppt 1.2.3.7.8- PCDD, and some or all contained varying levels of HxCDD, HpCDD, and all 9 furans analyzed. This is enough to raise some red flags on 2,4-D. Getting the actual data out of EPA is likely to be a battle, because the manufacturers have uniformly claimed "Confidential Business Information" status on the entire data submission. Making a big stink about what we do have may be the quickest way to force the data out in the open. i The red flag for the Agent Orange issue is readily apparent. The studies c o n d u c t e d on V i e t n a m v e t s d i s c o u n t e d 2 f4-D exp o s u r e entirely, on the assumption that 2,4-D contained no dioxins and therefore was not relevant to the studies. (See attached April 17, 1987 l etter f r o m John J. Weaver, L T C O L , U S A F to U.S. Rep. Don Bonker, e s p e c i a l l y page 2). What this means is that "control#" veterans whose occupation or experience involved exposure to 2,4-D (e.g., as pesticide applicators, spray plane pilots, farming, road work, forestry, logging, or e v e n r esident i a l u se of W e e d 'n Feed) w e r e c l a s s i f i e d in the Agent Orange studies as unexposed. thus vastly diluting the results by narrowing the ratio between effects in exposed vs. "unexposed" veterans. Even the limited data reported in the memo -- showing 25% of the 2,4-D contaminated with 100 to 130 ppt 2,3,7,8-TCDD -- would be enough to invalidate the Agent Orange studies. (Adding the other dioxins and furans would further compound the issue.) Calling for a recalculation of the Agent Orange studies on this basis might force some of the actual data out, if some manufacturers try to defend their own products by producing negative data. It's even possible that a particularly nasty legislator or judge could force EPA and the manufacturers to produce the data. Similar data has been held not to be trade secret or confidential business information on the theory that it creates a commercial disadvantage rather than advantage. (This could likely be accomplished through the Freedom of Information Act, but having spent more than eight years in court to get EPA data from two of its biggest dioxin efforts -- the Alsea Study and the National Dioxin Study -- I don't have any hope of getting anything through the courts until it's ancient history.) Another angle might be legislation banning 2,4-D to reduce re-exposure of Vietnam veterans already entitled by statute to disability compensation for Agent Orange exposure if they develop particular disabilities. They are now being continuously re exposed to dioxins through widespread, heavy use of 2,4-D along state, federal, and county highways nationwide, on private and state timberlands, in agriculture, on powerline rights-of-way, and on parks, golf courses, ball fields, school and college grounds, 6tc. (One of the first experimental uses was on the White House lawn.) I strongly suspect that if all the data behind this memo were available, there would be enough for Con gress to force an immediate suspension of 2,4-D registrations. (The scandal alone -- see brief history below -- might be enough to p r o m p t t h a t .) BRIEF BACKGROUND [References for this discussion are available upon request.] 2 19C37 In October, 1980, the Canadian government reported finding several dioxins in commercial 2,4-D formulations (di-, tri-, and tetra-chlorodibenzo-p-dioxins, not including 2,3,7,8-TCDD). No dioxins were found in technical 2,4-D samples. This information was transmitted via Dow Chemical Co. to EPA and to Barclay She pard of the Veterans Administration. On Dec. 10, 1980, E P A issu e d a ''da t a call-in" to 2,4-D manufacturers via the 2,4-D Industry Task Force, asking for analyses of technical 2,4-D acids, and reiterating an earlier (August 1980) requirement of numerous acute and chronic toxicity studies on 2,4-D (including cancer, reproduction, and teratoge nicity studies). In January, 1981, EPA announced it had already begun dioxin testing of samples "collected from the complete range of 2,4-D manufacturers" and that the analyses were being conducted at EPA's Beltsville, Maryland, laboratories. Also in January, 1981, EPA's Research Triangle Park lab reported finding 2,7-DCDD and 1,3,6,8-TCDD in two out of three 2,4-D sample extracts, and strongly recommended more efficient cleanup "for conclusive confirmation, specific isomer assignments and accurate quantifi c a t i o n of T C D D s ." The lab r e p o r t a l s o r e p o r t e d fin d i n g 1,3,6,8TCDD in Dow's 2,4-D process (waste) water in 1979. EPA's "data call-in" for 2,4-D has dragged on for 13 years since it was issued in 1980. In 1987, 2,4-D was included in a data call-in for dioxin/furan analyses of all pesticides with the potential for dioxin contamination. (According to an EPA source, this included all pesticides made from or containing any chloropheno l compounds.) The a t t a c h e d M a r c h 2, 1993 m e m o f r o m S t e phen Funk to Jill Bloom summarizes some of the results on 2,4-D. According to Jill Bloom, the rat carcinogenicity studies required by the data call-in were and still are not forthcoming from the manufacturers; she said that because of this lapse, EPA could have suspended all 2,4-D registrations, but instead found that "the public health would be better protected" by allowing con tinued uses while requiring manufacturers to place "exposure reduction measures" statements on the labels. These exposure reduction measures are aimed solely at reducing exposures to applicators. The required exposure reduction measures provide no extra protection for Vietnam veterans. 3 UNHID ITATtl BNVmONMINTAL MOTIOTKW AOINCV WASHINQTON. D.O. M M M K \Ol li ! M 'l IA TOXIC f; C,AM|7.l(ilV MAR 2 1993 amecor WIVtTNOTKIIOoSkUPttIlTTAINOOIMIfAN*O KBMOjUUfDUM Subject* 3 ,4-D', 2,4-DB, and 2,4~DP and Thair Salta and Esters* Survey of Dibaneo-p-Dioxin and Dibensofuran Determinations. DP Barcoda D188268. CBRS No* 11419. From .Stephen Funic, Ph.D.. Chemist Special Ravlew seotion I Chemistry Branch II - Reregistration Support 1th Effacts Division (H7809C) Throught Andray Rathman, faction Head Spaoial Review Section X Chemistry Branch II r Reregietra on Support Haalth Effacts Division (H7809C) Toi Jill Bloom Spaoial Review .Branch Spaoial Review and Reregistration.Division (H7508) In June 1917 a data oall-in was isauad for information on tha polyhalogenated dibepso-p-dioxin and dibensofuran contants of eartain pastioidas* Tha call-in consisted of two parts* Ona part requested detailed manufacturing information for those pastioidas whost structura or mods of synthesis indicated a potantial for dioxin/dibanaofuran contamination. Tha othar part raquifad tha aotual analysis of certain technical pastioidas for 18 ohlorlnatad dibenso-p-dioxina and dibenacfurana. Tha latter group of pastioidas arm manufactured by prooaaaas dpoumantad to produce dioxin/dibanxofuran contaminants. Included in tha list of pastioidas that required analysis ware 2,4-D, 2,4-DB, 3,4-DP, and tha astars and alts of thess herbicides Severer dloxin/dlbeniiefuran data submitsions for 3,4-0 and related pesticides ware reviewed. Etch manufacturer of the registered technical pesticide vae requested to randomly eeieat seven tempiee of the pesticlde end to analyse by a gc/m* method capable of quantitation to specified concentration levels, or limits of quantitation (loq), for each dioxin and oibeneofuran of toxioologioal interest* The resulting submissions were reviewed for compliance with the 'analytical chemistry requirements of the data oall-in and for soientirio validity. Table 1 summarises the findings for 3f4-!>. Only 3,3,7,tetraohlorodibunso-p-dioxin and l,a,3,7,-pehtachlorodibenso-adioxin were found at or above the SPA log's* Tyo of eight technical 3,4-0's contained 3,3,7,8-1000 slightly above tha 0,1 ppb loq. Thraa of eight taohnioal 3,4-O's contained 1,3,3,7,8-PCDD at concentrations greater then the o.s ppb loq. Hone of the remaining thirteen chlorinated dibanaa-p-dioxini and dibanaofurana vara found at Or above tha 8PA loq'a in tha taohnioal 3,4-0. Data on tha 3,4-DB and 3,4-lOP acids and derivatives of all three aoide are too limited et this time to be useful to the 3,4-0 panel. Tabla 1: Summary of Wtauta for OWorinatad Ptbanio^PloxIna and Plbamofutina In Taehnloai 2a D HwbWdaa Analyta SPA Ibq1 <PP SAP Total Numbarof Taohnleala Numbarof Taohnioala Qraatarttian loq Obaarvad Maximum OohoantiaOon .w w ______ 8,9,7,B^TCOO ai 8 a aio ^ 1,2,8,7,84^000 0.9 6 3 8.0 1,8,3,4,7,41x000 * a 0 0.81 `lA SA ftfcH xC SD . ft I 1A 3,7,8,841x000 ft U M A 7 .9 HpCDO 100 8 8 9 0 o o 0.77 aos 1.8 9.arT.i-TCOF 1 'a ' 0 ftf I 1 1ft,3,7,84>CD7 6' 8 0 0.68 | 1 2.3,4,7,8*7007 7 0 0.73 I 1 U3,4,7,9>HxCDF 80 8 0 1.8 1 1,2,3,8,7,8*14x007 88 8 0 1 ft | 1,2,3,7,8,0-HxCDF. .88 8 0 1.4 | 3,8,4.0.7,941X007 . 88 8. 0 1.1 1 1,2,3,4,8,7,8I HpODF I 1,2,3,4,7,8A HpCDF 1000 1000 i 8 6 o o S3 1.8 | 1 U n it of qutntitPon raqufrad fay tha Agonoy and a rtflaotion of th t (aval of toxicologic) eoncam. * Ava raga 0 .07 ppb, w fatrt 8 0 * of damenatratad toq uaad for ahtfytaa not found, * Avaraga 0.63 ppb ; wham PH of damonitratad )oq usad for analytaa not found. i TO: Carol van Strum FROM: Tom Webster DATE: 11 May 1993 RE: 2, 4-D Dear carol, I have made some TEQ calculations on the 2,4-D data. The enclosed table shows the TEQ estimate based on the observed maximum concentrations: 2.7 ppb, We can't tell from the data whether the maximums for each isomer came from the same or different samples. The true average concentration cannot be calculated from the data in the memo. A lower bound on the average is around 0.39 ppb, calculated as: average 2378-TCDD + average 1,2,3,7,8-PeCDD * (TEF) (0.07 ppb) + (0.63 ppb)*(0.5) 0.39 ppb .1 The estimate does not include any contribution from the other, isomers. Although the authors are not completely clear, I assume that the average concentrations listed for these two isomers in the table notes are the averages over all eight samples. (Hots that it is unclear how they have dealt with 'non detects,' Sometimes calculations will use half of the detection level.) It's interesting that the 12378-PeCDD isomer dominates the total TEQ. Has this been found before? I haven't run across 'logs' before in my section of the j. dioxin biz. It does not appear to refect the analytic chemistry, since concentrations are reported which are far below some of the logs. Instead, it appears to be some regulatory (reporting?) reguirement with an imperfect connection to the TEF values. The logs are higher for les'- toxic isomers, but (with the exception of the hepta isomers) not . oportional to the TEFs. Of course, a rational' regulation m i jht be based on the total TEQl Note that the analysis leaves out the octa isomers, isomers which now have TEF values. Perhaps Cate J. might know where the logs come from. I think you have a case. Good luck, Tom. PCDD and PCDF in Technical 2,4-D Herbicides 2378-TCDD 12378-PeCDD 123478-HxCDD 123678-HxCDD 123789--HxCDD 1234678-HpCDD OCDD _ Observed Maximum TEF Cone. (PP*>) 0.13 2.60 0.81 0.77 0.88 1.80 2378-TCDF 0.1 12378-PeCDP 0.05 23478-PeCDF 0.5 123478-HxCDF 0.1 123678 --HxCDF 0.1 12378 9--HxCDF 0.1 23467 8--HxCDF 0.1 123 4678-HpCDF 0 . 0 1 1234789-HpCDF 0.01 OCDF 0.001 0.27 0.62 0.73 1.60 1.20 1.40 1.10 8.30 1.20 SUM TEQ (PPS) 0.130 1.300 0.081 0.077 0.088 0.018 Amount in one pound J u g)_ 0.059 0.027 0.031 0.365 0.160 0.120 0.140 0.110 0.083 0.012 2?74 1.25 SOURCES; . TEFS: li??SUre to Compounds. Concentrations;^USEPA^ (1993) . Memo from Stephen Funk to Jill Bloom. NOTE: ppb=ug/kg; 1 kg=2.2 lb. zrh^b) D E P A R TM E N T OF T H E AIR FORCE W ASHINGTON, D.C. 20330-1000 OFFICE OF THE SFCHCTARY 17 APR m l TWHhoaeusshHeinoognftooRrnae,bpDler.eCDse.onn2t0aB5to1inv5ekser w"*1 Dear Mr. Bonker: hAmaiirvsecFohonTarchdceiespp'tsirisoeRnvinaiso.nruceshphlyHeratbnoidcyiodSueturedmxyp.oosstTurhreeecoeisnbsvtuieoinuqrsualyiirsyerdeiqnuabbiroeeuhstaflufthroetfheiMnrcrc.lulJasorioeifniCcoaoftleioincnodnitvociedaruvnaoilnisdgwathnheyo SdgRtatvohrEcaaaoetltAnipuuedcRsipahlwlaoAolfcntiyHofotu,chrmbathilhnonicpCrovHadotaro-dehmar1irlmntiv3pasideae0oaradnsnesrpdatirinesiinnoorrchotnociroststrusmhpoca.lcerodafoalltlEo,nlyOyabbatiAnrdfecumifoghmtrilcamsHFwcaetoscaoahetnhdorroreteecfebrrdeh,iomtcabhlmCiwddaeegaieetttrcwpndShohOtoiuieucanetrerpahidgnnaslieninmbrxotggyentoeehsmmdteeGCoiaoabnnraeteRedcnptrShhoeatoosaiernsuf.wiracntsblahih,,tniewrhSUatHAeehsSanria,tAregtnrrAeFFdtaiaoa,eoscnlrireaagstc,dsreptrve((oSaraiivnsnEateedSkyAtlieeet)vaorr)hningapdagdaeneuttnarhajdnwaioslnstbthi,tt,oodhowneeees.tshevegc.noerc..lvso,ouenEwpprdTtaiieerlnhcrooihgnaeetl RcRSgwmoriaahnaonnnouictnccerphhtowPaa(lieHs9hHnr,yhae9efasiodn8ngird,2cdnhaeaeoeetrlrnrtoasdetcwdixaahninralsic)otdmlhRipunwscoadcaotunelwhsnutcdehtdeirrdreoiasedeHnaltnsegmaitntiniivhenfwdteieeehan1erdse9xp.t8tahaoae5nnynnW.d2sntsi,iuhIci2ctvnaaio6ilelplie9tampiemaptRrxeolholoaadryyvrnmt,sibadcifaiclhoediaptrdiyltoHoeynrtecrahtexeidniesoapdaicnmootecoarnrontson.ritwfsreatarocnnsoteldohlimvtrecagemaonrdsdnodatetuuobirnpdmtyoto,ylals,ytirahnaienmesnledadoRl1roerog9amctn8enatl2ecltyi,chhdtosyeameHnfcoldpdeaoraacnn2trtdeta,ira3es8oroc0-lshi9n9ss. yaeuoyptinhoxnossakcuepeuri)beotd,diriostecneuwctFnithqiprovootteuahrigrfleneitrgiasytaolortsotlaneuo.euthdoupstroeu..apsrc,tcisbcn.hWaAtuifomncopshirdaeTeidpmlntexeahaisttoatiredestntiwnian,ottsoiinhaslaidflv,neaoebrdtnywnheeosqeem.tuauahieirsTslnnesaeiuhtutdivraitemnoeiprbaoneyrbylaxnieostpesraittvnevohaieorragscerefvulha,ueirceclcapielodrnetsini.iscdtosatwlieuiancdmTeddatreihieleisernoeattimgalincdocdihgieaglavaednilitRdslditaytceheaasbdendwtlsruciiheimeghrrnainniecktnadHhliodgatfpeiaotlchoenitwaviahoidnsnnsefeeutltsryhbroedeevifhaseaiyna/(fnthlodvefhueue.eegsarrtnuht.beg,iemteneoxohencmptaconeaoogmsaolsnecrfuebtolirirzdelogfeoelteiafedwsltrcdeiwdetamatfeeehosatndnaeeers bcRtitHinshhoyaaaiosnaSntnphctEdeptheeAeTrtorhma,1Hihsnet),epiba1.tnn7tumagio3dtSntfietogiloaRrnimtutscahatrahenowreecysee1dhpsxe5rtesepeuHdtcpxediagiapermaytrnriealo,ecdarsnseeitnrstencerleounyestpdctaraoyoiehnentfvetsdcdeeeftoroimhn1tcn-roet,aepd5stst8uatcteta5holcishmntececadetuadosrixRtmonopebxblatdourieynngsolecuarbtlnhosthrybiueevowmtspHedhhCaytaefotdoeneocendlbhtotaatuaentilrvgtorrtdhercorseeorovfncyuefleoolwprigrhmbf.i/refasyoDypdutuilpimb(epsbtNptleh.eoeeoaoeeodrstndeeetaxt:cehppCatxeoeusoprssaTnqouasltusohyrreneeeeodsxnoltdpeAift(aolooCiynsr1oDsunh9trCaeFh0reriee)o,rbprrRewiooc.carttehinhhtdieAcaceedihhnrsst grptclRtetem2ehhoerxxoe,aiao4paopprnsnrnnut-oucoofhcDeperlrsshei5ntuur,eS.coeetrritH8difypnee.s5Vewesoacfeatai2.eenrteg,oplorr,ttldr1ueyseitfaheen3hrdrhtrge0(egceftse1rerehl.rf,bedwesndor8ebaaaiaeart2ciisttdpcy5Oidcaeftdiisaroirdongeendniotxeossuhsyanttisefthnreryleihnioyneashusteft),lnRotesssrahereteoiaado3tadbhefltnd6telhiachicb8ih2sevohstihey,erodue4rbpertehrHp-ruboaam.eDibehatsilgccirsna,atohecliicunnderHdbnxeieddaseuseploecnsre,tleftorliateyvsbtirt8tcxeelhuiheoi5telxxpcbarupie,ppiaoneerdospoosnsetcaerehussn4eodytouuerro6enOferrc9dcetti.feeeacxn4hri.nudgmp6a7aIrt9uapn2otttiehy0rsgaAnpdoessee5etah.odaifsdtotroypwUeoanatutsAtedytehanroalrasdsodesielc2lrt2eeaos,nbab4,olndeRf4oeeyp,tft5,atst5o5eSns-ni0aio2x-dTn.ontcT8n/pfaigh5t.tryoe.Bt.0ectedsoyhcoHusofIeNtnrnrcntlaaihestyoeinnRrnitimfndsitoaaetaioeecolnptdcnesrryedatxdcseo,hrihprsipvftietteo9enhieir,pdv0sHsgr2ebutuoeMc,aii4p.rrtaemcVnhret,leni5.dediiarTtse-dieieOctsTnthroseefwse,idnfmmgNtietnhhu1tnooanhna0arrrmoos0doaeeeertt, olgVP2pstueehtrpf,sehiui4reoresiido1,dustsl58iuoysoerp-lngNmTefyIpphnabeiaiy2noimroyncne,avesl4oda,soose-tn,rsn1grDhotset.eihJ8eccasysaeocsacetspyciufilaitnpmonaprsg2enwnwctsaa,ru,te4tietcrotitde,rhoooeh5fVydernnle-22TiatagseOn.,,linlrt44onikodekc,,tc55uxiNoenei--ppTvnslTaaTyoiphtmwssi,saisecieusab.c,trtixirhetsintpadeonlehwgResounteipvsrtiannerufhoeiespegnierrtleclogfraeraorere1lbolrpttdef,lihep0efcyfecud,e0eeoricdr0cartemVs1eadtcmdo-,kccisi0nsesioebeop0ltcinpniyfyn0rtlttaNaeadr9atcsracyaooi0bsoyocremlilnasnbsdfpe,itttee.oeccrerxarawfoozoprcttlenloeseihoesruoxfa.nsaolplnushidtt.co.raWttcsevoTo,uiosoinsAhnrnarlabeygecntscyrcestdciuooenrbocclmaewesruaoltdeehmhnsnuwndeemettcounerencicfroceloootletixltyhtrsinnphaosedtoernttayrihafysstrooetpeiedluioydoeoingniwdxwcnerdspotileeo,dtdoonrdureessaipsauni.odvipdgnrfiftere.oero,learxotttaenhhmi1ttanddooy8eel pnccmooooamnsngsscminiobdiTmotielunhriptdeeyldetiaosA.nttiohtaralblTtFRehoaoonrenbncocseenhbecraoHovsfHmaeetltaapihinnloletidenhaebanrelSrtsset.teupcpdocoiryondMtntePrdmiaosruccloicskolttanloeosacodsgorwiieflicnliaecfdaletuhitgltisliehosytsnuerrddeaiigbeslaipcsearu.ossdsst.seeoTnhsftheieaasttllhtuAhedsiyeyrlkeiobFcnritodairoscmencesaolrbHaceinuaedlashaltettdehahduletehiSrhyttueoldriktyehtehaliinyess 2 t^ s - racetthheoptoceenidemtsioietvnipmuWceupddieboioytsrohl.ottmiufhgTbnetiyhsihottseueypsuerhAhtpevoaarioirvvvsheosesFaircbrvaosrelneruevicyntioeiennefwHuixyesreicrtodeehotfxphsetttherihritioeemsqnmRuapeaeepronslaoiytfcndtihdooeptncmrhNoHsoei.luaoa,dgnllaoadoongsndfiagSsktt-twhsitu,eeidblrnlymRrociaehoonfnaetcshtpyh.ieoindruHueSeameonoprtdimihodmeleSeoitemrgumoidiocfobyavleletoarhrcnssefadoiloglwlhfwsottoowyuruoadl-ldusudy'rpstwhhsaleteoesalnascftdeofuvtimnhdoegeyner the adWdietioanpaplrecclaiartieficyaotuiornpeyrosuonraelquinetsetreeds.t in Mr. Cole and trust this information provides Sincerely, 4gn^' Attachment JOCOofHfnigcNreeJos.sfiWoLnEeagAliVsInlEaqRtui,virLeyTLDCiiaOvisiLsoi,noUnSAF 3 4 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY Reply to Attn of: ooo OREGON OPERATIONS OFFICE 811 S.W. 6TH AVE. PORTLAND, OREGON 97204 J u n e 4, 1993 MEMORANDUM SUBJECT: FROM: Preventative safety steps taken by the Oregon Department of Agriculture (OSDA) in the use of the herbicide 2,4-D on private forest land in Tillamook and Lincoln Counties. Dan Heister, FIFRA Project Officer USEPA, Region X, Oregon Operations Office TO: Senator Bob Packwood Attn. Hance Haney Oregon Field Office 101 S.W. Main Street Suite 240 Portland, OR 97204 In response to Mr. Tim Sill's (Senator Packwoods' constituent) concerns regarding the aerial application of 2,4-D on privately owned forest land in Lincoln and Tillamook Counties OSDA has taken the following steps: 1) Worked closely with the Oregon Department of Forestry and the involved aerial applicators to be appraised in advance of the specific sites, the weather conditions, and the time of each application; 2) Dedicated one OSDA inspector (Richard Angyal, 378-3776) for the purpose of consultation and coordination with the involved State Forest Practice Officers and applicators regarding label interpretation; 3) Offered on site OSDA observation assistance; and 4) Responded to any complaints from the public related to the misapplication of herbicide during any of these applications. Under the law, OSDA as the designated state lead agency is only required to do step #4. In summary OSDA is aware of the public concern related to these applications and has done its utmost to see that each application followed the letter of the law. At the Federal level the USEPA still has 2,4-D under its Special Review Process (mandated by the 1988 amendments to the Federal Insecticide, Fungicide, and Rodenticide Act) and is considering new data related to the herbicide's possible impact on human health and the environment. Ms. Jill Bloom (EPA HQ, 703-308-8019) is the Reviaw Manager for 2,4-D and I contacted her regarding the status of the product and the implications of the National Cancer Institute's (NCI) report on 2,4-D as a possible carcinogen. Enclosed please find a note from Ms. Bloom addressing both the NCI study, and apparent inconsistencies in Mr. Sill's article which cites the study. Also included in the attachment is a summary of the NCI study. It is worth noting that while Mr. Sills concerns regarding the perceived risks of 2,4-D use are shared with many other members of the public, the product is still registered with EPA as a "General Use" herbicide. As such 2,4-D is legal for use in the conditions described above (provided label instructions are followed). The spraying of these areas has now concluded for the season and as of the date of this memo no formal public complaints have been received by OSDA involving any of these applications. If you have any questions or if I may be of any further assistance please call me at 326-6869. cc Floyd Winsett, USEPA RIO Attachment S-C3-93 0 2:40 PM FROM OPP/SRRD/IO A) Pt * '' (& ; UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20410 OUR Pfi; ( T 1AJ ArlL_ lV FACSIMILE REQUEST ANO COVER SHEET Fl t^p or print in blcV ink only M r COIPOP!ICIAONPOTOXIC susiuxe SEKD FAX TO: EAMEiJ^Jiskrl Ofi ^-cu w\ X.______ FAX PHONE NUMBER: (S O ) ft7 fn-iTfig t OFFICE PHONE NUMBER: (* r & ) 5Zfe FROM: NAME: OFFICE: OFFICE PHONE NUMBE! OFFICE ROOM NUMBER: KAIL CODE: /% . PHON f703)*38-00to PAX (7C3IOB-SOA1 m) JILL BLOOM Review MANAQtR spaciau Review Branch SPACIALReviewAND ncRCaieTRATIONIVIAlON(H7808CI oppicc0o1p MpeBbTtRiRcBioTb,pS.rwo .gram WABHIMQTON. D.C.20AS0 DATE: < W k . V I W NUMBER OF PAGES (Including this cover): U PLEASE NOTE: EPA, SPECIAL REVIEW BRANCH FAX NUMBER IS (703) 308-8041 PLEASE INDICATE ANY SPECIAL INSTRUCTIONS I 0 6 - 0 3 - 9 3 2 :4 0 PM FROM OPP/'SRRD/'IO JUN 1993 Note to Dan Heister Eac(SarPnteiAnccealrect?oaiI"nrn.cPtehalelcekdHweooahrodadrlvie'gesshtcltrooiHocvtkeeeerrddalle2dot,)vt4.ee-rDrYttoiohnueMlismgru.hamtBtemrorofiaaorslktiszuse,yddoiaeutshhsateehnnaSdttew-ncsroahittnotowceren'rsannciloinontngek,ctebThreeontmwuaseseSe"inolwl'f2sh2,y4A,4-hpD-arDsilanni'2ntd8Oregon Sm2,e4ins-iaDmt,opraIr'nesbsde(spilwoiaenhrvsiaelpelethhtfrhtaaetbseyMSdetr)nh.aqeStuioalerrls't'stsiicoaclnerotnimbccyleaerycnpopsrruerasterectenthitnnisnoggatstnwhioniintshabeocemcututtiersbriamatpespeisrar,senpcsdsoeircuortnnievsbc,eta.irlnaegIfnecwtrehrideilnl pgaidctdoturterhseseotnhe aanpdplidceattaioilningofthFeIFARgAensctya'nsdraercdesntfoerffroergtus ltaotorreydauccteioenxpoonsupreestticoid2e,4s-tDo. the case of 2,4-D, bsHtIcM1hpna9eoaaesnl9odttcr2cingiytetfugkshriOcttiieOunentr'ecdgB'ef(rssyNtriptwtliiopyniCaeqamugrnpIustb)pieeao.cilsohnniufspodsDlohtuamlhfeerrtfde.hfatwichaOcUbo(ethiNyenn'oBtnAcihHNvtreugeeirCLieesrnnEenn)IsficPoiti2tinynyrshA,'4mastqao-htpDaup2feratpo,Mi4enHtoall-ieennacDoedlatnaetttctdcaohsooaalsreinn2lrgsiisr,cavnha4fieklnty-raanDoioHnwntemghddgeneeernsxSmtat.hptiohlcwadaoeiDnetotslyaviuy,ra2ra.ra,tcle4SZiZusoc-hsaatuaDleoeehthnsemsmthaairmn2rdaice,sedoie4rssnifsn-ettDqtiaatoaohunstptneecdoerbadamtoNleienlcnreyedaceinnsetsscakitrseiosss.tenudoeiaonsbaaftftlgjtfnaaere-ConcirebdntiayenOue-nedgctcceidetdtdooroebgtdsoer ' misleadTinhge: following comments attributed to Dr. O'Brien are inaccurate and/or * The carcinogenicity of 2,4-D has been tested in laboratory animals according to approved EPA protocols, but those studies are now being frtasahtenuueptdlietceiaeiaoptsrefaldwitteihinrlaelgtsbAthtuehigdgeeahinev"escaMryiwldaaoexobrrislmeeetshuni.nemotArMepfTgateieorsrrcltferhorearaxn1mttt9ee,e,9nddb5s.uDiavtotebsheaei.ncg"aahluyTessnehisoe,ouEfrgetPhshAuedltoddssieefotfseif,crtutmhhlteriynoneuinedgwhthnaot * Tgenrhoveuirp"oEncPmoAmenpptoaasnleeadl"dvocofocenaxvcpeyenrgetrdsounoponsm.AinpTarhitleed1pbaaynndeglo2dvwiedransnmoatenndtee,xcitineddrenuasthtlreayrd,evuiwsseoarrs,yand insufficient information to confirm the cancer link. The panel preliminarily |?S~a 0 6 - 0 J - 9 3 02-40 FM FROM OPP/SR RD /K 1 2 sihsdapueiemdnctiateihnfsiase,ttdet.tshhteeeTdlhe,aepbaionpdrdaeamnttoehirloa'ysltorangeniopcimomdraateltcsahdhaawotnuaeilrsdsmehbwofewoearaekdvclaaytinlhasceubeglrleigncewkastiuwtisvhaaeinstiooiamfntmphcrooeounblltidanhbk.bleeinin the * Tpehsetic"iNdCesI arnepdoNrtH...fLir.stIphuabvleishaettdacinheOdcatocboepry1f9o9r2,y"ouisrarerfeevrieenwceof(Zstauhdmie,s on SRbisdne.eieHtesesiel.nr.iabega5ses-ne2trei-d:anyc5legal4Byn8ldia5niaoniSadrge-c,as5c,pAm4uta8.rean8adldiSc1gyf)9ndr.9aioos2nmTg.ttshhtPledeyheomesssnuutpai'mmtchbimgomsdtmeeraatsararcNyy.atHnaoadtfLntrdt,nihbobecnuuo-tdtnHeodttoeghndtesotygtskuDdiodnorfy.'sgt-Ohtelhiyt'sBemaprndpiaeohpangoensmraa.wplaop.eOgeroaeCnureanssnotctoer iiicbMosnnnuatedfthuomcoeierasrvrmreeupmisdsratsuaeheruotatairbiztalonhsetcnmtideoa2ornenno,ei4rnfnt-ioibwtDvuts2eehe.nc,lr4ecyadea-L,ueCDntmirskahnesweno.oetrctehaATeerblerleghneeReasernupltegeicbmisvaidyesjiteaieeitwvcdwmretceihdsedhiyodcaanlaaaronbosregdeytftisiihccnbatulhtdyreshmeepitnautaahnedgdsnxaisifpotsetfe"soifpwrc,rsnauriehttnaoalhiotllvvesaetissaedos.ce"dsereoveudsxlcittTispiuimtonahhodrytisoeiyi"neuosamsneproteaafeosisnrntstauethetosodlesonipopaepseneosgteucsenotisdnfrhiyitbtecsolier several studies Is not necessarily a "smoking gun." adoisnpsifddetduahtiskhdeteirerrsyDsesrrrvaei.eemdsprZeeearana.lerthscioemTfhfine.hhtdpeaeBsrtrtieeyhvspeeielneisanredwtwriae,vshfdiafdoaidltutihvaaaNiedtlsisCodorrwnreIyes.seus,prslTaeetasnwdnidneootlvfhIoimehttdeehepdoreeanrtbrn'itenyehsbglietgsehadhlerimildecyAvhusresgoebtestenibhpnfcaeeoytcproteutbephbdeteelhc,nicaepnutaoceosnonxeme-ttiehlonrmewfdneutpaahnslsutetbaruplydinimcevdr,ripuesiaoosolyenrdraydtsar.pcnthhacAeenelrelsl, influenced by comments from industry. A good number of National environmental advocacy groups were invited to submit and present public comment, but all declined. My guess is that they lack the resources to cover this issue. vipcqvtmhleieueeerspoawitftroAi,yecsiosgitendhefNdgDenepsorwctonn.hyohtoaeZneehntnanoagftthsafeihsaminetttnlhahoottetc,ateeoosas-xpnrotnsieasffcadqln-iiyattucehidyrtlniseeirogso-eetoardfssturfh2tnaniia,mnr4ottceet-tmoetDshuarrtuirencenndeskigovtcAontetewoglgorsyweuxsitniiinahltcdecyoniedytt2dlyegi,wx4tneratt-eeeekeDsaapsnentkossiamynerirottngeaohenndfefctouhaotrarfghemeacee2scccnpu,tuas4tlularrest-ra,csftDieeitnan,geo.gnlouftydghair.neareandttgAleisilrcrsdietedwtdrqsyiaetisutsncid.imlotroaneasttMmaaeeilnsdbrletyt.ania,nasStinegniin.lcdloofEoawuWfrllPesdhorAiebl'ese 0 6 - 0 3 - 9 3 0 2:40 PM FROM OPP/SRRD/IO 3 rrai""duccseeaatiSesmtslarnetpaeteccrmemthriiieicntvmcairpsinoateztiiCgselraointntneirnRoasoentgdknnsei)sihbtdcvt.fdraeioiaoateecznryIrfwshagdefyira2e"fgfdaoitn,cntt4,roiasg"ehas-.neDd2attascfh,z;hi4Unetanetior-tsrondDhivdncilareitn,eltedihaesesgawadexssknndsriso/ssidptbvenifthavsieiesscwseten,swotartierwuriehtrlficylinebiceoiitvtrtdsunphhmieaeteaaeaeen'swnunsdrsyarseosrletodoltntyeaoerfesqargsmitebiuosntDesphnlaortemrtoernmto.arttruro2titiZidifsnis,syotia4kebeksnhs-.bestDcwtmhlymhriaIeheie,nnlcbuvearadtestefwithuishthrbketstebesphhseertAeseranc(settegaatc"eocfeesnaafwieepnftinddenesp.ccoiceiybegetotfNsihreetfait2nhtdseit(a,ceeexwo4citftu-dpfoicha,DtreeaeesrtbsS,nv)theptrhipncwiedbioceeteneelesilrAcygdlnefiaoagseocaartrrseerliisea"oesnsRunknnectssooseyaesvtfodkiwrintotieonhigwwlglen.trhee itnhethkisintdypoef aocftcioanses.uggested by the Senator's concerns. The statute offers little latitude iwdsrerdptimmhuaxoaaoilonspdtstpplpaessgoellbie.eeenesbinmeumntlcoTysrThweceifqehoananhrrulennertttaeieoatscgbstsusoitAetenteoinlfasinoltgomoe.tin2eguncinig,enenhtg.4Iohoncta-vhfrobyiiDnToncyaowglih2dvrutterpiy,eiiehdn4sedneeget-tAngaaaDesifatsrsnipgsptntyultdaerrptrsdsyneacrorptahwtecopahfiedsyeodoneenetdnrrrurbseotieescixdceya.opdttplnbanpuiialooteTeaocnaavnhsobahrdcuesifltteecndrauilhol2odestaneu,aen.ts4xirhnnbstt-pecyaoTiteDydtoihtsfanhetusseontgrateudchhet,iryrtsuscegoe,ie,ooliaftwesppmnwhrrttuhuereeahhpmadbebneneientullnderiioileocccaeiwtttxtncswhiiaptauoaesoheniouotrnmpeiddueslordeusipleenpstndrgrdchnotdeoiohobetsopigevfatrnterrrunenesgaiabrstdbmumnibeeeuteasdrtahyptclssrtietceunttefiioonlhhoorbcsyfmarseunlmuist2abomeetdmit,mtnerxt4ehutmvrp-eseieenaDesaodpddsciassrtoituuutoybeirbboocrrqnyayrinaeeunrobst,oiytgha(rohftadeeuhentdtahddteue risk) to neighbors and bystanders is more of an unknown than the potential for applicators, but some of the measures will have direct or indirect effects on neighboring lands and people. The Agency used the findings of the NCI epidemiology studies to work out the particulars of the exposure reduction program with the registrants. I'd like ywtsoueiagtshrgtsoeruesatstnstldhathauintantdssietimhtruiopnaslgteeiofsmnitrsuestdaw,sieghusrereresaesut,gltysghueelcsohtpworeaitrsseknnrsitosifkato.lrrefiounrsdiienvxgipdcoulsaoultshreiwnIhgsowveaorprypnhlidiegudhr.i2n,g4T-haDpeposlvtiuceadrtiimeosnaanlyso PackwoIohdo'spoeffthicies hreefleprss. toIs?thCaatlhl aifndIwcarnittbene noof tfeurtthheeratatsascihsteadncceo.rrespondence Senator Attachment; SJipllecBilaoloRme,vRieewviBewranMchanager Special Review and TOeRffleeicpreehgooinsftePr:aets(i7toi0nc3id)De3iv0Pi8sri-oo8gn0r1a(9mHs7508W) United States - Envi'onmontal Prelection Agency Press Office (A*107) Washington DC20460 Environmental News rrr/,:. EPA ASKS FOR MORE INFORMATION ON HERBICIDE 2,4-D R-75 FOR IMMEDIATE RELEASE TUESDAY, A P R I L 29, 1980 O 'Neill (202) 755-0344 Barbara Blum, Deputy Administrator of the U.S. Environmental Protection Agency, announced today that W the Agency is requesting additional information from manufacturers to determine whether 2,4-D, a widely used herbicide, is safe for humans and the environment. "We have made this decision following a review of health e f f e c t s studies of 2,4-D," Blum said. "The review showed that significant information gaps exist on the effects of 2,4-D, preventing a definite conclusion on the safety of the herbicide. "We will ask the manufacturers of the weed killer to commence the studies to provide the missing evidence.." m Blum said that if the manufacturers fail to notify EPA within 90 days that they will provide the necessary information, EPA will use a stringent new provision of the pesticides law, Section 3(c)(2)(B), which allows the agency to stop all uses of the pesticide. If the manufacturers comply, Blum said, EPA will allow 2,4-D to continue to be used while studies are underway. However, should any of the new studies demonstrate a major health or environmental .problem, she said EPA would then take appropriate regulatory 1a c t i o n w i t h o u t w a i t i n g fior c o m p l e t i o n of all the s t udies The name 2,4-D refers to the phenoxy herbicide 2.4-dichlorophenoxyacetic acid and related salt and ester forms. There are approximately 1500 2.4- D products which are used to kill undesirable plants in home lawns, forests, right-of-way, drainage ditch banks, rangeland, pastures., aquatic areas, cereal crops, sugar cane and commercial turf. \ (more) ^ K. IB. 11653 H -2 Basic manufacturers of 2,4-D include Dow Chemical Co., Midland, Michigan; M o n s a n t o Chemical Co., St. Louis; Diamond Shamrock Corp., Dallas', PBI G ordon Corp., Kans a s City, Kansas', T h o m p s o n H a y w a r d Chemical Co., Kansas City, Kansas', A m C h e m Products, Inc., Ambler, Pa. "EPA conducted its review of health-effects studies on 2,4-D because of increasing citizen concern about the high level of exposure to 2,4-D around the country and because of its chemical similarity to the dioxin-contaminated herbicides, 2,4,5-T and Silvex." Blum said. There also has been concern because 2,4-D was a component-- along with 2,4,5-T-- in Agent Orange, the defoliant used by the military in Vietnam. Although never approved by EPA for civilian use in the United States, its use in Vietnam has resulted in numerous c l a i m s of a d verse h e a l t h eff e c t s -to A m e r i c a n m i l i t a r y personnel. These claims are now under investigation by the Veterans Administration. EPA, about a year ago, imposed an emergency ban on many major uses of 2 , 4 , 5 - T aftd Silvex'. M o r e recently, the agency o p e n e d hea r i n g s to determine whether all uses of these chemicals should be banned on grounds that.they can cause cancer, birth defects and miscarriages. EPA's review, of 2,4-D studies showed that the evidence of adverse health effects weighs far more heavily against 2,4,5-T than against . 2 . 4 - D. "For one thing," said Blum, "there is no evidence at this time that 2.4- D conta i n s any f o r m of dioxin', the c o n t a m i n a n t in 2 , 4 , 5 - T > associated with cancerous tumors and birth defects." Blum stated that "toxicity studies of 2,4-D have either showed that significant adverse effects were unlikely at expected human exposure levels, or they were inconclusive, or they were not conducted ~ in a m a n n e r a c c e p t a b l e by toda y ' s s c i e n t i f i c s t a ndards." & .At.this point, she said, the agency, while taking no actibn restricting use of the chemical, will, require the manufacturers of 2,4-D to provide additional information in the areas bf Oncogenicity (tumor-inducing), reproductive effects (particularly effects to the fetus), and metabolism: in animals. She said EPA also plans to conduct certain reproductive studies on 2,4-D in its .own laboratories, while awaiting the industry results. In addition, EPA will consult with its Scientific Advisory Panel during its May 28-30 meeting to determine if there are additional studies necessary to determine the safety of 2,4-D. Following the findings of the Scientific Advisory Panel, the agency will formally specify to the manufacturers what studies are needed. Details of the agency's review of the health effects information o n 2,4-D are in the attache d fact sheet. ... . R-75 #I# 2.4-0 FACT SHEET I . B ack ground 2,4-0 is one of the most widely used herbicides in the United States. There re approximately 1,500 products containing 2,4-0 registerec with E?A, and more than 70 million pounds of the active ingredient are distributed annually. The term "2,4-0" refers to the phenoxy herbi cide 2,4-dichi orophenoxy acetic acid and its 35 derivative salt and ester forms. 2,4-0 is used to control broadleaf weeds in a variety of places including home lawns, cereal and grain crops, commercial areas, commercial turf, rightsof-way, and forests. Public concern about the potential adverse health effects of 2,4-D has intensified since the emergency suspension of 2.4.5- T and Silvex in March 1S79. This concern stems primarily from 1) the chemical similarity of 2,4-0 and 2.4.5- T as phenoxy herbicides, and 2) the question of 2,4-0 dioxin-contamination, especially contamination with tetracnlcrodioxfn, a manufacturing contaminant in 2,4,5-T, which causes cancer and mi sc arriages. Oue to the chemical similarity of 2.4- 0 and 2,4,5-T, the public has expressed concern about the potential for cancer and miscarriages from the use of 2.4- b. There is also concern because the controversial military defoliant Agent Orange, used in Viet Nam, was composed of 2,4,5-T and 2,4-0. Agent Orange was never registered by EPA for civilian use in the United States. Its use in Viet Nam by the U.S. military has resulted in claims of adverse health effects to American military personnel. The Veterans Administration is studying these claims. Prompted by*these concerns and EPA's need to resolve the questions surrounding the use of 2,4-0, trve Agency initiated a review of the available informa tion on the potential health effects of 2,4-D. This review was conducted in part to determine if the herbicide should be reviewed under the SPAR process (Rebuttable Presumption Against Registration) or if another regulatory action was appropriate. 11. Agency Review and Conclusions Based on the results of this review, EPA has concluded that a) the presently available information on the potential adverse health effects of 2,4-0 does not support a regulatory action to remove 2,4-0 products from the market; b) information from scientifically valid studies does not indicate that the continued use of 2,4-0 poses an imminent hazard or unreasonable adverse effect when used according to label precautions and direction for use; and c) the Agency should act quickly and vigorously to obtain better toxicological information on 2,4-0. <qo> These conclusions are based on these following cons icerat ions: 1. There is no evidence available at this time that indicates 2,4-D contains any form of dioxin. This includes the tetrachloro-dioxin (TCDD), which is a manufacturing contaminant of 2,4,5-T and causes cancer and miscarriages. TCDD is not theoretically expected to be found in 2,4-D. The manufacturing processes and starting chemicals from which 2,4-- D and 2,4,5-T are made are not the same. Although other much less toxic dioxins are theoretically possible in 2,4-0, they have not been found despite thorough chemical analyses. 2. Because products containing 2,4-D have been registered for use since the 1940's, most of the scientific data submitted to support the product registrations now on the market were developed many years ago. While some of these studies are scientifically valid, many others do not meet today's standards for scientific testing. As a result, there are significant information gaps in several areas including cancer-potential, reproductive effects, neurotoxicity, and metabolism in animals. 3. The studies most pertinent to the question of tumor-causing potential (oncogenicity) of 2,4-D were considered inadequate and inconclusive. No valid conclusions could be drawn one way or another from the data. 4. Animal tests conducted on the potential reproductive effects of 2,4-D show that, unlike 2,4,5-T with its contaminan TCDD, severe life-threatening effects were generally absent from 2,4-D treatments at moderate or high doses. However, new tests will need to be conducted at lower doses to clearly establish no-effects levels. In comparison, TCDD, which is present in 2,4,5-T and not in 2,4-D, produces serious life-threatening effects on the fetus at minute doses including the lowest dose tested in many studies. 5. The scientific evidence available at this time does not indicate the potential human exposure is sufficient to result in human health effects. 6. The most vigorous authority available to EPA under the pesticide law to fill information needs is a new section of FIFRA (Federal Insecticide Fungicide Rodenticide Act) passed in 1978. This provision, known as 3(c)(2)(3), allows EPA to request any additional data from pesticide registrants that is considered necessary to maintain the registration of existing products. The Agency can immediately require the 3 ma nufacturers to develop the data where gaps exist. The registrants have 90 days to show that they are complying. Their product reg ist rat ion s may be summarily suspended if they fail to meet the A g e n t ' s conditions. No other action could obtain this information any faster. EPA is putting the data requirements into final form and they will be issued to the registrants after review by our Scientific Advisory Panel. These scientific experts will review and comment on the data requireman"s to assure that they will provide the information EPA needs to more definitively answer the questions on potential health effects of 2,4-0. 7. Based on a review of the toxicology data (see section IV below), and a review of the risks of other pesticide chemicals now undergoing regulatory action, the Agency believes that the risks of several ether pesticides are higher and better documented than those associated with 2,4-D. To put the review of these other higher priority chemicals aside in order to devote EPA resources to taking action against 2,4-0 would not, in the Agency's opinion, best serve the public interest. III. Additional Actions In addition to requiring several important studies cf the manufacturers on 2,4-0, EPA will also: 1. Conduct several tests on reproductive effects (through our Office of Research and Development) of several derivatives of 2,4-0 in order to quickly get new information and have a good basis for comparison with the company-produced data. 2. Continue its ongoing review of forest pest control practices. This review will evaluate all chemical and non-chemical controls to identify the most environmenta1ly protective ways to control forest pests. The Agency believes that a piecemeal approach to forest chemical regulation only leads to confusion, both to the industry and to the public. Unless we review the whole range of possible controls, examining one chemical at a time only gives rise to questions about the chemicals which would be used to replace those examined and prohibited from use. 3. Review all new data as it comes in to determine if a change in our regulatory posture is warranted. This includes evaluating the results of new animal tests as well as looking into reported incidents involving human exposure to the chemical. 4. Continue to support field tests to measure exposure to 2,4-0 during the present,growing season. 5. ERA is informing the Inter-Agency Work Group, established by the White House to study the possible long-term effects of Agent Orange, of the actions being taken, i?A will also share its scientific findings with this committee. IV. Toxicology Background The potential hazard of a chemical is usually measured in laboratory animal tests. Animals are given doses of a chemical over a specific time period. Scientists attempt to derive from most of these tests a ".no observable effect level" (NOEL) -- the dose level below the dosage where effects are first observed. From the animal tests and NOEL's, the potential effects on humans and other animals can be estimated. A set of brief definitions is provided below to permit better understand!' ng of the subsequent discussion of toxicological findings. A. General terms * 1. Acute o ra 1 tc x ic itv fLD 50 ) - this test determines the dose level w m c n prccuces death in half the test animals after a single oral dose (short-term test). Used to predict the near- term toxicity of the chemical immediately upon contact with people or other non-target animals. 2. Chronic feeding tests - animals are fed for most their life span (usually greater than 13 months in rodents) in order to determine the dose level which shows no toxic effect in test animals. This is the test from which the NOEL is (usually) derived. 3. Oncogenicity testing - animals fed relatively 1a rge doses" of the test chemical for their life span (usually 13 months to 2 years in rodents) to try to induce tumors. These tests are used to predict whether the chemical may pose a cancer hazard. 4. Reproductive testing - these tests evaluate the effects of tne cnemical on the fertility of both the male and female parents by exposing the animals for a period of time before breeding. The tests also measure the possible effects of the chemical on the pregnant female and tne fetuses through several generations. (The test with rodents through 3 generations runs approximately 14 months.) I 1. I j 5. Teratology testing - these tests evaluate the effects oV tne onmical on fetuses by exposing . pregnant females Curing the short period of time j that the fetus is most susceotible to congenital ; malformation. Teratogenic effects include cleft j palate, centra^ nervous system deformities, eye ! and limb deformities, and internal organ malfunction. ? These are considered to be 1ife-threatening effects that put the animal at a disadvantage for surviving in its environment. 6. Fetotoxicity - fetotoxic effects can be seen in either the reproduction or teratology tests. Toxicity may be seer, in the extreme form as fetal death or as less severe problems, such as delayed formation of bones, reduced body weights at birth, or edema (abnormal fluid accumulation in the tissue). Most fetotoxic effects appear to be reversible once exposure to the test chemical is curtailed. Therefore most fetotoxic effects are considered to be less serious than teratogenic effects, with the exception of fetal death. B . Summary of Toxicology Review Most of the data in EPA files on the potential health effects of 2,4-0 are centered on the acid form, even though there are many derivatives, such as salts and esters. This is because the many forms of 2,4-0 metabolize to the acid form in the environment and in the body. The discussion of animal data below, therefore, concerns the acid form of 2,4-D unless otherwise noted. 1. Acute toxicity - low to moderate. The potential for immediate poisonings from contact with the chemi cal is unlikely. 2. Neurotoxicity - There is little definitive information "on the possible neurological effects of 2,4-0. In several reported cases of impaired nerve function, it was not known if the individuals were peculiarly sensitive to that type of effect or were exposed to other toxic materials. 3. Reproductive effects (effects on the unborn) Tests have been concucted on rats, mice and hamsters to evaluate the possible reproductive effects of 2,4-0. 2,4-0 causes some of the less serious fetotoxic effects, such as edema (swelling of tissues) at the lower dose levels tested, and causes 1ife-threatening birth defects (skeletal malformations) and cleft palates only at the very high levels tested. Based on available animal studies, E?A estimates that the level of exposure in a "worst case" situation (eg. a person standing directly under a spray plane)would be SCO to 1030 times less than the dose level that might cause an effect. Much of the data available to judge these effects was generated by old study protocols, has deficiencies in the test methods, and needs cl arification by further study. EPA also reviewed summaries of tests conducted in Russia which state that some derivatives of 2,4-0 produced adverse effects on unborn animal fetuses at much lower levels than indicated by the data in EPA's files. These summaries could not be used in the Agency's review because the identity of the test material, and its impurities, was unclear, and because there were no numerical data to back up the summary conclusions. In some cases tests need to be done on specific derivatives of 2,4-0. 4. Oncogenicity (potential for causing tumors) Several rocfent studies have been conducted to date. The tests were conducted a decade ago and are considered to be inadequte and inconclusive by today's scientific standards. New studies on rodents are needed. 5. Mut acen 1c ity (inheritable effects) - The vast majority of the mutagenicity studies conducted on 2,4-0 are negative. However, there are three positive studies. Taken as a group, the results of the studies can best be described as inconsistent and inconclusive. A new series of tests being conducted by the Department of Health, Education, and 'Welfare will be reviewed by EPA when they are completed. 6. Epidemiology - No epidemiological studies of human health effects from 2,4-0 exposure have been completed. However, EPA is currer.lty investigating reports about alleged adverse effects from potential chemical exposure in several parts of the country. EPA will be looking at the results of those studies and will decide in the near future about additional field work . I (s> V. Exposure to 2, 4-p There are at least three ways that the average citizens might come into contact wi^h 2,4-0 - through the diet, during home use, and drift of the herbicide from nearby use. a) D iet The E?A has set tolerances for residues of 2,4-D in various food crops. The Food and Drug Administration (FDA) routinely samples a variety of foods (the Market Basket Survey) which FDA considers to be representative of the average American diet. Samples are analyzed for pesticide re si dues. During the period of 1374 to 1377, no 2,4-0 residues were found in any of the products in the Market Basket Survey. However, during the 1355 to 1977 period, a variety of other food products were analyzed under ether surveys in which about 1.15 were positive for 2,4-D in very minute quantities that were well below EFA's tolerance (allowable residue) levels. b) Home use There are currently a number of registered home-use products which contain 2,4-D in a variety of formulations. Exposure to the herbicide in home-use situations will depend to some extent on the specific formulation used. If care is exercised by the homeowner in adhering to the directions for use and precautionary statement on the label, exposure to 2,4-D should be low. c ) Drift "Drift", the airborne transport of pesticide materials to a non-target area, is a common source of exposure. Sometimes, a pesticide will drift during application, depending on climatic conditions (temperature, wind speed), type of formulation used, terrain (forests, mountains), and type of application method used (aerial, ground spray). Several States have imposed restrictions on 2,4-D use in order to cut down on drift potential. Once on the ground or target crop, the herbicide may become airborne again by the process of vaporization. This particular type of drift has been the subject of intensive research by the producers of 2,4-D. Since the introduction of less volatile forms of the herbicide over the last few years, this kind of drift has become much less extensive. VI# E n v i r o n P $ r s i s i s n c 2 2,^-9 is not a persistent pesticide. Breakdown of the herbicide begins almost immediately after application at a rate dependent on several environmental factors such as temperature, humidity and medium (air, soil, croc, water). The rate of loss (commonly referred to as the half-life) is a measure of the time required for half of the substance to be degraded or lost. On sp^aved vecetabl e s , the half-life varies from 1-3 weeks depencing on geographic location, climatic conditions, vegetation type, application technique and formulation usee. In soil , the half-life varies from several days to 2 weeks, depending on acidity, soil type and amount of rain. In w ate r, the half-life varies from a few days to several months depending on factors such as oxygen concentration, acidity, light intesity, water temperature and formulation used. April 22, 19SO IiNi'Tf D l/UTLO'D 1 OA*MV,[ mi o r A G R I C U L T U R C FOKI"-..! M UV!C.I WO 140 Integrat..-' Post T'.anc. f i ' V. 0 Posticidc-Usc /.'iviscry Kcmorar,dun lie. 26C Reginral Foresters, Station Directors, and Area Directors Enclosed is a copy of a memorandum from Dr. Philip C. Kearney, Chief, Pesticide Degradation Laboratory, documenting a telephone conversation c o n c e r n i n g a recent Canadian report of dioxins found in 2,4-D. As Dr. Kearney indicates this disclosure may receive considerable press coverage and we are, therefore, alerting you to this finding. We understand that EPA is accelerating the collection of samples from all 2,4-D products manufactured and used in the United States for analysis for dioxins. The analyses will be conducted by Dr. Warren Bontoyan, Branch Chief, EPA Chemical and Biological Investigation. A fact sheet abstracted from a paper by M. L. Long, "Comparative Toxicology of Various Chlorinated Dioxins Related to Chemical Structure," CIPAC Proc. Symp. Paper I, .1.979, edited by Dr..Dontovan is also enclosed. U El MAR L. ROGET Chairman, Washington Office I-ntegrated Pest Management Work Group Enclosures LIMITED DISTRIBUTION cc: S&PF WO-IPMWG F ie1d-1PMWG Ch aimien Dave Ketcham, EC Bob Ekblad, MLDC MAG - Davis Logon Morris, PRW E. Bradford Wa'lkcr Director of Foresi? Dept. of Forcsts <c< Parks Stat*' Office Fuilding Konip *!ier, VT Uo02 Principal Silviculturist Forestry Commission Research Station A1ice Molt Lodge Wrecclesham Farnham Surrey ENGL AND \<K C , 3 .^iLTv' United States fyli(. h. f)..f.,n:r,`jn t of Agriculture Science and Education Admmistr;;tion October 16, 19S0 Agricultural P?e^carch Northeastern Region Beltsville Agricultural Research Center Beltsville M nryland 20705 SUBJECT: Dioxins in 2,4-D TO: Terry B. Kinney, Jr., Administrator, AR .On Thursday, October 1-6, 1980, I received a telephone call from Dr. Etcyl Blair, Vice President and Director of Health and Environmental Sciences, Dow Chemical * Company, Midland, Michigan (517-636-5509), concerning a report they have from a Dr. Cochrane in the Canadian Government. Dr. Cochrane has been analyzing samples of 2,4-D for dioxins and has detected a TCDD isomer. This is not the highly toxic 2,3,7,8 isomer, and Dow suspects it is either the 1,3,6,8 or 1,3,7,9 isomer. This finding has been confirmed, and the concentration range is 100-300 ppb. Dr. Cochrane will present this finding at a dioxin meeting in Rome next week. Dr. Sam Epstein is also attending this meeting. Ed Johnson in EPA has been alerted to this finding by Dow. Dr. Blair told me that this TCDD isomer did not show up in U.S. samples, but only in samples produced in Canada. Dew shut down the Canadian plant some time ago for economic reasons not related to this incident. This TCDD isomer is considerably less toxic than the 2,3,7,8 isomer. Its acute toxicity is in the range of mg/kg. It is also less acneogenic. I am alerting you at this time since there is liable to be considerable press coverage on this disclosure. It also impacts on the Veterans Administration Committee and certain activities in the Department. I have contacted Barclay Shepard in VA. As requested, I will put this memo on the telecopier this afternoon. I will try to convene a meeting with Drs. Shaw, Hilton, Fertig, and Klingman to discuss a unified response. /) I^ ^ * V* '6 PHILIP C. KEARNEY Chief, Pesticide Degradation Laboratory Agricultural Environmental Quality Institute cc: W. C. Shaw -- D. Graham FOREST SERVICE PECnvrn o n 1930 f *\ ,.t ;:g ci & MANAGEMENT I ! I l j I ( ! y- v 19 Fact Short on TCDD's* Origin Low levels of chlorinated ciibenzo-p-dioxins arise as byproducts in the manufacture of chlorophenois under alkaline conditions at elevated temperatures and pressures. Trace amounts of the highly toxic 2,3,7,8-TCDD are formed during the manufacture of 2,4,5-trichlorcphonol. This TCDD is carried through into products such as 2,4,5-T and hexachlorophene. Condensation of 2,4,6-trichlorophenol produces the expected 1,3,6,8-TCDD as well as the isomeric 1,3,7,9-TCDD. The toxicity of TCDD isomers is strongly dependent on the position and number of chlorine substituents. Acute Oral Tcrcicity A comparison of the acute oral LD50 (pg/kg body weight) shows that the 2,3,7,8-TCDD is many thousand tines`more toxic than the mixed 1,3,6,8-; 1,3,7,8--TCDD isomer. Dioxin Rat Guinea Pig Mouse 1,3,6,8 } . , ^ mixed 1,3,7,9 2,3,7,8 >100,000 22 (M) 45 (F) Enzyme Induction 0.6-2 280 The ability of TCDD's to induce enzyme production is also correlated to struc ture. The 2,3,7,8-TCDD is a potent inducer of 6-aminolevulinic acid synthetase (ALA) and aryl hydrocarbon hydroxylase (AKH). By comparison, the mixed 1,3,6,8-; 1,3,7,9-TCDD isomer is a weak to negligible inducer. Chloracne The 2,3,7,8-TCDD is a powerful producer of chloracne. A concentration of 0.04 ppm 2,3,7,8-TCDD produced a positive response in the rabbit ear test. comparison, a concentration of 5,000 ppm was needed to produce a positive response with a mixture of this 1,3,6,8- and 1,3,7,9-TCDD. By Summary Although the data is sparse, the limited results currently available suggest that the mixed 1,3,6,8-; 1,3,7,9-TCDD is at least 10,000 times less of a human or environmental hazard than the 2,3,7,8-TCDD.* *This fact sheet is abstracted from a paper by M. L. Leng, Comparative Toxicology of Various Chlorinated Dioxins Relntc-d to Chemical Structure. Cii'AC I'roc. Syrnp. Paper 1, pp 141-169, 1979. EJ. W. Bontoyan, CIPAC Limited, hertfordshire. England. United States Department of ag riculture FOREST SERVICE . wo r e p l y t o : 2140 Integrated Pest Management NOV 1 7 1980 s u b j e c t : Pesticide-Use Advisory Memorandum No. 271 t o - Regional Foresters, Station Directors, and Area Directors As a followup to Pesticide-Use Advisory Memorandum No. 266 (October 30), enclosed are two additional items on dioxins in 2,4-D. They include: 1. An October 23 press release from Eugene Whelan, Agricultural Minister, Agriculture Canada. 2. "Analysis of Technical and Formulated Products of 2,4-Dichlorophenoxy Acetic Acid for the Presence of Chlorinated Dibenzo-p-dioxins," by W. P. Cochrane, et al., as presented at a meeting in Rome. You are encouraged to make this information available to all personnel who may be questioned about 2,4-D, its use by the Forest Service, and the presence of dioxins in this herbicide. ElMAR L. ROGET Chairman, Washington Office Integrated Pest Management Work Group Enclosures (2) Limited Distribution cc: S&PF WO-IPMWG Field-IPMWG Chairmen Dave Ketcham, EC Bob Ekblad, MEDC MAG - Davis Logan Norris, PNW E. Bradford Walker Director of Forests Dept, of Forests & Parks State Office Building Montpelier, VT 05602 Principal Silviculturist Forestry Commi ssion Research Station Alice Holt Lodge Wrecclesham Farnham Surrey ENGLAND 1 S U B J E C T ; 2, 4-D T e s t s Ottawa, O c t o b e r 23, 1980 Agricultural Minister, Eugene Whelan today announced that tests conducted by Ag Canada have identified previously unannounced contaminants in some samples of the herbicide 2,4-D. Scientists in Agriculture Canada, Food Production and Inspection Branch using state-of-the-art technology have found that some 2,4-D products contain dioxin contaminants. It has generally been believed that 2,4-D products are dioxin free. The majority of world tests have focussed on what is recognized to be the most acutely toxic member of the dioxin family, the 2,3,7,8-TCDD isomer. This dioxin has never been identified in 2,4-D. _______ ____ The intensive Ag Canada tests just completed have again confirmed the a b s e n c e of 2 , 3 , 7 , 8 - T C D D in 2,4-D. O t h e r d i o x i n c o n t a m i n a n t s were, however, identified in some 2,4-D products, while no dioxin contaminant was detected in other 2,4-D samples tested. "We are now assessing these results in concert with officials in Health and Welfare Canada who work in cooperation with us in pesticide regulations "The decision on how our new findings will effect the prescribed uses of 2.4- D will be made before the 1981 growing season", Mr. Whelan said. "The herbicide 2,4-D is used to control broadleaf weeds in everything from lawns to cereal fields. About eight million pounds of 2,4-D is used in Canada each year. This represents about 25% of total herbicide use "These findings clearly identify dioxin contaminants in some, but not all, 2.4- D samples examined. Work is continuing to gain a broader and more detailed understanding of these new findings". "When some pesticide products were registered highly sophisticated testing equipment did not exist. The investment m y department has made in high priced lab equipment and in highly trained scientists is paying off with results like these". "My main concern is about the safety of all pesticide products used in Canada." "I c a n g u a r a n t e e t h e p u b l i c t h a t Ag C a n a d a w i l l c o n t i n u e to w o r k h a r d in keeping agricultural chemicals under constant review and to provide answers to concerns that may arise as a result of the review process", Kr. Whelan said. 196.67 ANALYSIS OF TECHNICAL AND FORMULATED PRODUCTS OF 2,4-DICHLOROPHENOXY ACETIC ACID FOR THE PRESENCE OF CHLORINATED DIBENZO-P-DIOXINS U.P. Cochrane, J. Singh, W. Mlles, B. Wakeford, J. Scott Laboratory Services Division, Food Production and Inspection Branch, Canada Agriculture, Ottawa, Ontario Canada, K1A OC5 ABSTRACT Sixteen samples of 2,4-D ester and amine, both technical and formulated products, representing current Canadian supplies, were analysed for the presence of different chlorinated dibenzo-p-dioxlns. The method of analysis involved extraction, par titioning, multiple column chromatography with final quantitation being performed t y gas chromatography/mass spectrometry using a packed column. Isomer identification was achieved on a capillary column while dioxin identity was confirmed using high resolution mass spectrometry. The methodology provided for recoveries in excess of 857. with the limit of detection being 1 ppb. Eight out of nine esters and four our of seven amine samples were found to contain di-f trir- and tetra-chlorodibenzop-dioxlns. Ester formulations showed significantly higher levels of contamination than the amine formulations. The tetra-chlorodioxin observed was the 1,3,6,8isomer as verified by the synthesis of an authentic analytical standard. In addition ten 2,4-D technical acid samples from 4 different sources did not con tain any mono-, di-, tri- or tetra-chlorodioxins above the 1 ppb detection limit, although low levels of polychlorinated biphenyl ethers were observed. KEYWORDS Css chromatography-mass spectrometry, chlorinated dioxins, 2,4-D formulations, TCDD isomers. INTRODUCTION There are 75 possible isomers in the class of compounds known as the polychlorodibenzo-p-dioxins (PCDDs). PCDDs together with the polychlorinated dibenzo-furnns (PCDFs) and polychlorinated diphenyl ethers (PCDDEs) have been found as microcon taminants in commercial chlorophenols (Nilsson and Renberg, 1974; Jensen and Rcnberg, 1972; Firestone and co-workers, 1972; Rappe, Gava and Buser, 1978b) and in pesticides which use chlorophenols in the manufacturing process. While the her.ahepta- and octa-chlorodibenzo-p-dioxin isomers have been reported by various workers (Woolson, Thomas and Ensor, 1972; Villanueva and co-workcrs, 1973; Johnson and co-workers, 1973) in trlchlorophenols, tetrachlorophcnols and pentachlorophenol (PCP) at levels ranging from the low ppb (i.c. HxCCD) to 1000 ppm (OCCD), the highly toxic 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) has not been found in commercial PCP (U.S. EPA, 1976) since the appropriate precursors are not present (Johnson and co-workers, 1973). However, trace amounts of 2,3,7,8-TCDO have been found in 2,4,5-TCP (Firestone and co-workers, 1972; Elvidge, 1971) at levels ranging from 90 ppb to 6.2 ppm, in addition to ppm levels of 2,7-dichlorodlbcnzo-p-dloxin, 1,3,6,8-TCDD and pentachlorodloxins. Also, 2,3,7,8-TCDO can be carried through into products made from 2,4,5-TCT, such as 2, 4,5-trichlorophenoxyacetlc acid (2,4,5-T) (Elvidge, 1971), hexachlorophene and mixed 2.4-D/2,4,5-T formulations (1:1 mixture of butyl esters known as Agent Orange on Herbicide Orange) Herbicide Orange was found to contain 0.1-47 ppm 2,3,7,8-TCDD together with smaller amounts of other less toxic PCDDs and PCDFs (Rappc, 1978; Rappe and co*workers, 1978a). Similarly, condensation of 2, 4,6-trlchlorophenate during its manufacture aider alkaline conditions produces the expected 1,3,6,8-TCDD, as well as the isomeric 1,3,7,9-TCDD by Smiles rearrangement (Leng, 1979). Recent reviews have summarized the current situation with respect to dioxin analysis of PCP, 2,4,5-T and the polychlorinated biphenyls (Firestone, 1977; Rappe and co-workers, 1979). In the area of the lover chlorinated phenols and phenoxyacetlc acids, no PCDDs were detected in 2,4- and 2,6-dlchlorophenols (Firestone and co-workers, 1972). Woolson found HxCCD in 1 sample of. 2,4-D at a level between 0.5 and 10 ppm. Only tetra-, hexa-, hepta- and octachlorodioxln results were reported and none were observed in 23 other 2,4-D samples, as well as, three 2,4-DO and two 2,4-DP samples. Similarly, no di- to hexa-CDD isomers were found in older Scandinavian formulations of 2,4-D although one 2,4-D sample did contain 0.06 ppm tetra-CDF (Korstrom and co-workers, 1979). However, the analysis of 2 Herbicide Orange samples showed the presence of 1,3,6,8-TCDD (in addition to the expected 2,3,7,8-isomer) and 1,3,7-tri-CCD which vere postulated as being formed from condensation products of 2,4-di and 2,4,6trlchlorophcnols (Rappe and co-vorkers, 1978a). As part of a continuing program concerning the identification and quantitation of ' microcontaminants in pesticide formulations, this paper reports the results of dioxin analysis of 2,4-D amine, esters and acids. EXPERI1ENTAL Sample Preparation 2.4- P ester. Transfer 2.0 g sample onto a silica gel column (50 g of Merck Kclsclgcl 60 activated overnight at 125C. Elute with 150 mL of 30% CH,C10/hexane, discard first 30 mL and collect remainder in a 250 mL RB flask. Concentrate to 1-2 mL and proceed to alumina column clean-up. 2.4- D acid. Dissolve 10.0 g sample in 400 mL of 1:1 acetonltrlle/vater with 102 methanol added. Partition three times with 100 mL hexane. Combine the organic layers and wash twice with 50% methanol/water. Dry and concentrate the extract to 1-2 mL and proceed to the alumina column clean-up. 2.4- D amine. Dissolve 2.0 g sample In 100 mL water and partition three times with 25 mL hexane. Use iso-propanol to* break any emulsions. Combine organic layers, ash twice with 20 mL water, dry and concentrate to 1-2 mL and proceed to the iumlna column clean-up. Alumina column clcan-up. Transfer sample extracts onto alumina colurn (15 g Woelm Basic Alumina Activity I). Elute with 100 mL hexane and 100 mL 2% CH-Cl./hexano, discard. Collect the next 100 mL 5% OI,Cl,,/hcxanr. and 100 tuL 10Z CH,Cl7hexa..c. id. ii Concentrate to 1-2 mL and transfer to a 5 mL graduated centrifuge tube. Evaporate to dryness under a gentle streaxn of nitrogen. Dissolve residue In appropriate f olume of hexane. CC-MS analysis A 25 m fused silica capillary colusn coated vlth'SP 2100 (Hewlett Packard No. 19091-60025) was coupled to a Flnnigan 4000 quadrupole mass spectrometer equipped vith the INC0S data system. Analysis were performed lsothermally at 225C using the splitless injection of samples at a 20 p.s.l. column pressure. PCDDs were monitored using specific masses - m/e 218 and 220 for Isomers of monochloro-, 252 and 254 for dlchloro; 286 and 288 for tri-chloro- and 320 and 322 for tetrachlorodioxlns. Specific Isomers were identified by comparing their column retention vith reference compounds and confirmed by high resolution mass spectrometry analysis via elemental composition and fragmentation patterns. The lover limit of detection was 1 ppb. For hlgh-rcsolutlon CC/MS analysis, the gas chromatograph was equipped with a 6 ft. x 1/4 in. glass column packed with either 3Z SE-30 ultra-phase on Chrom 750 (80- 100 mesh) or 3Z OV-17 on Chrom 750 which was coupled to a Kratos MS-50 mass spec trometer by means of a single stage glass jet separator. Single ion monitoring was carried out at m/e 321.8936 at a resolution of 20,000 (10Z valley) for tetra- chlorodloxins. Source temperature 250C, separator emission current 500 uA, accelerating voltage 8.0 Kv, detection limit 20 x 10** g. Full scan data was acquired at 10,000 resolution using the INCOS data system. The major peaks of the Isotopic chlorine cluster were all within 10 ppm of the correct mass value* RESULTS AND DISCUSSION The levels of PCDDs found in the 2,4-D esters and amine samples analysed are shown In Table 1, and represent current Canadian supplies of these products. Since these formulations contained varying amounts of active ingredient the quantitation of the PCDDs was based on the guaranteed 2,4-D acid equivalent for easier com parison of results. The six 2,4-D iso-octyl esters showed levels of 2,7- or 2,8dichlorodioxin ranging from 104 ppb to 4.2 ppm. These di-CDD isomers are the ex pected dimerization products of the Intermediate 2 ,4-dichlorophenol used in the 2,4-D manufacturing process (Leng, 1979). Levels of trl-CDD varied from 346 ppb to 2.0 ppm while the presence of tetra-CDD ranged from 226 ppb to 1.7 ppm. The tetra-CDD present in the 2,4-D samples displayed a 0.80 retention time relative to the 2,3,7,8-TCDD isomer on the 3Z SE-30 packed column. It was identified as the 1.3.6.8- isomer via capillary column and high resolution fragmentation comparisons with an authentic standard. On capillary column two peaks were resolved, l.e. 1.3.6.8- and 1 ,3,7,9-TCDD, the normal and Smiles-rearranged dimerization products of 2,4,6-trichlorophenol. The tri-CDD in all samples appeared earlier than the 1,2,4-isomer, used as an Initial standard, and resulted in baseline separation between the two on capillary column. Since the 2,7- (or 2,8)-dlCDD and l,3,6,8-/l,3,7,9-tetra CDDs had been Identified, it was found that the cross condensation product of 2,4-dlchlorophenol with 2,4,6-trlchlorophenol gave a single trl-CDD peak with the same rrtcntlon time * that found in the sample on both packed and capillary columns. Therefore, this i-CDD is probably the 1,3,7- or 1,3,8-isomer as expected from the above conden sation reaction. A comparison of the high resolution mass spectra of the syn thesised trl-CDD and that found in the samples were identical. The mass spectral difference between the 3:0 (l.e. 1,2,4-isomer) nnd the 2:1 (i.e. 1,3,7-isomcr) ring chlorine substitution becomes very apparent in the m/e 50-150 rar.gw U u r TABLE 1 Levels of TCDDs in 2,4-D Technical M aterials and Formulations Sample 1 2 3 4 5 6 Type Iso-octyl ester II M M M ft Percent 2,4-D Acid Equivalent 65.4 65.4 50 65.1 60 70 7 8 Mixed butyl ester II Technical 50 9H Technical 10 Dimethylamine salt 50 11 12 1 II ' 50 50 13 14 M M 50 60 15 II 50 16 H 50 Di- ini 4200 104 1238 109 102 - 200 5 - 33 - PCDDS (ppb) 1.3,6,8- Tri- Tetra 346 2079 1632 639 1825 929 226 717 1752 315 852 486 684 317 --- 160 210 38 54 584 278 54 20 -- 533 208 - -- a/ Level not reported due to co-eluting Interferences. and Rappe, 1978). Recoveries of di-, tri- and tetra-CDDs from spiked samples vas greater than 85Z when added in the 1-1000 ppb range. While all 2,4-D iso-octyl ester samples contained PCDD contaminants, only tvo of 'the three 2,4-D mixed butyl esters and four of the seven 2,4-D amines shoved the presence of chlorodioxlns (Table 1). Also the esters products shoved significantly higher levels of contamination than the amine formulations. In addition, ten 2,4-D technical a d d samples from 4 different manufacturing sources vere analysed for mono-, dl-, trl- and tetra-CDDs dovn to the 1 ppb level and hexa-CDD at the 10 ppb level and none vere found. Hovever, the presence of lov levels of dichloro-, trlchloro- and tetrachloro-dlphenyl ether Isomers vere observed in all cases. The results reported in this study differ from those found for Scandinavian formulations of 2,4-D (Korstrom and co-vorkers, 1979). Although significant variations exist betveen individual samples, other contributing factors may be cross-contamination, the source of starting material and/or the process used in the manufacture of the 2,4-D esters and amines. REFERENCES Buser, H.R., and C. Rappe (1978). Cheraosphere, 2, 199-211. Elvidge, D.A. (1971). Analyst, 9 6 . 721-727. Firestone, D . t J. Ress, N.L. Brown, R.P. Barron and J.N. Damico (1972). J. Assoc. Offlc. Anal. Cliern., 55, 85-92. Firestone, D. (1977). U.S. Ford and Drug Administration By-Lines, 2, 57-89. \.afC0 Ff[ Jensen, S., and L. Renberg (1972). Ambio. 1, 62-65. fq ^ / / Johnson, R.L., P.J. Gehring, R.J. Koclba and B.A. Schvetz (1973). Environ. Health Perspect., 5 , 171-175. Leng, M.L. (1979). Proceedings of the CIPAC Symposium, Baltimore. June 5-7. Nilsson, C.A., and L. Renbcrg (1974). J. Chronatop.r. 8 9 . 325-333. Norscrom, A., C. Rappe, R. Lindahl and H.R. Buser (1979). Scand. J. Work Environ. and Health, 5, 375-378. Kappe, C. (1978). Ecol. Bull. (Stockholm), 27, 31. Rappe, C., H.R. Buser and H.P. Bosshardt (1976a). Chemosphcre, 5 . 431-438. Rappe, C., A. Cava and H.R. Busscr (1978b). Chemosphcre, 7 , 981-991. Rappe, C., H.R. Buser and H.P. Bosshardt (1979). Proceedings of the CIPAC Sym posium, Baltimore, June 5-7. U.S. Environmental Protection Agency (1978). Federal Register. 43 (202). 4844348617. Villanueva, E.C., V.A. Burse and R.W. Jennings (1973). J. Agrlc. Food Chcm., 21, 739-740. V'oolson, E.A., R.F. Thomas and P.D.J. Ensor (1972). J. Agric. Food Chem., 20 . 351-354. ? 1 .UNITED STATES ENVIRONMENTAL-PROTECTION- AGENCY.. ^ / aTA7n GTN .O.czQO ,t . ,. . .>-Jfiu p . iK LETTER TP 2,U-D MANUFACTURERS rc5TtClOC5 AoNrOnTeOeXIoCr 1U01TANCC*; tV*.' 2,4-D Industry Task Force c/o John D. Connor, Counsel Sellers, Conner L Cuneo 1575 Eye Street, NW Washington, D.C. 20005 , Dear Sirs: - This letter responds to several questions and corollary issues raised at the Industry Task Force Meeting held on November 14, which I attended with Patricia Cohn and Dudley Thompson. The Task Force expressed an interest in coordinatin' the Canadian government on 2.4-D testing. We are evith representatives of Agriculture Canada anc Weal I Ml * W ^ ..,, A Welfare Canada tc Coordinate Canadian and U.3. review efforts on 2,4-D. This coordination will enable us tc conduct an efficient review effort and will also ensur e a consistent approach to the testing r e q u i r e m e n t s . If you wish to have a Canadian liaison work with the Task Force, in a role comparable to mine, I would be hap * .rcontact the Canadian ministries on your behalf ana tto r p for their represer.taticn. The Task Force raised concerns about the required cr. 2 , 4-D t e c h n ical a tiid,pr o d ucts cal teso;ng 'f hi*V*_yfKf_f. __ used as the test substance. Specifically, you r 2 1SOC questions concerning available laboratories and the analytic methodology for dioxin testing. Agriculture Canada is in agreement that we work with you to identify 5 cr 6 laboratories which can conduct thu necessary testing of technical 2,4-D acids. Since the analytical methods developed by the Agriculture Canada Laboratory have not been validated, this group of labora tories could carry out the required procedures to validate the methodology and have it accepted by A s s ociation of Officials Analytical Chemists (ACAC). -, (f i 7 3 I suggest that we use samples of each 2 ,4-D technical acid set:',`aside by.'yoOr companies as the .substances' ta'Ue tested;' * ;Thiii` woUld*'provide yfti -with'.the an-aiyt'ic'al specif feat L o n s ' /..-ter ;each pcoduct a n d ;p;rpy4de -input .to the.-decision-on which product should "be used as the test substance for the required studies. W e ;will, of course, make a l l 'the necessary arrangements in advance to maintain confidentiality of the testing results. We propose that the A g r i c u l t u r e Ca na da La boratory take the lead in this project, wi t h E P A ' s .laboratories at Be l t s v i l l e and Research Triangle Park participating. Mv understanding is that you w i s h to use the Do w L a b o r a t o r y and the l a b o r a t o r y _ at eith er the U n i v e r s i ty o f N e b r a s k a or Wr^ight_ S t a te U n i v e r s ity Any o f th es e l a b o r a t o r i e s is a c c e p t a b l e to the Agency. After you have selected the laboratories you will use and the necessary administrative arrangements are completed, we will arrange a meeting with representatives from each laboratory to discuss the analytical methods and specifi cations for the substances under consideration. We agree with the approach to use one 2,4-D acid technical product as the test substance for all the required studies on the 2,4-D acid. When the analytical results on the technical products are a v a i l a b l e , our s c i e n t i s t s will be available to consult w ith you in c h o o s i n g a test iLcs-tonce..- ./ AgencyAs we stated in th| Task Force meeting, the will shortly put out a notice tp modify the requirement for acute oral and ^dermal toxicity teats on all 2 ,4-D p r o d u c t s . We will defer the testing requirements on end-use products until we have grouped these products. However, we will still require acute oral and dermal toxicity studies on e a c h manufacturing-use product, in accordance with the schedule in the August 29 ORDER AMD NOTICE. | We have received request dated October 30. from John D. Connor, Jr., on behalf of the Task Force for a waiver of the - time schedule for submis'sion of studies to allow the "Task. Force to complete the necessary analyses of 2,^-0 compounds. The schedule in the August 29 NOTICE allows a reasonable amount of time to complete and submit the studies if they are initiated in a timely fashion. We realise that this will not be possible for all studies. Therefore, we have developed a priority listing for studies which we feel must begin now. We will consider revising the time schedule for the studies listed below on a study by study basis, if we receive an adequate rationale explaining why additional time is needed and proposing a new date for submission of the studies. We will defer the schedule for submission of those studies wh.ich. are .not .Qn .th is-..fir.st., list . . . . . ,, As Mr ....Connor, nated in-his- request;- we*'.most have dnadeouete-- .chemicalanalysis of. each 2 ,4-D -product.used- as` attest .* substance. We also recognize that there, is scme.,negot iati'.o.n ^ a:ocf*fe&'ondlnati6n*;-ihV'olV'e'd*-`in'-`get'tihg''the1-'Vt ud'ies' under way! The negotiations to obtain commitments- for laboratory space and to develop protocols should continue while the analytical work is being completed. We will not grant time extensions based on the fact that-these negotiations were deferred pending the o u t c o m e t h e analytical work. i We have consulted with Canadian representatives to make a careful comparison of our data requirements on 2,4-D with the requirements they intend to impose. Based on this, we have jointly developed the priority list of testing requirements on 2,4-0. While most of the U.S. and Canadian testing requirements are consistent, there are several studies which are being required by Agriculture Canada which EPA is not requiring. These studies are indicated in the list with an asterisk. We are not adding these studies to our req u i r e m e n t s , but we are deferring initiation of seme of our required studies so that these can get under way. The priority listing- of studies presented below includes a schedule for submission of those studies which arefrequired by the Agency. The dates are taken from the August' 29 NOTICE. As noted above, we will consider r e q u e s t s for time extensions. However, we encourage you to begin r.^w to reserve laboratory space and to develop protocols, The tests which we feel should be. initiated as soon as possible are: Tests Acute Toxicity f Test Substance 1 Submission Date Acute Oral Toxicity .Each manufacturing use 2,M-D product 5/1/81 Acute Dermal -Toxicity -- - Each manufacturing ----- use 2 ,4-D product-- 5/1/31 Acute Inhalation Toxicity* Subchronic Toxicity ( V 5/1/81 Subchronic Oral Neurotoxicity 2,4-D acid in rat 9/1/81 d i m e t h y l a m i ne salt ------- of 2,4-D in rat and dog (we will not require testing in the chicken at .time) .. Chronic' t o xlcl~ty ' '~BL /Ter at sg e ni ci ty * 'Butoxyprbpyl ester Teratogenicity . . .alkan.olamine ester dimethylamine ester* 2, il-Dichlorophenol 8/81 Oncogenicity in rat 2 ,JJ-D acid Reproduction 2.4- D acid Metabolism V - 'i 2.4- D acid isooctyl ester PG8E. dimethylamine <l Exposure studies* . ^Studies required by Agriculture Canada and Health and Welfare Canada, but not by EPA. j. If you have any questions concerning this priority /listing or general comments which you care to make feel fr<fe to contact me on t703) 557-8195, or Pat Cohn on (703); 557-7973. /. V' D - Sincerely vcurs, A 'L''* \ ///.*^ /y Kevin Kaney, Chief Chemical R e view Branch II Special Pesticide Review Divisio: 1 ,<* I Y \ O.' \HG>7G> OATS - , 'c t U liCU J IM I C I'l* \ January 16, 1981 1>iu it\w i i -..Analyses for 01 and Tetra Chlorinated Oibenzo-p-dioxins in 2,4-0 om T THRU: Robert Harless HERL, ETO, ACB (MO-69) Mike Oellarco, Dioxin Project Manager Special Pesticide Review Division (TS-791) Office of Toxic Substances 401 M St., SW U.S. EPA Washinaton. DC 20460 ETO/HERL-RTP, NC 27711 Three sample extracts of 2,4-0 were received from EPA, Beltsville, MO, January 5, 1981. An ACB ID number (151) was assigned to this shipment^ The extracts were subjected to a previously described HRGC-HRMS method of analyses for dichlorodibenzo-p-dioxins (OCDDs) and tetrachlorodibenzop-dioxins (TCDOs). A Varian 311A mass spectrometer equipped with a 30 meter 0V-101 WCOT glass capillary column was utilized /or these analyses. The analytical results are shown in Table 1. The criteria shown below were utilized for confirmation of 2,7-OCCO and 1 ,3,6,8-TCDO. ANALYTICAL CRITERIA USED FOR CONFIRMATION ANALYSIS A. HRGC-HRMS retention time of DCDO and TCDD. 3. Simultaneous HRMS-MIS responses for M+ and M+2 of DCDO and TCDO. C. Co-injection of sample and standards (2,7-QCDD and 1,3,6,3-TCDD). D. HRGC-HRMS peak matching analysis in real time to confirm the elemental composition of DCDO and TCDO molecular ions, 251.9745 and 319.8965. -2- DISCUS5I0N HRGC-HRMS MIS Analysis A compound was detected in each of the three extracts that satisfied the analytical criteria for 2,7-DCDD. The concentrations shown in Table 1 are based on the concentration of 2,7-DCDD standard supplied by EPA Beltsville, MD. No problems were encountered in the DCDD determinatons. The analyses for TCDDs were performed at higher sensitivity. A compound that satisfied the analytical criteria for 1,3,6,8-TCDO was detected in 70462 and 011123. The 1,3,6,8-TCDD concentrations shown in ~" Table 1 are based on the concentration of validated DMP 2,3,7,3-TCDD standard. 2,3,7,3-TCDD was not detected in the three samples at the stated detection limit. High concentrations of other chlorinated contamination were also detected. HRGC-HRMS Peak Matching Analyses 500 ul of each extract was concentrated to 40. yl for determination of exact masses. The exact mass, 251.9745, corresponding to DCDD was confirmed in each extract. In addition to 2,7-DCDD, the presence of isomers in lower concentrations were also confirmed. The exact mass, 319.8965, corresponding to TCDD was detected in each of the three extracts. In addition to 1,3,6,8-TCDD, several isomers in low concentrations were also detected in 011123 and 70462. TCDD isomers were also detected in 70459 but in lower concentrations. Extremely high concentrations of chlorinated contamination were also present in these extracts. The major masses which interfere with t76 79' -3TCDO analyses were determined to be 319.9165, 319,9016, 321,9113 and 321.9091. Conclusive identifications have not been assigned. I suggest (emphasize) that these samples be subjected to a more efficient clean-up procedure for conclusive confirmation, specific isomer assignments and accurate quantification of TCOOs. The capillary column used in these analyses was severely damaged and late eluting TCDDs would not have been detected in the contamination. SUMMARY DCOOs and TCOOs were detected in, samples of 2,4-0. The presence of 1,3,6,3-TCDO in 2,4-0 is not surprising. This laboratory reported the presence of 1,3,6,8-TCDO in a 2,4-0 process water to ERA Region 5, in early 1979. Attachment cc: Ron Thomas N. K. Wilson O. E. Gardner 19677 January 1981 EPA Regulation Of 2,4-0 In April 1980, the EPA completed a review of critical health effects studies on 2,4-0. No 2 , 3 , 7 ,8-tetrachlorodibenzo(para)dioxin (2,3,7,8-TCDD) has been found in 2,4-0 as it has in 2,4,5-T. In the course of this review, a number of gaps in the data on 2,4-0 were Identified, resulting in a decision by the Agency to require additional studies from registrants (manufacturers) of the herbicide. Those toxicity studies considered scientifically acceptable showed that signi ficant adverse effects were unlikely at human exposure levels which might be expected from current 2,4-0 use patterns. New studies were needed on oncogenicity, teratogenicity and repro duction. In September 1980, registrants were notified of these requirements (see enclosed copy of the data call-in notification). EPA 1s coordinating Its health effects review activities on 2,4-0 with Agriculture Canada. In late October 1980, the Canadian government made public the results of tests conducted on 2,4-0 samples manufactured 1n Canada. Employing sophisticated analytical methods, Canadian scientists confirmed the absence of 2,3,7,8-TCDD, but found other, reportedly less toxic dioxins, ranging 1n concentration from 5 ppb to approximately 8,000 ppb, In some of their samples. Consequently, EPA began a series of tests to detect the presence of dioxins in samples of 2,4-D produced 1n the United States, employing the same analytical methods as used by Canadian scientists. Testing of samples collected from the complete range of 2,4-0 manufacturers is being conducted at the Agency's Beltsville, Maryland, laboratories. EPA is also collecting information on manufacturing processes which may help to explain how dioxins can form during the manufacture of 2,4-D. To date, the Agency has tested 30 samples Including both technical 2,4-D acid and ester products, and products contain ing amine salts of 2,4-D. In preliminary findings, employing tests sensitive to dioxin concentrations as low as 1 ppb, 27 of the samples were found free of any dioxin. Three samples contain the 2 , 7-dichiorodiox1n in concentrations below 100 ppb. Thus, preliminary results of EPA sampling have confirmed a significant difference between 2,4-D products sold in the U.S. and in Canada, possibly due to differences between U.S. and Canadian manufacturing processes. 0 -2- EPA Is continuing to assess the safety of 2,4-0 by additional sampling of U.S. produced 2,4-0 to determine whether manufacturing processes consistently produce 2,4-D in the range of U.S. products already tested. The Agency 1s also conducting a detailed review of health effects data on the dioxins identified in 2,4-D products. In addition, new acute and chronic toxicity data supplied In response to EPA's 1980 data call-in notice, described above, will contribute health effects Information needed for the comprehensive review of 2,4-0 which is part of developing a registration standard for this chemical (see enclosed fact sheet on registration standards). Although development of a registration standard for 2,4-D 1s the Agency's long-term goal, EPA will review toxicity studies and dioxin analyses as they are submitted to determine whether a change in our r e g u l a tory position is warranted. I . t 1. I .. i..- ki . . l` f . Is . O1 M , .|I I- : l . s t. . ti l . I l P O L n ' j n . t i . :.. - Vt -.t ,, 1 . . . i.'c / I t ' . (1. 1<. i -vs I:.,... :f. k .'* (. ! I. ,, a . I S, 1... . . V. | a - | O , U JM tiv. . iM- s : I .i 11 vl ^ ' ; ,v j *i c.{. *., *. : o ! ,,1-1.k '!ic n o i t . nr |*n -1'. - . i .i . * ' i / / ` il l ` . i a Mir . !K : 5 3 h SS. ( 's--: e a . P. j *` 7. I I . - r >1 sovt 111 j i (.1 1 il l u i Jc ru*. ^1 ->n 1f t 1V > *s j i t o n l>\ . 5 .7 .S 11 D t j . 1: ,11 in ., HUM ,jl S . m p U s i u Ml o. 1 j . l t * . Jd c l o f i * c Ik miic .il i n j n s l r . ! if, P . i " : i l . M . J'x h t >i r f ; .* u . . p , . n . i . j , A k .'! . II. . M< *.<. , : m .t ,1 i f - * H u; | f \ f u c l ; l j i 1 l J ' J.I ,UKf L I 1' ! J J l t J n i n t i i b c ii i d i a t i , i ! i :'j tt * U in.*1!', .li .U>. ' a i / r ' , a M o s .i 51 : t;. M .Njv . 1y 7 J. i 1 a,. i ' i i i. / f t * * .u l i i k - n i >! ; ;.>du> l i o n u lv P .i ! J iIk ii '! : ). ,b P.i. ,'! . 1. !.. I " . 1 -11 .J, M. . S.'.iwi't . I, Vt. IITJv. ! L . k :` i -1-k \ . 1. . .i . t . | .1 .HI 1 . A. , - l i t i i ' l. k-'V.i, f . 1''7-1. . i; 11(i v k j t (i .. h \ klii uti i a- J h> <J'' 'l a r b o r i b , I o n * t d in 1 ! k . : - J u t lu>n \>\ 2 , A .5 s o d i u m ' .. h l o f p V ' 'o >. y dL C l ,\l L l ` .. 1 '/. 1in C 1. i, J i . j *2- *. s. | i f .[ !.. ; k , de it .k . , k u b ' c , * Pj / tier t v j , J.; L u k j s . t . 1<''f. 1 *t- U r 4L n c . {> i< jbv 'a . .i I j r d s f aff i u l h c f of r . ; i v j . i >i b> l. i . . i d l 'b. / (j;>. { (in Ct** M u r ,) . 2 7 . . k i'S. j i: . -s k , L ., K j b ft k . K u b k c , k . 1073. A n . r c b lo flin and p u ; i l - i i t U l j n c j l . i i i l u b> (he , fO.JuctlO.'l o ` h e r b i c i d e . ( y c f- / 1--\f[ ( i n O t t l i i a s . 3 tr t, .i `S u l u n i u c t i l u r p u U a j l i u n l u b i u j i s 2 9 , ! 9 h J vsist-d: j - e v p l e d f u i '*?i( . i t i u r i A p i il 21, O S O . ik i ` j u c s K fo r f c p r m i i ' i t o u t d be bi ni lo: Jan* I ' u / d c r o v i * Vrlvii`ko\ j. M.D., Pl>.{... Kl.nika m ::o.i povul J-*i, Prague 2, IJfcijl V> Skill dCbk.l W ( /tx h u iiu V :M.'. Trlrarblomazobrnzein* in iM-I)iohIoro;iiiiline and Its Ilerbit idal Derivatives PropaniL Diuron, Linuron, and Neburon KOB! R I M HI l i . K . l'Ii.U. / I l.DA j. ROLLI \ H V KLNATL I) M M Iia O U O U , M.D. DONALI !.. MKoi l , B.S. . \R K Y L NI. L U I . U t. Ph.U. ( ci iter fu: Discase ' iiliul !' ohe I k 'jltli Seri wi L' b. Dcp.i: imeni ot Health jnd Human Servii es A:'anta, (.teurgia ABSTRA< I. The |"e>cnce of 3,3 ,4,4 -letrachloruj/olx' /> in* (TC A li) was determined In high performance liquid chromatography in 3, 4-dichloroauitinc and herbicides made therefrom. I fie concentrations of T( \B in 3, 4-dt .nloioanilines and m different herbicides from a variety <,t manufacture's rang. t from 9 to 1400 pg/g (ppm), l h iliM rjuiegenic potential of these products, as determined b, rabhil ear test, suggests that it is in the same range ni J I, 7, )i ti iraeliiiirndihen/odioxiii, j known potent chlor a< ii.genii agent. RLC.f N IL Y , sur' n i).:tbreaks of ..liluracne in groups ol themita! wurkcis h.r.e been attributed to 3 ,3 ',4 ,4 - tctruchloioa/obcn/eiie ' ICABj anJ 3,3 ,4,4-teiracliioroa/oxybenzene i K.AOB) as contaminants in 3,4- dichloroaniline and its herbicidal dot ivativev, J These contaminants arc b> p; .ducts of ilia commercial syn- llutic process.1 In addition, severe! * 0ikei> have reported that th> herbicides dec .i le in soil produce l CAR and I l AOB ' hloiinaied i. obencem - ...e stiucv.iialK simi lar isosUiic) to,the ih lo iinjted dine i/odius i> and dihen/i,f 11' .ms, which .a - cause clt! acne. Poland has repotted that vhloriiuh d JibviMot-.r.'.tns, dit i/odioxios, cl u u d r y PlJ< ; 'Voi, 4f>, N l' Pg. 31 -- PLAINTIFF MEMORANDUM I I tti-JLl jiivliai Voi. No. 11 Michigan Division Internal News Dow Chemical U.S.A. Midland, Ml 48640 December 7, 1982 cDhilvoirsioobnentozemneotphrboadlul ction Dcaonwcerrebaulltesgations As soon as negotia will enable us to deploy tions are complete, Dow our resources into more intends to suspend the profitable business manufacture of chloro areas." benzene and mothball the The Michigan Divi plant. sion is the only Dow Dow currently is location that manufac negotiating with Standard tures chlorobenzene, and Chlorine to supply Dow's currently employs 75 internal chlorobenzene people. These employees needs as well as our mar will be reassigned within keting obligations. Dow Dow once the mothballing intends to fulfill all process is completed. its marketing commit Gaska said this ments. announcement, made "It's hoped that yesterday, has no effect this will be accomplished on the Diphenyl Oxide by January 1, 1983," said manufacturing facilities Ray Gaska, major manager and business, both of for Inorganic Chemicals which will continue to Production, Energy and function as usual. Utilities. "This action is being taken due to the For more details, watch poor overall economic "Business Brief" during conditions in our the lunch hours Wednesday country, and a severe and Thursday. Featured slump in the chloroben on the program is Ray zenes business. It also Gaska. Employees asked to reduce vacation carry-over Salaried division em ployees are being encour aged to reduce by half the number of vacation days they carried over in 1981. The reason, according to Carl Bauer, major mana ger of Employee Relations, is that funds are accrued each year to account for vacation time that is earned and not used. This is considered a liability for the company because if an employee were to quit, he/she would be paid for this vacation earned and not taken. "While this added use of vacation won't result in a cash saving for the comp any, a reduction of days carried over will reduce the amount of money which the company has to set aside," Bauer said. "If all employees use four days more vacation than last year, this could mean an improved profit of about $1 million for the Michigan Division." That $1 million re presents an average of each salaried employee using four days more vacation than last year. (A story appeared in the local newspapers last week alleging unusually high rates of cancer deaths from sort and connective tissue sarcomas among white females in Midland County. The following is a response written by Joseph LeBeau, Dow U.S.A. director of Health and Environmental Sciences.) .Last week, an employee of Michigan's Department of Natural Resources, acting on his own initiative, re leased largely unpublished data obtained from the U.S. Environmental Protection Agency which he states in dicate an unusually high rate of a rare form of can cer deaths (soft and connective tissue) among white females in Midland County (Michigan). (The new data comes from an EPA re port titled "U.S. Cancer Mortality Rates and Trends 1950-1978," now' in press). And he suggested as a poss ible underlying cause operations of The Dow Chemical Company's Michigan Division plant. Inasmuch as we do not yet have the EPA data in hand (we are seeking it), our comments at this point can only be tentative and 'preliminary. But we would like to note the following: -- We are concerned by this report and have assigned our top health and environmental scientists to study the question. We agree that further evalua tion of this issue by S(tovaetre) \HCeV(o Dow rebuts cancer allegations cont'd. . . . Health officials is in order. And we will cooperate fully in that effort. -- But we urge caution and care in interpreting the data: The numbers involved -- one female death due to this very rare cancer about every two years over 28 years for a total of 13 and one male death about every three years for a total of nine -- are quite small. This is not to say we are not concerned. But con clusions drawn too soon from such a small sample could well prove mis leading. The pattern among females and males does not seem consistent. Among women, there was one death in the 1950*s, five in the '60's and seven in the '70's. But among men, there were two deaths in the 'SO's, four in the '60's and only three in the H O ' s . If exposure to an environmental agent of in dustrial origin were the root cause, one would expect a higher incidence among men than among women. And one would expect con siderably more than three deaths among men in the '7 0 's. Yet just the re verse seems to be the case. In the past, diag nosis, coding and abstract ing of death certificates was far from an exact science, although there has been improvement over the years. Re-examination of the certificates in ques tion could very well lead to different conclusions. And since the numbers involved are so small, any change could make a big difference. Furthermore, the hard data we do have does not support the suggestion that there is a problem associated with all cancer (1) According to "U.S. Cancer Mortality by County: 1950-1969," published by the U.S. Department of Health, Education and Wel fare, total cancer is significantly less among the population of Midland County. And (2), a r e cently completed mortality study of Dow men employed in our Midland plant cover ing the years 1954-1978 shows that deaths from can cer were only 95 percent of that expected. In other words, the Dow cohort has fared better than the national population as a whole. Moreover, the Dow cohort performed better than did a similar industry-oriented (but non chemical) community-based study group elsewhere in Michigan. Deaths due to cancer were seven percent lower. (For a more complete discussion of this study, see "The Point Is...," No. 57, October 29, 1982 -- a Dow publication.) This episode illustra tes once again the critical importance of orderly science grounded in sound research followed by peer review. Sidestepping this well-founded procedure at any point can only waste resources, as the parties involved pursue red herrings. More important, in the case of health questions, it can cause needless stress, anxiety and suffering. -- Personnel changes -- WEN CHENG has been promoted to research associate in the Organic Chemicals sec tion of Chemicals Research, where he is involved with the terephthaloyl chloride pilot plant. JOE DARLING has been pro moted to senior quality control analyst at the Bay City Plants. JAMES W. EDMONDS has been promoted to group leader in Chemicals Research Lab of the Michigan AS&T Labs. Jim is responsible for pro duct and process research for aromatic monomers, zeo* lite catalyst technology, DPO, phenyl phenols, and Dowtherm heat transfer fluids. DAVE GESSFORD of the Chemi cals Research Laboratory has been promoted to senior research engineer in Ludington. Dave has been a part of the new calcium chloride dryer team from early in the construction phase through the recent successful start-up. HELEN SMITH has been pro moted to senior administra tive office assistant in Salary Payroll, BERNARD P. SWIERCZ has been promoted to foreman in Capital Construction Pro jects, assuming new first line supervisory duties of a mechanical construction operation. LARRY WILSON has been pro moted to project leader in the Designed Polymers & Chemicals Research Lab. His current research in terests involve the development of polyamido- amines as a new water soluble polymer family. t: Vol 126, No. 26 28 Pages ,,Wednesday, June T, 1983, Midland, Michigan V. '-i v'i''i"Vl'tT.?*'qA.1.4.:4;V<r---V*-**--V-.'4T*33T ^. - V .F .v. Dow to spend $2.5 million .-<v l .,.r * on diox cawpgcscvigtDasfD'm;rnyoiuiioaanlradioonsrgaDePnnalnrnocoiwwelgntndnfxcrtfoienhDopti't'teneus-tMswsnh,peruppapsrdcetuanrceiamoowboetipiCedenoecDrsnnliMcapfaaeeoeihnnmahaduacraBsdneMluitlaeitsniytgamssaundtmneylmpenodelhatynicldPt.LriucduiaanesesebxcwoNrleoanlnrtcOnsaeariaotgucntunidaeaeeoltslhntfhrRdstttlwlettyopahcrddedteCytiaofFIufamelshireraoEhroaaaCPilepd.ssvacnrabnmxdsvutayOoehSonddztaatoitibibluuon;sfHotaiieofuaeiiloomcn$ddofrhunlwipfAttihxitdtc2ywfianentdeyhfttfaiN.iytHaihetoeditn;5eertrheooo,lchroiEegfsraeeetesfxthatsmhh;feeneslaohUsionotud,;twanrlnMuaeieafotcainmln.aoentriholbhaln-dcMddiiixouvxtaldtvoeedfdiiipgniniDfulsenisostrnraucyachssehnroenoinhnnue.sntneidnstswoididnddaoe--;r cccdpiscitntaaahaiaowiOHnnnasdfxnntotbiroiteiDuognethnwfhnteoffohcddorbiweucalere-uevtimsiainescssetsrxeoaiterMstopdhri,cotrdenbeaioiclhdihyDstblvtleuecaootwcehdmnowrodisadamn,ttathao^htvitbnaiohtaitudhansanerhslcee,k.nltge"eieoltnaode"ehtlononvWctteu.tehehhrrl.aaaphsawntHulaosgobdpitfegerliduidondahicbxoilfiilafsitxoitinyocss-r . ceo"tttmahhiWexfrneeeorOAipunsessunrsuteeisnehknoabftyaategtnlfhnidvebidctctidaeehhnWe"riciigidcnsasnoth.srogd.ngbyin.tidtacio.ineoitececttWidhcriitothsnsheieeumnahapirrst'tssehttsoiesamvatidlaiavsniemn.etkke"d,iavesaoewopfOmtnhailriatvvoercoareicatvirenifskehteofgentniionfhc'gotDfD.eahaaraTootallslwwhooccelaletoovtid.sdnnteoo"ooel,ff. smvdalwislopdt1mttoneituhonoeataouvcceTioIhireDol"nttlnlNdvalnenerWahesluutoetelydApbeAtoCreindsbwJosedlsfecetasaLaatwocanwos$,uwaes$bgnh"ffUmiea1semimdtoa2leotdO,aailtia,Dllytlphn5ferirsmlpleensrooc,looosc0wEenrltelor.cxh.ifiwit,,iffwlsDtsehon0toatiefDlaieToensifiintrga0dhxyicocodh.oIrfyhndre0iheNeahnrrwmeciirudbaTetelSnsahrvd'l'cnpTywsrosaihlywsiaetnurdiMeHnointe.eoiadolovlautlllxtaiedlptnl.eEpeuhdnaedisswriseacdaolnn.ssadbeitiapdrltveultt,sdte'yaielais.siseseWddpafgstcdosno.tdiaiyrntooaeun.onludhaosnlwmtsodjnausrht'vTwi,aoeco.yarlsnopeisdhneeii,odnn,wtaxnn,ge:sdoeauilrdadtneiaoawnclimmasedobnvdvncejsotpolototensiuioeuhitutenilirriedcheidvnldnennntalwdidyoeeestr'r- !,CcdBdwttvpdsltczsihihinaiioeoeiiunsouhaooteeigDTl"rlDrslokduZnivhxxIrtvtgcuhr-trnueoe,iziAios.hstcseneeendwctrheahiaynstxJaDeslteiooifnacal.eachd$nilsnriaMusaio'rDmtmas.foo2etcdtavltoam"nlwsm5hdpohDsgloiiieRr,0cenddwttpaepetnsbPhh,ameehw.k1rato0,BieaHaratteat0nS0pwioaecsbolusdMcty0lauenutmetrzhayohpu;otf"ullyt>thzfiihn,afedwweahoecncecoeiteae1:rmlhihrti/ldiearanl0sol'sltttsqiaetsiebloosant0sogn,hienbuduare,rlnd:tm.auesiepydOieladvd'tnfxli,sebtpsydya,iceeiesreepanteoDb,onevi.ppisyclivhtxfoteieoaaiitodDasfiivbitluifcsgrrg<iurirvoiafoeiitcertoheeoasfmtelewMelwtasiirnwlateinsccwosiineevomiao,daettinhlpvd"lnolkdefefianel.yeeehderatlvulBsss-stksna-ygoehuua,dhefui.-ntnlsfaour?pnoyeas^df1idSor^--frlf,-;' --'I dBfldeoiaevorAraexdDcllihtfoinho;sf'oer1Mcuasposagoepfnhte,btC1atl.eehoma-vensieretnerlsoaboithesifrii d"1.pannastapM"waucpdmoiioem:znirIipdentehacefoheorerd-nthiAAiuoeoeiaudettciosanen$ingnahnnhfscnt2tatcttieo.shoo.cht5nwcadrGthefoee0ehleomtodeifpt,sobtetdn0hretedoerqgesl0eadraihjb,nfuam0aondneraSfeeenckxvtDaziariayshieinihefacznKtuonDlyeiviroaewanodmdd,himiptdtnnee!ii(i -Q (X3 25< Per Copi r t Althou?!g>h;trh.ereis nVo -na,tiovn<a>-l-: sta;i>:- - dBllbeievroaexDclihionis;feIMatpo8rfnpe*tb;C,ac.bmahstiernobahetrieoc<tnxe.n^itnnijendte:htnQ;<ef);eT-tdoitmhthaeest y jcaapt.nas-wlm.cipdorizAiInp.ea&ehfoyefernniuc.iaodteticnohao-iaefh-tcncttesiVshco.cthaf.wGhofeeletotdipfoe.odrrtvtdufqsieegarlij.hodnnnfaaWSxfetzenraiiaiiasefcnniulty^iv^teddjnh,iiatneedtii'nopwso'enrAtaleerenihvk>stnfel,reiawiwsxdtdmtaieiehenhsinnaddBitgkvttin,nhsibtosrfnthgec.ohaarehnelrtimomeiittyohrer,angedrainacataesose--tl anpM' moeointc-ohdAhueeine$gnnt2atbn5drf0eetm,sot0eeo0dranm0erecvBiyhenoDleowadupt!wgttrehwacenhontUutolondloifsvhgpeynerdnsaidiitmnyhdeaoedsf ;btawematPliihteolntoryiroreeoBnrtetnditet.aFaoesdoitddslc,tBfiiswdsnuy$satouict7anrohaizabhil5asnxzinlnae0lcyuegygAdra,h,lne0gzfdfgwa.di0eeim1iedxe0oishnddblro.oaxilciiywadrosimty'exdicox/aota.mfmiarhymlnnjtt.ba*,hepashxuSDbal.:le~aaenotEsotTrsDiarrttnwcKhoaussoiveit'pdpewsanaiearyewner'inolsrny.xtnafiqce-pgcosmOufaeiutofpnaqepelnfadusaunwdsibtreiotecipiiaanillndn-r-lt '.alrsttlweoihertaaeuhc"rAtb.eTrhtad"l,nsatee"hiketeleiev,afOssdoOewmrrrtsreihyehfqtpfeafhfoieDfritneiwoscco.apee"retwllheldesrsiae'wosnupidfdgollhiti.ouoseetlxd"adhorW,ilafntc"shteItoch'iinlwepswlesnrsieliodceaeleebalh,rvslho;eaiteseupmciatedtccsshleioetetaprhilos-ttff 4- -0 - ^ <> 0Q -O -jg -> Lincoln County Watershed Watch P.O. Box 343 Seal Rock, Oregon 97376 Telephone: (503) 547-4294 May 19, 1993 REQUEST FOR LINCOLN COUNTY DIOXIN TESTING ORDINANCE Lincoln County Watershed Watch asks the Lincoln County Commission for an emergency ordinance requiring dioxin analyses of all 2,4-D products used in broadcast applications within Lincoln County. This request is based on the following informa tion, which is keyed to tab numbers in the attached information packet: 1. The U.S. Environmental Prote c t i o n A g e n c y rec e n t l y d i s closed that some, if not all 2,4-D contains dioxins and related compounds, including the most toxic dioxin, 2,3,7,8TCDD. 2. The EPA previousl y found 2,3,7,8-TCDD in environmental and human tissue samples from Lincoln County and other parts of the Oregon Coast Range. EPA attributed the 2,3,7,8-TCDD found in small birds and mammals, other wildlife, domestic water supplies, deer and elk meat, and tissue from a baby born without a brain to forest and roadside spraying of herbicide 2,4,5-T. Sediment levels of 2,3,7,8-TCDD from a tributary of the Alsea River were the highest ever recorded in the Pacific Northwest. 3. EPA calculated t h a t fish levels of 2,3,7,8-TCDD w o u l d equal sediment levels, but did not follow up with actual fish studies in the Alsea drainage. Fish, particularly trout and other salmonid species, are exquisitely sensitive to TCDD, which bioconcentrates up to 159,000 times water levels in fish tissues and causes toxic effects and death at the lowest doses ever tested. EPA scientists have warned that concentrations as low as one part per trillion TCDD in fish could be a reproductive hazard to human consumers. 4. In some forest areas, EP A has found high soil levels of 2,3,7,8-TCDD from forest spraying decades after the last herbicide application. Nevertheless, neither EPA nor any other government agency has followed up its findings in Lincoln County, to determine whether the high levels found in the Alsea watershed are reflected throughout the county. 5. A 1980 prelimina r y U.S. Centers for Disease Control study suggested a link between aerial 2,4-D spraying and a 13-fold excess of neural tube birth defects in Lincoln County. 1 /9<Sb 6. EPA never attributed environmental dioxin c o n tamination to 2,4-D, because it was thought that 2,4-D contained no 2,3,7,8-TCDD. EPA required 2,4-D manufacturers to test their products for dioxins in 1980, but did not disclose any results of that testing until March, 1993. EPA's summary of those results does not reveal which manufacturers' products contain dioxins, or how many samples contained some, if not all, dioxins. EPA will not release that information because manufacturers have uniformly claimed trade secrecy status on their dioxin analyses. 7. In light of these d i o x i n results, E PA has re q u i r e d 2,4-D manufacturers to add "Exposure Reduction Measures" to their 2,4-D labels. However, these label measures are aimed primarily at reducing applicator exposure, and will not significantly reduce dioxin exposure to others or the envi ronment. EPA has not required 2,4-D manufacturers to dis close the dioxin content of their products on the labels. The disclosure that any 2,4-D contains dioxins, including the most toxic 2,3,7,8-TCDD, raises strong concerns about adding any dioxin to the levels already accumulated in Lincoln County sediments, soil, fish, wildlife, and humans. Therefore, in order to protect the public health and natural resources of our area, Lincoln County Watershed Watch requests the Lincoln County Commissioners immediately to require full dioxin analyses, to be funded by the manufacturer or purchaser, of every batch of 2,4-D destined for any broadcast application in Lincoln County, with full public disclosure of analytical data and results before such applications are begun. Broadcast appli cation means aerial, roadside, or high-volume ground application. Lincoln County Watershed Watch also asks the Commissioners to request from EPA the complete list of all pesticides for which EPA has required manufacturers to submit dioxin analyses, in order to determine whether any product used by Lincoln County (e.g., Garlon used by the Road Department) or others for broad cast applications in Lincoln County may be adding to the dioxin levels already accumulated in county sediments, soil, fish, wildlife, and humans. Respectfully submitted, Daniel Blackwell Carol Van Strum Lincoln County Watershed Watch 2 I969( nm * TAB 1 1993 U.S. EPA, Dioxins in 2,4-D >2% (IN IT IO STATttS B N V IR O N M IN TA L M O T IC T lO N A O IN C Y WASHINGTON, D.O. 80460 ( 'lilM 'U . q IJf.A lOXK C,AM|7Jf;iv' MAR 2 1993 Office 6 f rfiaviNnoN. e u n o e c e tqmocuhtanoii *m* KWIJIDUM Subject* 2,4-D, 2,4-DB, and 2,4-DP and Their Salts and Estere* Survey of Dibenzo-p-Dioxin and Dibeneofuran Datermimition. DP Barcode D188268. CBRS No. 11410. Fro n t Stephan Funic, Ph.D.. Chemiet Special Review Saotionl Chemistry Branch XI - Reregistration Support Health Effect* Division (H7509C) Through! Andrew Rathwan, Saotion Head Special Review Section X Chemistry Branch XX r Reragiatra on Support Health Effects Division (H7S09C) Tot Jill Bloom Special Review.Branch Special Review and Reregistration.Diviaion (H7508) In June 1817 a data oall-in was isaued for information on tha polhalogenated dibenzo-p-dloxin and dibenzofuran contente of certain pesticides* The call-in consisted of two parta one part requested detailed manufacturing, information for those peetloidee whoaa structure or mode Of synthesis indicated a potential for dioxin/dibaneofuran contamination. Tha other part required the actual analysis of certain technical pesticides for IS chlorinated dibeneo-p-dioxina and dibeneofuran*. Tha latter group of peatiolde are- manufactured by processes documented to' produce dioxin/dibanzofuran contaminent*. Included in the list of pesticide* that requited analysis ware 2,4-D, 2,4-DB, 2,4-DR, and tha eaters and alts of these harbicidee. ^ ssjasase s.- :; 2 .. , . v ieveral dloxin/dlbanaefuran date submit!Iona for 2,4*0 and related peeticldea vere reviewed. Saoh manufacturer of the registered technical pesticide vie requested to randomly aalaat seven aamplee of thevpestioide and to analyse by a go/as method capable of quantitation to specified concentration levels, or limits of quantitation -(loq) v for aach dioxin and dlbensbfuran of toxieologioal interest. The resulting submissions vara reviewed for compliance with the analytical chemistry requirements of the data oall*in and for scientific validity. Table l summarises the findings for 2,4*0. Only 2,3,7,8tetraehlorodlbenso*p-dloxln and l,2,3,7,8*pehtachlorodibenso~fi* dioxin vara found at or above the SPA loq'a. Tyo of eight technical 3,4-O'a contained 2,3,7,8-7000 slightly above the 0,1 ppb loq. Three of eight taehnioal 2,4-D'a contained 1,2,3,7,8-PCDD at eonoentrations greater than the 0.5 ppb loq. Hone of the remaining thirteen ohlormated dibenao-p-dioxina and dibantofurana vara found at tor above the IPA loq'a in the technical 2,4*0. Data on tha 3,4-DB and 3,4-DP eolde and derivetlvaa of all three eoide are too limited at thie time to be useful to the 2,4*0 panel. TTeaobhlentio:uli8um,4m0tHuiyrroWfoRWeeaeule for Ohlorinated Dibenso-fl-Dtoxine andDibentofurtnt In Analyte * * 7>T 0DD Bl(oW>aA1 ai 2t4*D TTNeouotmahlbnetertolsf 8 * TONeunom*hb*nebrrtaohbfan .100 i 3 vMOobanxeoiemarvnuemrdanon j w i ______ 0.13* 1,2,9,7XKH2D 0.8 3 3 8,* 1,2,3,4,7,844x000 as '* a 0 0.81 1,2A 8,7X 4xC0D i a 8 o '- 0.77 , , , , , * x12 3 7 8 0 14 000 i t s 8 o aae H1ApC3D,4O,8f7.8- 100 8 0 1.8 9..t.-tcdf 1 0 as7 1A 3,7X>CDF 8 ' 0 I0.92 | 2.3,4,7,9-PODF 8 7 0 I0.73 I 1,2,3,4,7,844xCDF 28 8 0 1.9 I I 1,2,3,9,7X 4x001* 28 8 0 |1.2 | 1,2,3,7,B,0-HxCOF. 28 : 8 0 1.4 . . | | .8M 9,7X 4xeDP . 28 a. 0 J1.1 ! H1,p2O,3O,4F,8,7,8* 1000 8 o J8.3 II H1,p2C,3D,4F,7, | 1000 8 o |1.8 c1ojAnLJvcivme#erintnrtio.s&f*q*0u0.t0|nW7th^peppttbbo,rfwiwrhheeeqrrueeirOWeQdK*byopffthddeeemmAoognnesnsttcrryaattaeendddtko>tqqruuefssleeteddUffooonrr ofth* level oftoxicological aannaellyytteees nnoott ffoouunndd,, pages 1-3 4-5 6-7 8-15 16-17 TAB 2 Oregon Dioxin Data U.S. Forest Service/EPA Oregon roadside animals, ana lyzed 1974, reported 1978. E P A r e s u l t s of 1979 A l s e a S t u d y s a m p l e s P h a s e I. EPA results of 1979 Alsea Study samples Phase II. [EPA later claimed that samples UN 159-173 were not from Oregon but from Midland, Michigan, near Dow Chemical Company's herbicide factory. In four years of subseguent litigation, however, EPA produced no valid documentation of the "mixup" story, and the origin of these samples is still unknown.] EPA dioxin results on Oregon/Washington deer & elk EPA results of 1984 resampling at Five Rivers, Oregon. / 1-173 FOREST SERVICE-USDA PACIFIC NORTHWEST REGION FJNAL ENVIRONMENTAL STATEMENT VEGETATION MANAGEMENT WITH HERBICIDES USDA-FS-R6-FES(Adm)75-l8 (Revised) Prepared in Accordance with Section 102(2)(C) of Public Law 9l" 190 The National Environmental Policy Act of 1969 Responsible Official for National Forest Lands: R. E. Worthington Regional Forester Pacific Northwest Region Forest Service-USDA P. 0. Box 3623 Portland, OR 97208 Summary I. Draft ( ) Fi na1 (X) II. Forest Service III. Administrative (X) Legislative ( ) IV. DESCRIPTION OF PROPOSED ACTION Approximately 150,000 out of 2*4,333,61 2 acres of National Forest lands within the Pacific Northwest Region of the U. S. Forest Service are proposed for vegetation management with herbicides for the Fiscal Year 1978. The areas are located on National Forest lands in Washing ton, Oregon, and Del Norte and Siskiyou counties in California. The preferred alternative is to use all the methods available to the Region for vegetation management. These methods include using all the registered herbicides available at this time, mechanical clearing, manual clearing, biological control, and prescribed burning. In addition to the preferred alternative, four other alternatives are discussed and evaluated. These alternatives vary the combination of vegetation management methods and funding levels to accomplish vege tation control. Environmental impacts of the preferred and other alter natives are described for both immediate and cumulative effects. The proposed action has been reviewed in light of the guidelines set forth in the Interim Directions issued to implement the National Forest Management Act (P.L. 9*>"588), and is determined to be consistent with those guidelines. ? Type of Sample Date Collected/ S prayed Site N urnber T A B L L 7. !' O H U S T (Retyped to improve rljrity of rrpruduotion from T.lblo 7 ;i11 to Iktohrr J>-(I.r li.nu N . (h ,i H' ,) 2,4,5-T Application Rate (lb/A) TCDD 2 , 4 , 5 - T Level in A c c e s s i o n Lot N o . 7 2 ,4 ,5-T N unbor Sample Ree. Coir. Percent T C D D Det. TCt Weig h t For PCB? R e c o v e r y L i m i t (PPT) 1 Level Oregon Meadow Mouse Hermit Thrush Bewicks Wren Hairy Woodpecker Bowny-Woodpecker Rainbow Trout 5 Deer Mouse Bewicks Wren 3 Dendrocopos Pubescens - - Hairy Woodpecker Hermit Thrush Deer Mice Winier Wrens Rainbow Trout Downy Woodpecker Deer Mouse Bewicks Wren Dendrocopos Pubescens Song Sparrow Stellers Jay Fox Sparrow Mountain Beaver Spofefced-SkunksCutthroat Trout Coho Salmon Rainbow Trout Chestnut-Backed Chickadee Deer Mice Deer Mice Deer Mice Brush Rabbit Spotted Skunk Spofcted-SkankSpetted-Sktjnks-2 Fox Sparrow Short-Tailed Weasel Stellers Jay Wren Deer Mice Deer Mice Deer Mice Deer Mouse Mountain Beaver Thryomanes Bawickii Rough Skinned Newt Rainbow Trout Pacific Giant Salamander Deer Mice 6 Spotted Skunk Varied Thrush 4 Mountain Quail Scrub Jays 2 Rainbow Tro u t 10 Ruby Crowned Kinglet KierotBs-bengieoudas Pipilo Porcupine Porcupine Skin Freshwater Leech Salamander Long-Tailed Meadow Mouse Piryon Mouse Fox Sparrow News 2 Pipiie-Eryfchrophfehalotss Stellers Jay Mountain Beaver Varied Thrust 3 Golden Crowned Sparrows 2 Water Dogs 3 Hebo Unit A Hebo Unit 3 Waldport Unit A W a l d p o r t Unit 16 Wa l p o r t Unit 20 Chetco Unit 112 Brookings Unit ] 22 u Brookings Unit 125 3 u 3 1. 5 Amehem 6310 <0.1 ppm h Amchem 6 310 <0.1 ppm Am6c3h10e m '0.1 ppm Amchem I UK 4-26-326 332 329 336 - 328 330 240 253 260 261 334 328 330 333 327 - 325 245 246 247 252 2C 3 265 268 - - 248 250 251 2 54 2C2 264 26 6 267 268 337 318 317 320 3 15 no 3 31 323 331 323 5.0 5.0 3.0 20.0 10T0 5.0 10.0 20.0 10.0 10.0 5.0 10.0 5 .0 10.0 10.0 8.0 - 20.0 20.0 4 .0 10.0 10.0 10.0 30.0 10.0 - 10.0 20.0 20.0 5.0 10.0 10.0 10.0 10.0 10.0 4.0 10.0 10.0 20.0 No2 Yes Mo2 NO3 H- Yes NOJ Yes Yes Yes Yes Yes Yes NO1 Yes No 2 - No2 No 2 Yes No? No^ No 3 No2 Yes - - No2 Yes Yes Yes Yes Yes No * No1 Yes Yes Yes No3 No 2 20.0 No * 20.0 10.0 2 t 0 Yes No i-- rs 10V0 20 .0 Yes 102 32 41 55 43 65 43 40 28 40 40 82 65 43 29 68 - - 13 34 36 5 4 67 94 16 3 17 48 6 46 52 17 34 16 37 37 21 43 31 1!) J4 39 5H 66.0 20.0 31 .2 3.0 14t6 ND ND 83 ND NB 9.6 14.6 ND ND 25 19 4 4.0 21 ND ND ND ND 9.4 9.6 14 .6 35.8 4 .0 - 17.2 ND ND ND ND ND - ND 3.8 60.2 550 92 5.6 7 .7 37 - - - 773 20.2 7 .5 254 8 .9 68.7 47.4 11.0 35.6 32 .2 10.2 15.4 3.6 a --^ ND ND ND ND ND ND ND - - - ND ND 12.,' ND 14 .J ND ND 14.4 ND 13J .J ND ND ND L3 .8 ND 1 1 NI) 21 .G -- ^ 136.1 290 NB 2 .9 ND l?<o?8 11-87 <2- tarli: 7. - c o n t . FOREST e of Sample Date Collected/ Sprayed Site Number 2,4,5-T Application Rate (lb/A) TCDD 2,4,5-T Level in Accession Lot No,7 2,4,5-T Number Sample Rec. Corr. Percent TCDD Det. TCDD Weight For PCD? Recovery Limit(PPT)* Level(PPT beer Mice 8 fountain Quail Fox Sparrow scrub Jay Snails 2 Stellers Jay 2 Golden Crowned Kinglet Dus k y Footed Wood Rat 2 Rufons Sided Towhee Rainbow Trout 5 Racoons 2 Song Sparrow Song Sparrows 2 Bewicks Wren White-Footed Mice 2 Winter Wren Banana Slug Brookings Unit 125 6361 " " 3 Amchem <0.1 ppm 6310 ** " H" "* 321 20.0 Yes 322 20.0 No1 324 20.0 No 319 20.0 No 225 15.0 Yes 226 20.0 Yes 227 5.0 Yea 228 20.0 : N o J 229 5.0 Yes 230 5.0 Yes 17 12.8 ND 46 5. 1 ND 45 4.6 ND 25 10.0 ND 27 14.5 e. ND 25 6.6 3CM 27 27.Q 143,0 59 4,8 ND| 24 47.3 ND 10 45.2 ND"* *TCDD detection limits and levels are corrected for recovery values. ^Recovery value was not corrected for PCB interference PCB level too high for accurate correction. 3Recovery correction for the presence of PCB was unnecessary. ^Recovery value was not corrected for PCB interference due to broken sample tube. ^ND means that TCDD was Not Detected in the sample. ^Instrument malfunction prevented PCB correction. ^Herbicides beginning with "MM" are Dow Chemical products; those beginning with "A3" are Chipman ViscoRap products; the remainder are Amchem products. * 1^71 3 25 Table III. Sample No. UN 1 UN-1 UN 2 UN 3 UN-3 UN 4 UN 5 UN-5 UN 6 UN 7 UN 8 UN 9 UN 10 UN-10 UN 11 UN 12 UN 13 UN-14 UN-14 UN-15 UN-15 UN-15 UN-16 U N - 16 UN-16 UN-17 UN-17 UN-18 UN-19 UN-20 UN-21 UN-22 UN-23 UN-23 UN-24 UN-25 UN-25 UN-26 UN-26 UN-27 UN-28 UN-29 U N - 30 U N - 31 UN-32 UN-32 UN-33 UN-34 A n a l y s i s of W a t e r and S e d i m e n t for TC D D (Alsea, O r e g o n Study - Phase I ) . Sample Type Ngs Cone Det % Isotope Spi ke (PPt) l i m i t R e c o v e r y R a t i o Data Report WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER WATER SEDIMENT SEDIMENT SEDIMENT SEDIMENT in CN 2.5 .067 .02 2.5 .027 .005 75 65 2.5 .76 .04 85 2.5 .092 .01 2.5 .023 .009 90 45 2.5 .067 .03 2.5 .041 .03 80 50 8.5 ND .008 55 2.5 .061] .03 2.5 .31 .02 50 50 2.5 ND .03 75 2.5 ND .04 2.5 .040* .03 60 65 2.5 N D .007 55 2.5 ND .04 2.5 .070 .02 60 75 2.5 ND 3 60 2.5 13 5 60 2.5 ND .9 45 2.5 30 14 55 2.5 2.0 1.4 1.9 .2 2.5 5.9 3 30 105 ND 1.5 N D .7 19 9 80 2.3 .5 2.5 ND 11 60 2.5 .061 .03 70 2.5 ND .02 120 2.5 ND .04 70 2.5 .083 .02 90 2.5 .065 .03 60 2.5 .0081 .005 60 2.5 ND .05 80 2.5 .11 .04 60 2.5 .011 .009 50 2.5 .081 .06 45 2.5 ND .004 55 2.5 ND .07 45 2.5 ND .07 40 2.5 ND .08 2.5 .17 .03 40 70 2.5 ND .08 45 2.5 ND 9 70 2.5 N D .4 65 2.5 ND 4 \ 85 2.5 ND 4 90 00 2-IVB 3-IV 2-IVB 2-IVB 3-IV 2-IVB 2-IVB 3-IV 2-IVB 2-IVB 2-IVB 2-IVB 2-IVB 3-IV 2-IVB 2-IVB 2-IVB 3-1 3-IV 3-1 3-IV 3-V 3-1 - 3-V - 3-V 3-1 .83 3-V 3-1 3-II 3-II 3-II 3-II 3-II 3-IV 3-II 3-11 3-IV 3-II 3-IV 3-11 3-11 3-11 3-11 3-11 3-1 3-IV 3-1 3-1 1^700 -H 7 35 S E D I M E N T 36 S E D I M E N T 37 S E D I M E N T 38 S E D I M E N T 39 S E D I M E N T 39 SEDIMENT 40 SEDIMENT 41 SEDIMENT 41 SEDIMENT 42 SEDIMENT 42 SEDIMENT 43 SEDIMENT 44 SEDIMENT 45 SEDIMENT 46 SEDIMENT 47 SEDIMENT 47 SEDIMENT 48 SEDIMENT 48 SEDIMENT 49 SEDIMENT 50 SEDIMENT 51 WATER 52 WATER 53 WATER 54 WATER 55 WATER 56 SEDIMENT 57 SEDIMENT 58 SEDIMENT 59 SEDIMENT 60 SEDIMENT 61 SEDIMENT 62 SEDIMENT 63 SEDIMENT 64 SEDIMENT 65 SEDIMENT 26 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 ND 22 ND ND 38 11.1 21 34 11.7 20 4.4 ND l 1.3 ND ND 3.6 3,6 4.4 5.8 * ND ND ND ND ND .08 ND 64 40 24 7 32 60 7 7 5 ND 9 58 14 5 13 9 4 .7 3 16 1.6 12 .5 1.8 .4 12 .9 1.2 .4 1.4 .6 .9 .8 .03 .06 .07 .03 .10 17 8 13 3 4 12 4 2 2 2 4 5 35 35 70 75 35 55 35 25 20 60 60 45 50 40 60 60 65 80 55 100 75 45 55 55 70 50 35 35 50 45 55 80 75 o CO .63 .83 .86 .78 31 Table VII. Analysis of TCDD in Biological and Envi ronmental S a m ples ("Alsea, O r e g o n P h a s e II ptoject" ) . Sample No. Sample Type Ngs Cone Det./ / % Isotope Spi ke (EEt) l imit R e c o v e r y R a t i o UN 159 UN 160 UN 160 UN 161 UN 161 UN 162 UN 162 UN 163 UN 164 UN 164 UN 165 UN 166 UN BLANK UN BLANK UN 166 UN 167 UN 168 UN 169 UN 170 UN 171 UN 172 UN 173 UN 185 UN 185 UN 186 UN 187A UN 187A UN 188A UN BLANK UN BLANK UN 188A UN 188A UN 191 UN 192 UN 193 UN 193 UN 194 UN 195 UN 196 UN 197 UN 197 UN 198 UN 199 SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SEDIMENT SLUDGE SOLVENT SOLVENT SLUDGE SLUDGE SLUDGE SLUDGE SLUDGE SLUDGE WATER WATER WATER FILTER WATER FILTER CAT LIVER PRODUCTS OF CONCEPTION PRODUCTS OF CONCEPTION PRODUCTS OF CONCEPTION SOLVENT CHARCOAL PRODUCTS OF CONCEPTION PRODUCTS OF CONCEPTION MOUSE SHREW MOUSE MOUSE MOUSE MOUSE MOUSE SHREW SHREW SHREW SHREW 2.05 2.05 2.05 2.0 2.0 4.0 2.0 2.0 2.0 1.85 2.05 Extracted 2.0 10.0 10.0 Extracted 2.5 2.5 2.5 Extracted 2.5 2.5 2.45 Extracted 2.5 2.45 2.5 ND 120 - 105 - 30 - * 210 - - 220 ND ND - 160 5800 470 283 - .38 ND ND ND only. 3 ND ND only. ND ND ND only. ND ND ND only. ND ND ND 19 30 15 40 8 16 80 41 13 50 12 680 24 50 48 10 140 75 4 50 1 70 8 8 12 56 10 48 .25 .2 5 50 5 15 50 19 50 - .21 1.63 2.00 1.96 - .96 .90 .78 .78 .80 .79 2.16 .84 .39 Analyzed elsewhere. 2 50 12 50 12 20 1 Analyzed elsewhere. 4 55 3 55 18 6 Analyzed elsewhere. 2 50 3 50 3 55 Analyzed elsewhere. 8 30 7 . 50 4 65 Data Report 10-IV 10-IV 10-V 10-IV 10-V 10-IV 10-V 10-V 10-IV 10-V 10-V 10-IV 10-IV 10-IV 10-V 10-V 10-V 10-V 10-V 10-V 10-V 10-V 10-11 10-VI 10-11 10-11 12-1 10-11 10-11 10-11 10-VI 12-1 10-1 10-1 10-1 12-11 10-1 10-1 10-1 12-11 10-1 10-1 10-1 1 7 ^ (o Q UN 199 UN 199 UN 200 UN 201 UN 202 UN 202 UN 203 BLANK 001 BLANK 002 BLANK 003 UN 203 UN 204 BLANK BLANK BLANK UN 204 UN 204 SHREW SHREW BIRD MOUSE BIRD BIRD MOUSE SOLVENT SOLVENT SOLVENT MOUSE NEWTS SOLVENT SOLVENT SOLVENT NEWTS NEWTS 32 2.5 2.5 2.5 Extracted 2.5 ND ND ND ND ND only. ND 11 .98 5 50 2 60 3 50 Analyzed elsewhere. 3 30 Extracted 2.5 2.45 2.4 2.5 Extracted only. 3 ND ND ND ND only. Analyzed elsewhere. 2 50 5 50 4 50 3 55 1Analyzed elsewhere. 10-VI 10-VI 10-1 10-1 10-1 12-1 10-1 12-11 12-11 12-11 12-11 10-1 10-1 10-1 10-1 10-VI 12-1 (<? 7 o 3 7 /o 1/2 ? A c e s s i o n #: 9 Title of Project: DMP Deer and Elk Study Status of Project: in p r o g r e s s Location of Sampling: Oregon and Washington Herbicide Use: forest Sample Media: deer and elk adipose tissue Range of Limit of Detection: R T P : 0.8 - 6.0 ppt W S U : 8.0 - 34.0 ppt Average Limit of Detection:RTP: 2.7 ppt WSU: 14.8 ppt # of Samples Collected: deer: 6 elk : 9 of Samples Analyzed: 15 # of S a m p l e s S u s p e c t e d Po s i t i v e : : deer: 3 of 6, 50.0% elk: 7 of 9, 77.8% Comments : It is important to note that four samp l e s were a n a l y z e d below 50% recovery of the 37C1 TCDD standard and therefore require re-extraction and re-analysis according to standard Dm p procedures. These samples are # OR-D-1, WA-D-4, WA-D-8, and WA-E-7. N e v e r t h e l e s s , the d a t a i n dicate the p r e s e n c e of 2,3,7,8 TCDD residues in both deer and elk. A l s o it is i m p o rtant to no t e that RTP r e p o r t e d the p r e s e n c e of o t h e r minor isomers in a d d i t i o n to the m a j o r 2,3, 7 , 8 T C D D isomer (based on the DMP analytical criteria). The result of this study indicates that additional sampling may be useful in p r o v i d i n g more i n f o r m a t i o n a b o u t the- e x t e n t of dioxin contamination associated with the use of 2,4,5-T and silvex in this geographic area. I S 7 o 4- un*-y Adipose Sample Description Toxicant Analysis Center Sample # deer deer deer deer deer deer deer Method Blank^ elk elk elk deer elk elk elk elk Standard Solution^ elk 1elk fc P -0 OR-D-5 WA-D-1 OR-D-1 Control WA-D-4 0R-D-6 WA-D-8 WA-E-2 0R-E-11 WA-E-6 . Control 0R-E-7 0R-E-9 WA-E-5 OR-E-8 WA-E-4 WA-E-7 ppt (c ) Native TCDD Added to Sample 7 0 21 14 Research Triangle Park T L //z-7 Wright State University TCDD RTP Detected wsuTCDD 37CT.(d ) Detection % Recovery # (ppt) (c) Limit (ppt)() TCDD TCDD 37CL Detected Detection % Recovery (ppt)() Limit (ppt)() 124<0) 12 125 ND 126 ND 127 9 128 1 2 9 (e) ND 7 130 7 131 ND 132 (e) 9 133 1 3 4 (e) ND 54 135{a) 34 136 24 137(e) 5 138 1 3 9 (e) 12 4 140 23 141 (e> 142 21 ND 2 2 4 2 3 2 4 3 2 2 0.8 6 3 3 3 1 2 2 4 89 \ 50 34 78 36 84 31 50 67 71 100 50 50 100+ 57 87 100+ \ 2.(9 ) 2 3 (g) 4 NA 5 6 (9) 7 NA 8 9 10 (9) 11 l2 (g) n (g) 1 4 (g) 15 76 16<9> 36 1 7 (g) 31 21 ND 21 ND 34 14 13 14 . ND ND 13 24 8 ND 8 68 10 41 . 8 29 8 ND 8 ND 19 ND 10 17 11 21 11 ND 25 46 46 29 51 59 33 105 97 79 150 102 98 43 84 76 70 32 (a) Method' extraction procedure using solvent only. (b) Standard Solution: a standard solution containing 2,3,7,8-'tetrachloro^dibenzo-p-dioxin (c) ppt: parts per trillion (d) corrected for recovery loss (e) two other isor.ers in addition to 2 ,3,7, 8-tetrachloro/dibenzo- ln the major isomer^were observed (f) WSU analyses reported here are the average of two runs (g) evidence of PCB contamination in sample I NO: Not Detected NA: Not analyzed by WSU due to limited amount of sample NB: Sample vt. for all samples was 5g.; 37CL TCDD addition to each sample is 5 nanograms (ng) except Control Sample RTP-135/WSU-10 which contained 1.33 ng. UNITED STATES ENVIRONMENTAL PROTECTION AGENCY H E A L T H ( E L E C T S R E S E A R C H L A ROT! A T O M Y RESEARCH TRIANGLE PARK N O R T H C A R O L I N A 2771 1 DATE: December 17, 1979 SUBJECT: Results of Capillary Column GC/HRMS Analyses Performed on Extracts of Deer and Elk Adipose Tissue for 2,3,7,8-TCDD Residues FROM: Robert Harless s f r & v * HERL, ETD, ACB (MD-69) TO: Mike Dellarco, Dioxin Project Manager Special Pesticide Review Division (TS-791) Office of Toxic Substances 401 M Street, SW US EPA Washington, DC 20460 THRU: Dr. R. G. Lewis, Chief Analytical Chemistry Branch HERL, ETD Per your request,., these samples were not analyzed until the most high priority samples, "Vertac", etc. were analyzed. This shipment of sample extracts was received from the EPA Pesticide Monitoring Laboratory, Bay-St. Louis, Mississippi, 9-6-79, and was assigned the identification number ACB-108. The sample extracts were subjected to a previously described capillary column GC/HRMS multiple ion monitoring method of analysis for 2,3,7,8-TCDD residues utilizing a Varian 311A mass spectrometer interfaced with an SE-30 WCOT glass capillary column. The criteria utilized for confirmation of 2,3,7,8-TCDD were: 1. Capillary column GC/HRMS retention time of 2,3,7,8-TCDD. 2. Co-injeccion of sample fortified with^Cl-TCDD and 2,3,7,8- TCDD standard. 3. Molecular ion chlorine isotope ratio (m/e 320 and m/e 322). 4. Capillary column GC/HRMS simultaneous multiple ion monitor ing response (m/e 320, m/e 322, and m/e 328) for TCDD. 5. M/e 320 and m/e 322 MS response greater than 2.5 mm noise level. // The capillary column GC/HRMS retention time of 2,3,7,8-TCDD was 15 min utes + 1 5 seconds. The MS mass resolution (8,500) was sufficient to resolve TCDD from contamination. The masses monitored during these analyses were: 1. m/e 318.9793 PFK reference 2. m/e 319.8965 TCDD 3. m/e 321.8935 TCDD 4. m/e 327.8847 37C1-TCDD Results The results are shown in Table 1. The recovery of 37 Cl-TCDD was below 50% for specific sample extracts. Therefore, the results should not be reported. These specific samples should be subjected to analytical clean-up and GC/HRMS analysis again to confirm the reported results. TCDD isomers (3) were detected in RTP-124, 129, 132, 134, 135, 137, 139, and 141. The isomer having exact GC/HRMS retention time as 2,3,7,8TCDD was the major isomer detected (high concentration). No problems were encountered in these analyses. Summary 2,3,7,8-TCDD and two (2) TCDD isomers were detected in deer and elk adipose tissue samples. CC: Dr. William Durham, Director Environmental Toxicology Division (MD-66) Dr. Nancy Wilson, Chief Chemical Characterization Section (MD-69) / 9 7 b 3 /a. Httf TABLE 1 ACB #108 ANALYTICAL RESULTS FOR 2,3,7,8-TCDD RESIDUES Sample ID RTP-124' RTP-125 RTP-126 RTP-127 RTP-128 RTP-12 9 ` RTP-130 RTP-131 RTP-132 RTP-133 RTP-134 RTP-135 1 RTP-136 RTP-137 ' RTP-138 RTP-139 RTP-140 RTP-141 ' RTP-142 Sample Weight (q) 5 5 5 5 5 5 5 5 4 5 5 5 5 5 5 5 5 5 5 ND not detected 37C1-TCDD Fortification Level (nq) 5 5 5 5 5 5 5 5 4 5 5 1.33 5 5 5 5 5 5 5 37C1-TCDD % Recovery 89 50 34 78 36 84 3150 67 71 100 50 50 100+ 57 87 100+ 76 36 TCDD Detection Limit (ppt)* 2 2 4 2 3 2 4 3 2 2 0.8 6 3 3 3 1 2 2 4 TCDD !Detected (ppt) * *12 ND ND 9 ND 9 7 ND 9 ND 54 34 24 5 12 4 23 21 ND Comments Deer Adipose Il II Il II Il II Il II Il ll Il ll Il ll Elk Adipose Il ll Il II Il II Il II Il II Il II Il II Il II Il II Il ll ppt = parts per trillion * = corrected for recovery losses ^ri~bi LoZB) University Dnyton, Ohio 45431 November 29, 1979 Mr. W. T. Hoi 1away U.S. Environmental Protection Agency Office of Toxic Substances Special Pesticide Review Div. (TS-791) Crystal Mall 2 1921 Jefferson Davis Highway, Rm. 728 Arlington, Virginia 22202 T.I I I i! uEC - 8.1513 :!:. 1 J\!. ___________t A .'______ Dear Mr. Hollaway: Attached is a table showing the results of analyses of the remaining samples in the batch of 17 which we have been analyzing. Results for the first nine samples were reported in our recent Quarterly Report. We are proceeding as rapidly as possible with the MS-30 modifications to permit isomer-specific TCDD determina tions, and will provide you with a status report on those develop ments in the near future. TOT/aam Attachment Thomas 0, Tiernan, Ph.D. Professor of Chemistry and Director of the Brehm Laboratory I? 7/o TABLE 1 RESULTS CF GC-HIGH RESOLUTION MS ANALYSES OF SAMPLE EXTRACTS PROVIDED BY EPA FOR TETRACHLORODIBENZO-p-DIOXIN (TCDD) BY WRIGHT STATE UNIVERSITY EPA Sample No. WSU-10 WSU-11 WSU-12 WSU-13 WSU-14 WSU-15 WSU-16 WSU-17 Run 1 Native TCDD Detected (parts-per-tr1ll1on) m/e 320 m/e 322 Average Run 2 Native TCDD Detected (parts-per-tri 111 on) m/e 320 m/e 322 Average Average Native TCDD (ppt) 31 43 37 25 23 24 000 000 000 15 20 18 18 26 22 000 48 43 45 35 32 34 000 000 000 14 16 15 17 20 19 000 41 29 0 0 0 17 21 0 Average M.D.C. (ppt) Average % Recovery 8 150 8 102 8 98 19 43 10 84 11 76 11 70 25 32 Notes a., -- a. a. a. -- a. a. a. PCB contamination of sample 1s evident b. This sample was supposedly spiked with only 1.33 ng total 37C1-TCDD, The indicated recovery however Indicates a possible error in spiking.  Region X irimle No . ALA6 ALB6 ALC6 ALAI ALB 1 ALC1 TABLE 1 INFORMATION ON SEDIMENT SAMPLES TAKEN FROM FIVE RIVERS, OREGON AREA IN AUGUST, 1984 ECL1 EMCL/RTP2 Sample No . No. Location Sample Type Sample .Weight D-907 D-979 Initial stream 6 inch location core 10 g D-908 D-980 D-986 Oppos ite side of stream Duplicate 6 inch core 10 g D-909 D-981 Approx. 25' downstream 6 inch core 10 g D-910 D-982 Approx. 45' Sur face further downstr. 10 g D-911 D-983 Approx. 40' Sur face further downstr. 10 g D-91 3 D-985 Approx. 30' Sur face further downstr. 10 g % Moisture in sample 13.4 36. 3 24.1 17.2 22.6 32.5 1. EPA's Envrionmental Chemistry Laboratory in Bay St. Louis, Mississippi 2. EPA's Environmental Monitoring and Support Laboratory in Research Triangle Park, NC fJ/iJbf <5^ Region X S a m D l e No. ALA 6 ALB6 ALC6 AIA1 ALB1 ALCI 2.4,5-T ND ND ND ND ND ND TABLE 2 ANALYTICAL RESULTS ON SEDIMENT SAMPLES TAKEN FROM FIVE RIVERS, OREGON AREA IN AUGUST , 1984 ECL1 Analyses 2 RTP Analsyes % Recovery 4 2,3 ppt, , 7 w , e 8 t - TwCtD.D5 2,3,7,8-TCDD ppt, dry wt.6 4 % Recovery 2.3,7,8-TCDD ppt, wet w t . 2. 3, 7,8-TCD! ppt, d r y 'w t .1 65 ND (3) ND (3) 98 2 (1) 2 (1) 76 50 (3) 78 (5) 92 23 (3) 36 (5) 86 33 (3 )7 52 (5 )7 60 4.5 (2) 6(3) 80 4 (1) 5 (1) 62 ND (3) ND (4) 98 3 (1) 4 (1) 57 ND (2) ND (3) 98 ND (1) ND (1) 61 4.5 (2) 6 (3) 98 4 (1) 6 (1) 1. S PA's E n v i r o n m e n t a l C h e m i s t r y L a b o r a t o r y , Bay St. Louis, M i s s i s s i p p i -2. E P A ' s E n v i r o n m e n t a l M o n i t o r i n g a n d S u p p o r t L a b o r a t o r y in R e s e a r c h T r i a n g l e Park, NC 3. ' NO = not d e t e c t e d ; m i n i m u m level o f d e t e c t i o n = 2 p p b . 4. % r e c o v e r y o f 5 ng o f ^ C - l a b e l l e d 2, 3, 7 , 8-TCDD. Th i s q u a n t i t y is a m e a s u r e o f m e t h o d efficiency. 5. N D = not d e t e c t e d ; m i n i m u m level o f d e t e c t i o n in ppt is i n c l u d e d in p a r e n t h e s e s . 6 . ppt, dry wt. = [ppt, wet w t . / (100 - % moisture)] X 100 7. Separate e x t r a c t i o n and analysis o f the same sample. Ub 1 TAB 3 EPA: Dioxin effects and bioconcentration in fish, 1987 I TP 30# 10I505Z 53:60 01/50 r 'i subject. U N I T E D STAY..: E N V I R O N M E N T A L P R O T E C T I O N A G E N C Y 4 February 1987 2,3,7,8-TCDD 1n Aquatic Environments rxOM TO Philip M. Cook. Ph.D. Chief, Hazardous Waste Research Branch, ERL-Duluth Jim Cunnings Office of the Assistant Administrator for Solid Waste and Emergency Response This memorandum 1s provided In response to your request for an update on the state of knowledge concerning 2,3,7,8-TCDD In aquatic environments. A considerable amount of new Information 1s being generated and much will be reported during 1987. Most of the Information I can provide results from our own research. I believe you have already received reprints for research results already published. I reported bloconcentration factor (BCF) determinations for 2.3.7.8- TCDD, 1,2,3,4-TCOD, 1,3,6,8-TCDD and 1,3,7,9-TCOD at the Society for Environmental Toxicology and Chemistry meeting last November. A journal publication 1s In preparation. The EPA Water Quality Criteria Document presently uses a value of 5000 for the 2.3.7.8- TCOD BCF. We determined a value of 66,000 for carp and 97,000 and 159,000 for fathead minnows at two different exposure concentrations. Our BCF data for the four TCDD isomers 1s sunmarlzed 1n the attached table. We concluded from this study that -- 1. BCFs for different TCDD Isomers vary greatly as expected from field monitoring data. 2. TCDD Isomers other than 2,3,7,8-TCDD have lower BCFs than predicted on the basis of structure or log Kow due to more rapid rates of elimination. 3. Differences In rates of metabolism probably explain differences in TCOD rates of elimination and thus BCFs. 4. The gill uptake efficiencies for the four TCDD isomers studied appear to be similar despite structural differences and different uptake rate measurements attributed to large differences In elimination rates. 5. Approximately 90X of the TCOD 1n the fish exposure water was associated with particulate and dissolved organic matter. Thus, BCFs calculated on the basis of organic carbon free TCDD 1n the water would be ten times greater. INTIS' 0# I0 lL0 / -2- C :6 0 0 10 U 6. The Water Quality Criteria Document BCF value for 2,3,7,8-TCDD Is very low because previously reported BCF determinations were made on the basis of very short exposure periods. Inadequate depuration data, static exposure conditions, overestimates of water exposure concentrations, and other factors which lower the estimate of equilibrium fish concentrations with respect to actual water concentrations. 7. 2,3,7,8-TCDD Is so toxic to fish that BCF determinations have not yet been made over long exposure periods without toxic effects and mortality occurring. No-effect levels are likely to be less than 10 ppq total 2,3,7,8-TCDD 1n water and possibly less than 1 ppq 1f only "dissolved" 2,3,7,8-TCDD 1s considered 1n the bloaccumulatable and toxic component. 8. 2,3,7,8-TCOD was lethal to carp at an accumulated dose of 2 ug/Kg. Rainbow trout appear to be a little more sensitive. This toxicity is comparable to the 1 ug/Kg L050 found for the guinea pig, the most sensitive manvnallan species known. Fathead minnows appear to be at least five times less sensitive than carp or rainbow trout. It is likely that fish b1oaccumu1st1on of PCDDs and PCDFs 1s greatly Influenced by food chain links to contaminated sediments and contact time of fish with sediment. Field monitoring data generally supports this premise. For example, fish collected from field surveys when analyzed for all TCOO Isomers generally only have detectable amounts of 2,3,7,8-TCDD despite the presence of greater amounts of other TCDD Isomers 1n contaminated sediments. Many of the TCOD Isomers have relatively low bioaccumulation potential as seen from our BCF measurements for 1,2,3,4-TCDD and 1,3,7,9TCDD and thus are not likely to be detected. 1,3,6,8-TCDD, however, would be expected 1n the fish 1n detectable levels 1f uptake from water was the major route for bloaccumulatlon. The lack of 1,3,6,8-TCDD 1n the fish is consistent with a kinetic effect Involving decreasing amounts of 1,3,6,8TCDD with respect to 2,3,7,8-TCOD 1n each step along the food chain to a fish and the absence of significant uptake from water. For higher chlorinated PCDD and PCDF congeners differences in elimina tion rates from fish and their food chain organisms create similar preferential bloaccumulatlon of 2,3,7,8-substltuted planar molecules which are likely to be metabolized at a slower rate. In addition, as molecular weight and size Increase with Increasing degree of chlorination, It 1s apparent that the rate uptake from water across the gills decreases. Absorption efficiency from Ingested material 1s also probably less for higher chlorinated congeners. The net result of the above considerations 1s that many PCODs and PCDFs found 1n sediments are not detectable 1n fish. The attached table on "Congener Dependent Bioaval lability of PCDDs and PCDFs" lc? 7 i < b P '. V H T t J T r p -> HJ # Ly i y b c ; h y M i ' :u -3- demonstrates how this same effect occurs for laboratory exposure of fish to municipal Incinerator fly ash. The effect Is more extreme when the " food chain chromatography" effect Is present and longer exposure times are Involved (much longer time required to reach steady state) as with the fish exposed to sediment 1n a reservoir. The compounds Included In the table are all members of the Hb1osign1f1cant fraction of PCDDs and PCDFs In that they do appear to bloaccumulate, are all 2 ,3 ,7 ,8-substltuted and thus all have significant toxic potential. Me developed a simple expression called the "b1oava1lab1Hty Index" (BI) for comparing relative b1oaccumu1at1on tendencies for different chemicals associated with different solid wastes on sediments. The BI 1s simply the ratio of chemicals accumulated per gram of fish U p l d to the amount present per gram of organic carbon 1n the solid material the fish are exposed to. The BI can be normalized to a value of 1.0 for 2,3,7,8-TCDD 1n order to make comparison of the other PCDD and PCDF congener^ Bis easier. Although the magnitudes of the fly ash and sediment Bis cannot be directly compared due to great dif ferences In the fish exposures, the normalized Bis for both fly ash and sediment show the same trends. For both PCDDs and PCDFs the normalized Bis decrease as the degree of chlorination increases. There also appears to be a tendency for 2,3,7,8-TCDF to be less bloaccumulable than 2,3,7,8TCDD. The penta-CDD and -CDF results for the sediment seem divergent and will be rechecked before this data 1s published In this form. We will soon have much more of this kind of data when results are obtained for Lake Ontario sediments and paper mill sludges. EPA is frequently faced with the question of what fish TCDD contami nation levels will result from known or projected environmental contamination levels. The use of a BCF value, no matter how accurate, for predicting fish residues has a major limitation 1n that environmental TCDD water concen trations can never be detected even with the most sensitive techniques. Even If water measurements could be made. It would be difficult to determine what fraction of TCDD In water Is not associated with dissolved or particu late organic carbon so that a laboratory derived 8CF could be applied. An alternative approach 1s to use expected equilibrium partitioning relationships for sediment and fish to predict maximum levels of fish contamination and rely on site-specific sediment to fish TCDD ratios to determine more realistic "approach to steady-state" relationships likely to exist between sediments and fish. This should be done on the basis of partitioning between organic carbon In sediment and I1p1d 1n fish. In theory there should be a simple 1:1 equilibrium relationship between sediment organic carbon and lipid concentrations for very hydrophobic organic compounds such as 2,3,7,8-TCOD which are very slowly metabolized and eliminated from the organism. There are data for compounds such as PCBs which Indicate approximately a four-fold preference of these compounds for lipids over organic carbon in sediment. Our 2,3,7,8-TCDD BI value of .27./or sediment 1s 4X less than the theoretical partitioning value of 1.0 and';M less than the 11 pid preference value of 4.0 at least 1n part because steady-state conditions were not reached when the fish were exposed to the sediment. In many environmental situations expected steady-state relationships between fish bloaccumulat1on levels and sediment contamination levels will 19^/7 -4not.be reached. -Kinetic models and appropriate rate constants are needed to accurately predict fish bloaccumulatlon levels. When an aquatic eco system has a constant Input of TCDD so that surface sediment concentrations are relatively constant, fish concentrations will approach a steady-state level dependent on rates of uptake from water, food and contact with sediment. For Lake Ontario we are Investigating sediment to fish TCOO ratios under present conditions so that remedial actions for Superfund sites and other sources of TCDD can be evaluated with respect to changes In fish residues which will result In the future. That 1$, 1f sediment TCDD levels are decreased or Increased In the future through man's activities, we should be able to predict eventual changes 1n fish contamination levels when a new "approach to steady-state" system results. In Lake Ontario our pre liminary data Indicates that fish lipids have only about 5% of the TCDD concentration found In the organic carbon fraction of the surface sediments. An extensive survey of sediment and fish TCDD levels throughout Lake Ontario 1$ scheduled for this summer. I<i7l8 iDniosoxmineleLvaeklseshifgisnh By Dudloy K. Pierson News Lnnsmy llmmu, V W y' 1*^ I.A N S IN d -- Spur', fish from :< *a < R some arena of the (rent Lakes and tributaries should not l*e eaten regu- Inrly licraosc llirv contain nnsntiafncforv levels of the cancer-cnosing chemical flioAin. rcporla the U-S. |sn- oirv-*.ri*r;V Jc :.< i UiilAL.vironmcntal Protection Agency The warning camr yesterday as the KPA released reanlla of a $2 million study that tested carp and other fish lor the most toxic form of jjfrti}UrtiM: 'ptteb'waa-, i[ot^Wr^rTTTNto^WiiuiYiiir'iFhtotnrlfofd^"*wVv(. dioxin. The rhemieol was found in 29 of 50 areas where carp were sampled throughout the (rent I-akea Basin. ;4Binaw B Most of the lorotinna are in wntera nlrendy thought to lie polluted witli industrial chemicals. But Chcnc nve the first general warnings based on dioxin levels. rant concern," anid Peter Wise, thu IvI'A'h director of the (m il Ijikes Nnlioonl Program Oliicc. lie said the P.I'A needs to do more monitoring of Please see Dioxin /(3AC A M ', A bottom-feeding fish high in fnt where loxic rlicmicnls tend to lie stored, is used by the K I'A na a barometer for toxics in more desirenble sport linh. "There mny hr a significant B|H>rt fish. The single highest level of dioxin .was found at fylidlupd llie home ol f7ow~Chetnical (g, where 'I ilinhnwnssee Itiver enrp containing 525 pnrta per trillion of dioxin were token. enough mngoitude (of dioxin) to war '97/? HV-de- s1olim/Jei (lairrrisat foLuankdesinfish t ' 11 " areas u. i in in , m 11. 1.1 m - l nin contain more Ilian I j>art por o_ano_n_o[ djqxJjL" _.!J0y.lll_ Frop* pags 1A h'iPf'f i3*b ^ h . officials mid they assumed that human health oincerm could tHrRin 1>lx- raised at coticentrntions of i^Hint I part per trillion." c a i i i * c o n t a i n i n g 21.1 ,0 ,( h |>rr Ir Ilion wore found in Hie Hi mgr River in Detroit and carp (MOtnininK from 2 7 to 11 part per (flllion were found in the Drlroit Hivcr Trenton Channel beside Gmaae U|. In the Detroit River near I'rllc lile, rnrp sample contained 9 parts |g>r trillion. To rnlculate lite dioxin levels in sport fish, the EPA used n rule of t(yimh that sport Halt prohahly con tain from l/.rt lo l/H the P'nmmt of djoxin found in Irotlom feeders such ns cnn. Oulslnte F,PA resrnrehers were cBirrmerl about dioxin levels in fish taken front lite Flinl River, Snpinnw l|)v , and the Grand Ifiver at Grand Ledge. -.In general the study showed that finke Ontario contained the highest level of dioxin-contaminated carp. Illowed hy lakes Huron and M ichi 19gan. then Erie and Superior. .F. S T U D Y , fregn in IPH.'l, ns pnrt of a national dioxin investigation 1 ft I will I * released to Congress thin summer, said E-PA Regionnl Admin j^ ra tn r Vsldas Adamkus. He said it is not intended In show which fish sre iiJe to eat, hut to provide a "snap- numberJmil" of a relatively few of lish apread over a wide geographic 16a. However, the snapshot included a numberItTiited of samples of skinned inlake trout fillets caught Lakes ^jchjgan, Huron, Ontario, St. Clair and Erie. Several of these contained level of dioxins high enough for the KVA to warn against eating them SIWIMAS regularly. sources, industrial wastewater dis "In a lot of national studies we find 20Wa lleye from Anchor Ray in take charges. Great takes Hah are very high nml St. Clair, for instance, contained di Wise, of the Grent takes National that's because they (the lakes) have a l l " from 2,8 parta per trillion to 5.8 Program Office said toxic chemical lot of fat, old fish," he snid. pnrta per trillion, take trout from contaminants in Great takes fish are He added that levels of other ta^e Huron near Alpena had from 5 "generally" higher llinr in other wa chemicals in Great takeH fish npi>enr pffts |>er trillion to 9.8 parts per ters. 'Mint's doe to hravy industrial to be decreasing and that indicate* trillion. and agricultural activities within the the amount of dioxin might also lie ^?n most of the areas where the Great takes Rnsin, he said. declining. EPA found dinxin-contaminnled c*q>. fish advisories are already in eff vnrning anglers which fish arc fib * to eat. These advisories had lieen issued based on findings of , r D D T and other toxic chetni- DIOXIN, CONSIDERED to he one of the most toxic chemical sub stances known, can cause cancera. tJf W - I Tittabawassee carp tops dioxin V7 State health officials, though, insist river sport fish are safe BY WAYNE SCHMIDT alent to about 10 Inches In 16 m il News Lansing Bureau lion mUcs. and DAVE ELLIS News Siali Writer , . __ . The only fish found to be above 10 * * * ' > p iris per trillion In Michigan wa ters were In the SaglDaw Bay and A Tittabawassee River carp was inland streams, Including the Tll- the most contaminated In a U S. (abawassce, Flint, Grand, Rouge Environmental Protection Agency and Detroit rivers. study of dioxin In Great Lakes fish, Carp fillets from the Tltlabawas- but state health officials say sport sce ranged from 12 to 325 parts per fish In the ftv ir are safe. trillion, said Richard A. Powers, The study, released Monday, chief of the D N R 'a toxic chemical showed dioxin contamination of evaluation section. fish Is more extensive than pre That was (he most dioxin the viously documented In the Great federal study found In any fish, Lakes. Powers said. State health officials, however, Powers said game fish from the contend contamination levels In river showed fewer than 10 parts lake trout are for the most part at per trillion of dioxin. acceptable levels. A whole carp from Saginaw Bay They also say the new findings at Cascvllle showed 10 parts per are neither unexpected nor alarming. The EPA study, part of a $2 million, multi-year effort, conclud 1 dioxin danger overblown? Ballot Box, The Back Page. ed that dioxin contamination of lake trout spans the Great Lakes. trillion, while a carp fillet con "It means that dioxin contami tained 13.2 parts per trillion. nai Ion Is pretty widely distributed V whole walleye from the same throughout the Great Lakes," said sl.e contained 6.8 parts per (rlllon David DeVault, coordinator of and a fillet harbored .7 parts per EPA's Great Lakes monitoring trillion of (he contaminant. program. The federal study was Intended The greatest amounts of dioxin to chart the worst-case scenario for In lake trout were found In Lake contamination. Ontario, which had up to four times For example, (he 6(udy sampled the levels found in fish from Great larg''. fatty trout in Great Lakes Lakes bordering Michigan, accord and bottom-feeding fish such as ing to the EPA study. carp In Inland waters. Those fish Dioxin is an Industrial byproduct are most likely to accumulate and In the manufacture of some herbi store dioxin contamination in their cides. It Is suspected of causing fatty tissue. cancer in humans. Popular game fish such as w al As a result of the study, EPA leye and perch, however, typically officials rccommondcd (hat Great have a small fraction of the levels Lakes states again review fish-eat found In bottom-feeding fisi), said ing advisories involving dioxin and Peter Wise, director of E P A 's other contaminants. Great Lakes National Program Michigan health officials con tend that fish are safe to consume as long as dioxin contamination is lowerthan 10 parts per trillion. Office. The EPA study Is expected to relgnlte a controversy over what Ten parts per trillion Is equiv Please see FISH, Page A-2 P 2 > k 3 51 (T* > Z z (it i CA >3 w J a3 IH7^-( FISH------------ --- 'onlinued (rom Page A-1 evcls o( contamination arc safe for luman consumption. The agency n the post lias criticized the way Michigan arrived at Its safety .ini it. It has again issued a coll for new studies by slates surrounding the Grent Lakes. According to the federal study, dioxin contamination was discov ered in carp and other botlomIcedlng fish from I I rivers, two Inland lakes and the Saginaw Bay In Michigan. Walleye from Lake St Clair and large lake treul In lakes Superior, Michigan a n j Hu ron also showed measurable le /els of dioxin. Additional warnings agalnsl eat- < w K W l"v . ing some lisli may be necessary in light of the new EPA results, said John Hesse, a scientist with the state health department. Other Michigan waters where bottom-feeding fish showed dioxin levels present but below health de partment limits were St. Joseph River, Berrien County; Kalamazoo River, Allegan; Muskegon River, Bridgeton; White Lake, Montague; St. Clair River, Algonac; Clinton River, Mount Clemens; Muskegon Lake, Muskegon; Pine River, Alma; and Detroit River, Belle Isle. Unacceptable risks of cancer In humans may be caused by regular ly ealingTtsh with only one part per trillion, EPA's DeVault said. TAB 4 EPA National Dioxin Study (1987) Tonto National Forest, Arizona Mark Twain National Forest, Missouri 1^7^13 1 1 134e epa United States Environmental Protection Agency Office o f Solid Waste and Emergency Response August 1987 EPA /5 3 0 -S W-87-025 Solid Waste__________________________________________________________________________________ National Dioxin Study 111-19 1983. Thirty-five samples and 1 sediment sample were randomly collected; 2,3,7,8-TCDD was detected in 9 soil samples at levels between 0.3 and 0.4 ppt. No 2,3,7,8-TCDD was detected in the sediment sample. No a d d i t i o n a l action is planned. Region VI Pointe Coupee Parish, Louisiana This site, used for growing sugarcane prior to 1985 and soybeans in 1985, was treated w i t h s i l v e x in 1983. Twenty-five soil samples were randomly collected from two fields, 2.6 acres and 2.7 acres in area. Twenty samples contained 2,3,7,8-TCDD at levels ranging from 1.0 to 2.5 ppt. No a d d i t i o n a l action is pl a n n e d . Region VI Rio Grande Plain Experimental Ranch, Kinney Co., Texas T h i s site is an e x p e r i m e n t a l ranch used for r e s e a r c h on brush control and livestock production. In 1981, parts of three experimental pastures (five acres each) were aerially sprayed with 2,4,5-T. Parts of each were left untreated as controls. Thirty-eight soil samples were randomly collected from the three pastures among the treated and untreated areas. Twelve samples contained 2,3,7,8-TCDD-- 5 samples from treated areas and 7 samples from untreated areas-- at levels between 0.2 and 3 ppt. No 2 , 3 , 7 ,8-TCDD was detected in a rattlesnake or in six vegetation samples collected from the sprayed pastures. No a d d i t i o n a l action is p lanned. Region VII Mark Twain National Forest, Missouri The herbicide 2,4,5-T was applied in 1977 to 3 sites totaling approximately 95 acres w ithin the forest, to facilitate the relief of shortleaf pines from competing hardwoods. A tractor drawn, high-volume ground spray tanker unit was used to apply the herbicide. A total of 50 soil samples were collected from 2 sub-areas at one of the 3 treated sites. These areas were located at the bottom of slopes, where herbicide runoff would tend to accumulate. Twenty-one of 50 soil samples contained 2,3,7,8-TCDD at levels between 0.3 and 120 ppt. No a d d i t i o n a l a ction is p l a n n e d at this time. The c o n t a m i n a t i o n is w i t h i n a forest area, not used for grazing. 1 Region IX Tonto National Forest, Arizona Between 1965 and 1969, 2,4,5-T, 2,4-D, and silvex were sprayed over more than 2,500 acres in the Globe Ranger District. This spraying project was designed to improve rangeland and to increase water runoff, resulting in increased water yields for downstream users. Soil samples were collected from three helicopter landing l o r r areas used as herbicide mixing-loading areas and from five other '7 ( 3 . 5 I I 1-20 locations within the sprayed area. Whole animals and animal tissues were also collected within the sprayed areas. Twentyfour of 77 soil samples had 2 , 3 , 7 , 8 - T C D D at levels of 2 to 564 ppt. Soil contamination was found at two of the three mixing loading areas. (The mixing-loading area where no 2,3,7,8-TCDD was found was later determined not to have been used for that purpose.) 2,3,7,8-TCDD was detected a short distance beyond the boundaries of the actual mixing/loading locations, but no 2.3.7.8- TCDD was detected at the other five locations. No 2.3.7.8- TCDD was detected in any of the animal samples. Forty-five additional samples, which included soil and fish, were collected from 3 additional and 1 previously sampled mixing/loading area. Twenty-one soil samples contained 2,3,7,8TCDD at levels from 0.4 to 6623 ppt. Four samples had levels greater than 1,000 ppt. No 2,3,7,8-TCDD was detected in the fish collected. The U.S. Forest Service has restricted access to the conta m i n ated heli-pads. EPA Region IX is reviewing alternative treatment technologies, focusing on in situ treatment. The Forest Service has indicated willingness to sponsor a pilot project. Region IX Santa Ana River, California The Santa Ana River Basin includes agricultural, industrial, and residential areas. Twenty-eight sediment samples were collected from stations along the Santa Ana River and a few of its tributaries. These locations have been routinely monitored for conventional and priority pollutants. Fish samples were collected at eight of the sediment stations where water flow was sufficient to support fish. One sediment sample had 2,3,7,8-TCDD at 0.6 ppt; one of the seven whole fish had 2,3,7,8-TCDD at 4.6 ppt. Region X Santiam Forest, Gates, Oregon A 75-acre area of this forest site was aerially sprayed with a herbicide containing 2,4-D and 2,4,5-T in 1976 and 1977. Twelve sediment samples were collected from a stream that runs through the sprayed area, from an area where this stream empties into the North Santiam River, and from an area of the North Santiam River near the confluence with the stream. Thirtyfive soil samples were collected from a wetlands area south of the sprayed area, a heliport used by helicopters that sprayed the area, and the heliport drainage area. One fish sample was collected from the North Santiam River sampling area. 2,3,7,8T C D D was detected in 3 of 12 sediment samples at levels of 0.2 and 0.4 ppt. No 2,3,7,8-TCDD was detected in the 35 soil samples analyzed or the 1 fish sample. 3.2.4 Findings o Contamination was found at a variety of the pesticide use sites where 2,4,5-T, silvex, and 2,4,5-TCP based pesti- ^ ^ -< 0 TAB 5 U.S. Centers for Disease Control, 1980 Preliminary Study of Birth Defects in Oregon pages 1-2 3-5 TAB 6 EPA 1980 Press S t a t e m e n t on 2,4-D EPA 1981 l e tter to p r i v a t e c i t i z e n o n 2 , 4 - D If 13? JUL 2 1 1900 MEMORANDUM SUBJECT: Epidemiologic Investigation of-'Birth Defects in Oregon FROM: M a r t i n P. Halper, D i r e c t o r ' / l ^ t Survey and Analysis Division (TS-793) TO: Edwin Johnson Deputy Assistant Administrator for Office of Pesticides Programs THRU: M a r i l y n C. Bracken/r' --(^ ^ i ^ / '' l " Deputy Assistant Administrator for Office of Program Integration and (TS-793) Information The Survey and Analysis Division (SAD) recently received the attached proposal from the Center for Disease Control (CDC). C e n t e r is p r o p o s i n g that OPTS supp o r t an e p i d e m i o l o g i c r e t r o s p e c t i ve matched case control investigation in w e s t e r n Oregon. The object of this endeavor would be to determine w h e t h e r p a r e n t a l e x p osur e to aerial h e r b i c i d e a p p l i c a t i o n is associated with the birth of infants having central nervous system (CNS) defects. Th ' This proposal was the result of a preliminary assessment of the situation by CDC personnel after they were contacted by Oregon p h y s i c i a n s and other c o n c e r n e d c i t i z e n s in the area. C D C 1s review of data amassed through their National Birth Defects M o n i t o r i n g P r o g r a m indicated that there were increases in rates of certain CNS birth defects between 1970 and 1979. Specifically, 8 cases of anencephaly were observed with 4 expect ed; 16 cases' of h y d r o c e p h a l y w e r e o b s e r v e d w i t h 10 expected. 19 72 .9 ::u8 -I- ti iAccordingly, SAD is forwarding a copy of the CDC proposal for review and comments. We would appreciate receiving all comments by J u l y 29 so that we m a y r e s p o n d to. CDC in a t i m e l y fashion. Attachment c c : Dave Menotti, OGC Jim Reisa, OTS i +df- ';> 1 8 j DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE PUBLIC HEALTH SERVICE CENTER rO S CISEASE CONTROL ATLANTA. GEORGIA 30333 TELEPHONE: (404)633-3311 404-452-4036 June 18, 1980 Susan Strassman-Sundy Survey & Analysis Division (TS-793) U. S. , E.P.A. 401 M Street, S.W. Washington, D.C. 20460 Dear Ms. Strassman-Sundy: As follow-up to our telephone conversation regarding a proposed study of herbicide exposure and birth defects, I am sending the report we prepared for the Oregon Pesticide Analytic Research Center (PARC) and the State Health Department. We feel the proposed study, if PARC and the Oregon Health Department decide to formally invite CDC to help conduct it, is very much the type of cooperative effort that would be covered by the pending interagency agreement between SAD/EPA and the Chronic Diseases Division, CDC. Our problem as mentioned in our conversation, is that we currently do not have the manpower or the funds to conduct such a large study. Because of our mutual interest in herbicide exposure and health effects, the proposal should be of interest to the E.P.A. If EPA finds the proposal of interest and current funding is available, we should explore our mutual interest as soon as possible in anticipation of the request for assistance from the PARC board and the Oregon Health Dept. Sincerely yours Larry Edmonas, M.S.P.H Epidemiologist Birth Defects Branch Bureau of Epidemiology I1 1 3 d REPORT TO THE PESTICIDE ANALYTIC RESEARCH CENTER (PARC) THROUGH JAMES GOOGINS, M.D. STATE EPIDEMIOLOGIST OREGON HEALTH DEPARTMENT June 10, 1980 Larry D. Edmonds Birth Defects Branch Chronic Disease Division Center for Disease Control Atlanta, Ga. 30333 I3 7 3 1 (4 During the Fall of 1979, a group of physicians and other concerned citizens from Lincoln County, Oregon reported their belief that an excessive number of babies in that county were being b o m with birth defects. They linked these data with herbicide exposure (2,4-D) and called for a ban on the use of 2,4-D until more data are available. Because of these concerns, and the results of the EPA Study of abortions and 2,4,5-T in Alsea, Oregon, the Birth Defects Branch reviewed the data available through the National Birth Defects Monitoring Program. That review indicated that there were increases in the rates of anencephaly in Benton County (8 observed cases, 4 expected), and of hydrocephaly in Lane County (16 observed cases, 10 expected) between 1970 and 1977. The BDMP findings, along Tilth the concerns of the Lincoln County physicians led us -to discuss these data with the Oregon Health Department. John Googin, M-D, State Epidemiologist, invited CDC to meet with the Oregon Pesticide Analysis iResearch Center (PARC) Board on November 21, 1979. The Board was formed to evaluate possible adverse health effects of chemicals used in agriculture. The PARC Board asked the Birth Defects Branch to review available data and make a recommendation- about what kind of epidemiologic study should be done to 'evaluate the relationship between maternal exposure to herbicide spraying and birth defects. Study Approach A retrospective case-control study appeared to be the most appropriate type of study for several reasons. First because birth defects are rare events, it would be difficult otherwise to obtain enough cases for a study with sufficient statistical power. Second, the ban of 2,4,5-T in 1978 eliminated the source of exposure. In addition, a retrospective study would also allow the opportunity to evaluate possible increases in malformation rates from sources other than herbicides. The definition of cases and controls would be relatively straight forward. Cases would be identified as Oregon resident births identified with central nervous system defects and controls as normal Oregon infants matched, on maternal race, place and date of birth- All cases would be identified, even those from urban areas, because the preliminary BDMP data found high CNS" defect rates in counties predominantly urban as well as those predominantly rural. A reliable, unbiased estimate of exposure would be needed for both cases and controls. Determining this rate poses some difficulty. Because of obvious bias resulting from questioning individuals about spraying exposure and the unavailability of a retrospective biochemical test, we needed some other'method of determining exposure. We undertook a pilot study to learn if it was feasible to obtain an unbiased estimate of exposure, and if it was, to learn the rate of exposure. The latter figure is necessary to determine an adequate sample size or to determine the statistical power of any smaller sample size. 197 fJ=tt*t3F page Two Pilot Study The purpose of the pilot study was to estimate the rate of herbicide exposure in Benton, Polk and Lincoln Councies as a measure of exposure in western Oregon. These three counties are primarily forested and Lincoln and Benton counties are where the initial concerns about birth defects were raised. For the pilot study, a random sample of 72 births was selected from each country using vital records. An equal number of birth certificates C12) were chosen for each year, 1973-- 1977, and one was randomly selected from each month. The residences of the 72 births were determined, and for those with rural addresses, the owners of tracts of land within two miles of the residence of the case were sought. Identified landowners were contacted and asked to give spray history occurring from 1 month before conception of the case to 3 months after conception. Results of Pilot Thirty rural cases were identified. The original approach to identify ex posures was not feasible; There were too many owners within 2.0 miles and the owners had no, or few written records, so they had to depend upon recollection of any spraying, when it occurred, or what was sprayed. It was obvious, from this pilot study, that we could not reliably document herbicide usage by question ing individuals or land owners. Extension of Pilot The only definition of herbicide exposure that appeared to be workable was for aerial herbicide spraying near a residence that is documented in some official form. With this definition in mind, we plotted all the sample births on county maps. We plotted the 30 rural births as before, and all the remain ing births listed with a city address were plotted as residents within the city limits. We also used computer printouts, generated for the pilot study by the Department of Forestry, to identify any forest land that was sprayed between Jan. 1974 and Jan. 1980. Under Oregon law, all land owners (excluding the U.S. Forest Service and the Bureau of Land Management have to file a pro posed spraying plan with the State Department of Forestry. The majority of the births plotted were not near U.S. Forest Service land so the state clearinghouse was a good source of information. We assumed .the U.S. Forest Service would furnish data if requested. We next reviewed the spray data to identify any aerial herbicide spraying that occurred within two miles of any sample birth. Using this admittedly crude estimate, we identified 8 births that had aerial herbicide spraying within 2 miles of their residence during the critical period around conception. There were 2 additional babies that had possible spraying within two miles of their residence. The exact location of spraying was unknown, but spraying occurred in the area. Thus, we identified a maximum >of 10 "exposed" infants, for a rate of 4.6%. This "exposure" rate should be applicable to the western i Q r r ^ a areas of Oregon where the vast majority of births occur. ' ' ""5- It is important to note that this "exposure" rate is only a rough estimate of aerial herbicide spraying within 2 miles of a residence, and not a measure of actual exposure to herbicides. It appears to be impracticable, if not impossible, to determine retrospectively what the true exposure of pregnant women was. We can only evaluate if aerial spraying occurred in the general proximity of infants with CNS defects more often than in a group of normal infants. The misclassification of women into exposed and not ex posed categories would have the effect of lowering the power of the study to detect possible teratogenicity. Sample Size Estimate The sample size needed to detect an exposure effect depends on the rate of "exposure", the increase inrisk among these exposed, and the statistical power desired. Using the estimate of 4.6% overall "exposure" from the pilot, if w e want to have at least an80% chanceof finding a 2-fold increase in risk, we would need 435 cases and 435 controls. If the attack rate is 1-1/2 times greater in exposed than in unexposed, we would need 1,533 each of cases and controls. A statistical power of 80% was the minimum figure w e had hoped for. Un fortunately, we can't find enough cases in western Oregon with documented exposure status to achieve this power. Table 1 presents an estimate of the number of cases that could be located, interviewed, and the herbicide exposure documented. This number of cases (264) and an equal number of controls would produce a study with a 62% chance of detecting a 2-fold difference in attack rates, using a 1-- tailed test at the 0.05 level of significance. If the attack rate is 1-1/2 times greater in cases than controls, then we have a 27% chance of finding a difference. Proposed Epidemiologic Study Hypothesis: The hypothesis to be tested is whether maternal exposure to aerial spraying of herbicide is associated with the birth of infants with central nervous systems (CNS) defects. Study Design: A retrospective matched case-control study in western Oregon. Indepth personal interviews would be conducted of 264 CNS cases and 264 normal controls to evaluate various mdte'rnal and paternal risk factors. Cost: To conduct this proposed study would cost approximately $192,000 (See attached budget). Required Time: With, adequate staff the study could be completed in 9 to 18 months after approval to conduct the study has been given. Summary: With completion of the pilot, some judgements can be made about the merits of the proposed epidemiologic study of "herbicide exposure" and birth defects. The measurement of exposure is troublesome. Lacking some better way to identify exposed mothers, we can only investigate the relationship between proximate aerial herbicide spraying and CNS birth defects. Such a study would compare these exposure rates in infants with CNS defects and normal infants- With the available sample of 264 cases and 264 controls, we would have a 62% chance of detecting a 2-fold relative risk. If there is a 50% increase in the attack rate among the exposed, we would have a 27% chance of detecting this difference. These power figures are not particularly encouranging. In addition, it may well be that these relative risks apply only to women with a specific level or type.of exposure. Since the available measure of ex posure is so coarse, the relative risks of "exposed" women based on aerial spraying data might be much lower. In that case, the statistical power would be even lower. It is important that the limits of such an epidemiologic study are identified in the beginning. We feel that if a study is undertaken, the casecontrol approach is the best approach. If you decide to go ahead with such a study, the Birth Defects Branch would be willing to assist the State Health Department and the PARC Board in planning and implementing the study. \4 177 3iT I !!',> Table I Estimated number of central nervous system cases in Oregon in the years (1974 to 1979) for which exposure can be documented. (Estimate based on Oregon rate from the Birth Defects Monitoring Program data.) 380 Estimated number of cases in eastern Oregon. (The exposure rate here may ba...lower than in pilot area.) 50 Estimated number of CNS cases in western Oregon, 1974-1979. 330 Estimated number of cases in western Oregon that we will be able to locate and interview. (Estimate of 20% lost to followup based on Atlanta experience.) 1^736 I Budget of Proposed Case-Control Study In Oregon Personnel - Salary and Benefits Person Years Category & grade Salary & Benefits 2.0 2.O' 1.0 1.0 .2 .50 Health Technician (GS-7) (case finding - 8 persons @ 12 wks) Health Technicians (GS-7) interviewing - 8 persons @ 12 T/ks) Coder (GS-5) Public Health Advisor (GS-11) Statistician (GS-13) Epidemiologist (0-5) $31,000 31,000 13.000 24.000 7,000 14.000 Travel Equipment & Supplies Rent and Communications & Utilities Printing Plus CDC Subtotal overhead @ 20% Total $12 35 1 2, 1, 16( 32 $19: \t 197 37 > ^ u d a l -' Da f e e : L :oc 3 P ? A lo t >vO -- Oregon, 1970-19781 ... A ' 1 .\ Lincoln No. Cases Rate Countv Benton Polk No . v No. Cases Rate Cases Lane No. Cases Rate - .it/ C ./d <- / 0 .'-V 1</ Total Lincoln i Benton, Polk, Lane Counties No. Cases Rate T All Oreson No. Cases Rata r * r' y i iC 70-77 U.S. Rate -.ar.caphaly .drocephaly 'ina Bifida 45 15.3 91 9.9* \ 65 4 4.4 5 10 11.0 12 4.6 23 6.2 17 6.6* i 21 5.6 t 9 3.5 20 5.4 85 4.9 4.6 39 4.0 4.4 72 4.1 6.2 CNS eft Lip 125 225 27 5 o. o 48 18.6 23 8.9 79 21.2 28 7.5 307 & 102 5.8 5.2 of; Palate 4* JLS w'J 1 cl 329 JiJ 7 7.7 1 1.1 33 12.3* 11 4.3 41 11.0 12 3.2 167 9.6 9.5 46 2.6 1.5 t 393 4 4.4 11 4.3 15 4.0 61 3.5 3.4 nal Agenesis 450 1 1.1 4 1.5 5 1.3 23 1. 3 1.0 cuccion Deformity 453 1 7.7 3 3.3 17 6.6 21 5.6 59 3.4 3.3 .ns 626 1 7.7 3 3.3 27 10.4 31 8.3 155 8.9 8. 1 Births in EDM? Monitored 1,307 100% 9,123 100% 25,360 89% 37,341 174,659 65% 7,903,544 33/, 3-77 significant increases Benton - anencephaly (observed 8, expected 3.7) p = .05 Total CNS (observed 23, expected 16.68) p = .05 Lane -.hydrocephaly (observed 16, expected 9.9) p = .05 cleft lip (observed 23, expected 11.6) p ** .01 reduction deformity (observed 16, expected 7.3T p -0 /0 , 0 0 o 01 . AEmge-in'ocnyrnontl Protection Washington DC 204430 Environm ental f EINPFAORAMS KASTIOFNORONMORE HERBICIDE 2,4-D -75 FOR IMMEDIATE RELEASE T U E SDAY, A P R I L 29, 1980______ O ' N e i l l (202) 755-0344 Barbara Blum, Deputy Administrator of the U.S. Environmental Protection Agency, announced today that the Agency is requesting additional information from manufacturers to determine whether 2,4-D, a widely used herbicide, is safe for humans and the environment. "We have made this decision following a review of h e a l t h "e f f e c t s s t u d i e s of 2,4 - D , " B l u m said. "The review showed that significant information gaps exist on the effects of 2,4-D, preventing a definite conclusion on the safety of the herbicide. "We will ask the manufacturers of the weed killer to commence the studies to provide the missing evidence." Blum said that if the manufacturers fail to notify EPA within 90 days that they will provide the necessary information, EPA will use a stringent new provision of the pesticides law, Section 3(c)(2)(B), which allows the agency to stop all uses of the pesticide. If the manufacturers comply, Blum said, EPA will allow 2,4-D to continue to be used while studies are underway. However, should any of the new studies demonstrate a major health or environmental, problem, she said EPA would then take appropriate regulatory action without waiting for completion of all the studies ! The name 2,4-D refers to the phenoxy herbicide 2,4'-dichlorophenoxyacetic acid and related salt and ester forms. There are approximately 1500 2,4-D products which are used to kill undesirable plants in home lawns, forests, right-of-way, drainage ditch banks, rangeland, pastures, aquatic areas, cereal crops, sugar cane and commercial turf. N (more) V ^ wr fcr- red I97Y O W fl l Basic manufacturers of 2,4-D include Dow Chemical Co., Midland, M i c h i g a n ; M o n s a n t o C h e m i c a l Co., St. Louis; D i a m o n d S h a m r o c k Corp. , Dallas', PBI G o r d o n Corp., K a n s a s City, Kansas; T h o m p s o n H a y w a r d C h e m i c a l Co., K a n s a s City, Kansas', A m C h e m Products, Inc., Ambler, Pa. "e p a c o n d u c t e d its r e v i e w of h e a l t h - e f f e c t s s t u d i e s o n 2 , 4 - D because of increasing citizen concern about the high level of exposure to 2,4-D around the country and because of its chemical similarity to the dioxin-contaminated herbicides, 2,4,5-T and Silvex." Blum said. There also has been concern because 2,4-D was a component-- along with 2,4,5-T-- in Agent Orange, the defoliant used by the military in Vietnam. Although never approved by EPA for civilian use in t h e U n i t e d S t ates, its u s e in V i e t n a m has r e s u l t e d in n u m e r o u s . c l a i m s o f a d v e r s e h e a l t h e f f e c t s -to A m e r i c a n m i l i t a r y p e r s o n n e l . These claims are now under investigation by the Veterans Administration. EPA, about a year ago, imposed an emergency ban on many major uses o f 2 , 4 , 5 - T ahd Silvex'. M o r e recently, the a g e n c y o p e n e d hea r i n g s to determine whether all uses of these chemicals should be banned on grounds that.they can cause cancer, birth defects and miscarriages. EPA's review, of 2,4-D studies showed that the evidence of adverse health effects weighs far more heavily against 2,4,5-T than against 2 . 4 - D. "For one thing," said Blum, "there is no evidence at this time that 2.4- D contains any form of d i o x i n t h e contaminant in 2,4,5-T > associated with cancerous tumors and birth defects." Blum stated that "toxicity studies of 2,4-D have either showed 'that s i g n i f i c a n t a d v e r s e e f f e c t s w e r e u n l i k e l y a t e x p e c t e d h u m a n e x p o s u r e levels, or they were inconclusive, or they were not conducted n a m a n n e r a c c e p t a b l e b y t o d a y ' s s c i e n t i f i c s t a n d a r d s . " At.this point, she said, the agency, while taking no actibn restricting use of the chemical, will! require the manufacturers of 2,4-D to provide additional information in the areas bf oncogenicity (tumor-inducing), reproductive effects (particularly effects to the fetus), and metabolism in animals. She said EPA also plans to conduct certain reproductive studies on 2,4-D in its own laboratories, while awaiting the industry results. I' In addition, EPA will consult with its Scientific Advisory Panel during its May 28-30 meeting to determine if there are additional studies necessary to determine the safety of 2,4-D. Following the findings of the Scientific Advisory Panel, the agency will formally specify to the manufacturers what .studies are needed. Details of the agency's review of on 2,4-D are in the attached fact R-75 II the health sheet. effects information 197V/ Ms. Judith L. Krott P.0. Box 145 Dolgevllle, New York 13329 APR 1981 Dear Ms. Krott: Thank you for your letter of March 6, 1981, requesting Information on Agent Orange. As you may know, EPA 1s responsible for administering the provisions of the Federal Insecticide, Fungicide, and Rodentlcide Act (FIFRA). This Act regulates the marketing of pesticides and requires, among other things, that such products be registered with EPA. Under the FIFRA, the regis tration of any pesticide 1s contingent upon the availability of data adequate to demonstrate that the product will not pose the risk of unreasonable adverse effects on man and other nontarget organisms or the environment when used in accordance with Its approved labeling. Herbicide Orange, which 1s a highly concentrated compound of the phenoxy herbicides, 2,4,5-T and 2,4-D, was never regis tered or used 1n the United States. It was used as a defoliant during the Vietnam conflict by the A1r Force. In 1971, the Department of Defense proscribed further use of the compound because of animal tests which demonstrated that a compound with the chemical name 2 , 3 , 7 , 8 .Tetrachl o r o d i b e n z o (p a r a )d1 ox1 n , or TCDD, a contaminant of 2,4,5-T, caused birth defects and other reproductive problems. The 2.3 million gallons remaining In A1r Force stocks were burned at sea under an EPA permit by the end of September 1977. EPA does have authority over use in the United States of products containing 2,4,5-T and 2,4-D, which are far less concentrated than was Herbicide Orange. Domestic uses of 2,4,5-T to which women of childbearing age were thought to be most likely exposed were cancelled 1n 1970 following the animal tests mentioned above. -2- In April 1978, the EPA Initiated Intensive review of risks and benefits associated with the remaining uses of 2,4,5-T through the rebuttable presumption against regis tration process. Subsequently, new evidence on human health risks came to light and on March 1, 1979, EPA announced emergency suspension of 2,4,5-T and sllvex, a related phenoxy herbicide, for use 1n forestry, pasture, and rights-of-way management. The Agency's Intent to cancel registration of these herbicides accompanied the suspension notice. Cancellation hearings to explore the long-term risks and benefits of 2,4,5-T and sllvex began March 14, 1980. Information gathering hearings on the remaining nonsuspended uses of these herbicides (rangeland, rice, and noncrop uses) have been combined with the cancellation hearings oh the suspended uses. The hearings were recently halted to provide time for the Agency and the other parties to explore the possibilities of reaching a settlement agreement. I have enclosed several documents explaining the Agency's actions on 2,4,5-T and sllvex. In April 1980, the EPA completed a review of critical health effects studies on 2,4-D. No TCDD dioxin has been found 1n 2,4-D as 1t has In 2,4,5-T. In the course of this review, a number of gaps 1n the data on 2,4-D were Identified, resulting 1n a decision by the Agency to require additional studies from registrants (manufacturers) of the herbicide. Those toxicity studies considered scientifically acceptable showed that significant adverse effects were unlikely at human exposure levels which might be expected from current 2,4-D use patterns. New studies were needed on oncogenicity, teratogenicity and reproduction. In September 1980, regis trants were notified of these requlrements. EPA 1s coo rdinating Its health effects review activities on 2,4-D with Agriculture Canada. In late October 1980, the Canadian government made public the results of tests conducted on 2,4-D samples manufactured in Canada. Employing sophisticated analytical methods, Canadian scientists confirmed the absence of 2 , 3 , 7 ,8-TCDD, but found other, reportedly less toxic dioxins, ranging in concentration from 5 ppb to approximately 8,000 ppb, 1n some of their samples. Consequently, EPA began a series of tests to detect the presence of dioxins 1n samples of 2,4-D produced 1n the United States, employing the same analytical methods as used by Canadian scientists. Testing of samples collected from the complete range of 2,4-D manufacturers Is being conducted at the Agency's Beltsville, Maryland, laboratories. EPA Is also collecting Information on manufacturing processes which may help to explain how dioxins can form during the manufacture of 2,4-D. -3- Currently, EPA cannot justify regulatory action which would either restrict uses of 2,4-D products or prohibit 2,4-D production In the U.S. Available data on the toxic effects of any of the dioxins found 1n 2,4-D samples Indicate they are significantly less toxic than 2,3,7,8-TCDD. The concentrations of 2 ,7-dichlorodioxin found 1n preliminary analyses of U.S. ma nuf act uri ng-u se products do not appear to pose a health hazard. Your questions concerning responsibility for the herbicide program 1n Yletnam, and the possible health effects which may have resulted, can best be addressed by the Department of Defense and the Yeterans Administration. The Veterans Administration (VA) 1s working with the Department of Defense (DOD) 1n an attempt to determine which soldiers might have been exposed to 2,3,7,8-TCDD from the use of contaminated chemicals 1n Vietnam. Through an aggressive YA outreach program these veterans are being given thorough medical examinations to determine If their health has been affected and to Institute corrective action as necessary. Dr. Barclay Shepard of the VA in Washington (address enclosed) 1s 1n charge of this program and can provide you with more details. The General Accounting Office (GAO), an Agency of the U.S. Congress, has Issued reports on the exposure of U.S. troops to Herbicide Orange 1n Yletnam and on the known health effects of the Ingredient chemicals. These reports are available from GAO (address enclosed). When ordering these reports, use both the date and reference number; November 16, 1979, FPCD-80-23 (troop exposure) and April 6, 1979, CED-79-22 (health effects). I am enclosing an extract of the report on troop exposure which you may fi nd u s e f u l . I hope this Information and that which can be provided by the sources cited above will answer your questions. S1ncerely yours, Enelosures Edwin L. Johnson * Deputy Assistant Admlnstrafor for Pesticide Programs 197-9H 6- TAB 7 U.S. EPA 1993 "Exposure Reduction Measures" for 2,4-D AGREEMENT on EXPOSURSEumRmEDarUyC-ATpIOrllN1M99E3ASURES for 2,4-D LABELS prpotdteahrrafctoeotethadghsanur,ergiacecormatTqaerclulehitaomidhaebrn.neeeeaddlenlgIsixntmrkbp(eaeybaaeol)desnm,stochduutaeiehrfitunaenieAocstcrtenmlwgeuuderoiotdlnioulfnreccesgbmyrte-ei.rpuouqe'relsnusoWtfetiivfrpareiihpinlcsnceeritdtogoirevaednfdnceousmtercitrwfvhetoorserqerroeeuvcixtuniiohrsprggneeeeohrtsmdesaitdmturiedhniircneepeeitntanlisegvradtesmmewl,d2iniere,uel4eenlnxc-sqtditaDasiupfmottioipinarnoerlecgynnmmes.tumtoeieobcfanamfsxtaasuriicemtr2itcgedi,uu4nissmro-gtroDrrehnaanateuptinpalospyyrlenlotrishdacdepeauoadrtpcfniiuvoetdcaanlatarsitbavioeofenelnsty, rPerdoudcutciotsncmonetaasiunriensg: the following active ingredients are covered by the exposure T2IIDI2DSsss-,roooio4iBiemdopi-putsDicrhreutoootoatiymppbcpxnlrhyyyyoolsl(lleolpa2aaaterma-hmlmosetnytptiiooliehnnhnrlfyeeeeaelso2nmhsst,sfoeae4aaixx2lr-nlltDtyy,teo4oaloo-f)csofDff2aeer22,t2ls4,o,its4,t4c-4oreo-D--drDaDifDsicou2ooioofdm,orp4rr2rrb-(o,diD22u4dspi,,t-oim44yoDeop--lxterdrDhyt2ooihate)c,prrn4ytihyahiao-llsalndycolaomaidlermcpmot2ihiripnic,toiln4shenopea-eredad2con2enii,2podc4r,o,4hixh,-4vl-deyal-(adoniadm2ticrocii,cohv4ciexhnpleh-tylodeashloaro:tieroec2cronhepo,p4otlhpaoh-xehdtreyneeoinaconpochxohexlyxetoyaaynratcaooececxpeteyhatta)etae-tnte,eo2x-yetahcyelthaetexyl ester Protective Clothing lAolnlguspearnstsa,nsdhomeisx,esrosc/lkosa.ders/applicators (M/L/As) must wear long-sleeved shirt, sMeaanqf/cueLlato/ytAsicegsdluaosscfesaeabpsgs.rroiocEdruuylccteoutcsrpakrmlpo,itutiesnsc.tdtiuaolssntoriiaswlne(oarirtgrhcehtsqe-umoifri-ecwadal-yfro,errsoiasaptdapnslitidcgealtoomvreassininatencndoamnfacpcelee, tesehtlcyie.)ldanodr Ualssoerws eoafrtueryfelipqruoitdecptiroond.ucts with "WARNING" or "DANGER" signal words must i mCoumstmalesrociwaleuasrecrhseomfiaclall-truersfislitqaunitdglporvoedsu.cts, except when used on golf courses, Nsaoltn,-acnodmmaceidrcpiarloduusecrtss amnudstusaelsros owneagroclfhceomuircsaels-roesfitsutarnftligqluoivdese.ster, Na (sodium) pNroond-uccotms mmeursctiaallsuosweresaarnrdububseerrsgolonvegso.lf courses users of turf liquid amine P5egraslolnonssw) hino ceanpgaacgietyinmoupstenalspoouwreinagr coofvceoranltlasinoerrschoefmoivcearl-r1esgiasltlaonnt (aapnrdonl.ess than / ^ Mechanical Transfer Systems* 2 r"cePomnrotoabvienalearnfsrdo5mpguaamlnlpo"enmssypostrtyemmcoosrnmetauiinnstecrba.peaucisteyd. fPorrotbraenmsfuersrtinbge tdheecocnotnatmenintsatoefd before Maximum Application Rates 2 lbs. acid equivalent (ae) per acre per application for pasture and rangeland 4 lbs. ae per acre per application for forestry site preparation 2 lbs. ae per acre per application for turf Maximum Application Frequency 2 broadcast applications per year per site for turf Hygiene Statements For agricultural, industrial, and aquatic uses; lApobcs"ohWlretofahooftdtowaedehisrrruniehencwgrhg.t,heo"oawawuortnksriioednt,rhahsgrnpo,o,epumdlfsdlatmuyoccrilevonialnekeguaaginnnantdhtgldihlrni,ysecago.lrpporfmriRrtordhessderivtinwm.uingocikotCutiha.vnslneogsddWt.oshaaasyiaWpnht'susgohaarwmanmshthediaexurndhiswnudtagcssanbil,tdnoaeefgstnrahkdcaasieneonslpgoadastpaonaaadsodarninmnnsdaogdasrwomsowbnarspeasaofahtwosespesirrpdpte.ihbloisulscDseessaopiiotabanaifpolgrnetaneotatraotenonilmrdflydeeittuwxfh.rsiianoestgme,r For turf uses: ssFkeopinragrwaritatenhluyslobaarepfporaroenddurecwutsas,ete,"rA.a"nftderpurosimngpttlhyisanpdrotdhuocrto,urgehmlyovweaschlohthainndgsaannddlaeuxpnodseerd Ftrchelooomrtrhooliiuvnqgeguhicadllysoptwshrooiaondsnghucaahtsnasd,npd"olAsassufaitnbnedldreeureasxnsinpedgopssatehrhadoistwesplekyrrin.o"bdweuficotthr,esriorneasupeseag,nlodavnwedsapbtereorf.morRpetelrymemaonovdveinsagt,urated i<17f 7 Restricted Entry Interval 3 Aprgorviicsuioltnusraolfutshees W(InocrlkuedrinPgrosotedctfiaornmsS)taannddarfdo.restry uses are covered by the sFdeuotrtrilnetdug.r"fa:pp"lDicoatinoont.alDloownpoetoepnlete(rottrheeartetdhaanreaapspulinctaitlosrp)raoyr pheatssdorniedtreoartmduesntthaarsea Effective Dates Afraenrgmyissctr)oanwnstiullamfhteaervre2A,t4ph-reDilnp1er5wo,d1eu9xc9pt4ofsfouorrrmeuursleeadtuoedcntiasoiftnteesmr oOetahcsetuorrbetehsraon2n3t,tu1hr9ef9(l3ianbocelrlu.sdoinldg bsyodt.he rAseongdyisftcaroramnnstsu)amwfteeilrrl2hJ,aa4nv-Dueatrphyreo1dn,eu1wc9t9ef5xoprfmoorsuuulraseteerdoendaufrtceetsriiodJneunnmteieaal1s5ou,rr1eo9st9ho4enrotrthuseroflldasibtbeeyls. t(heexcluding For more information, contact: RJS4WUi0pli.l1caSeshBc.MhiElaDionlnoSugvRmmtti.oe,ranov(Ss,in7.eW0mD(w73Ce.0)an33nt)a20dl038R04-P886re0-0or81et09eg1cio5tsirtornatiAogneDnciyvision (H7508W) - Men, women reverse roles non-traditional careers Headlight AHeraldPageB1 I 1 M iip rt.je rsm p t-iJ V . Wearable art at fashion show Pacific Coast Seniors, special section | 1 ' - "/KtOTSnWArCAVa' pproves ocean salmon season Page Cl Serving the people of Tillamook County since 1888 Vol. 105, No. 40 Tillamook, Oregon for the week beginning Wednesday, April 28, 1993 Five Sections, 74 pages, 50 cents Index on Page 2 Chemical weeding: Is the cost too high? Mcoontstecseuntitveencliefde ttoertmwsoToaWhfmDwfbewtdegAsbwsimtftgbhlrwrhincovntuoaieryyiieoeeihnehraeaeonedlyilTBlsldeollesmltoekAdleatkeTnussdbn-halsetruhDennbprie,edt,aartiadmnfzitRbgaaameesa-lnnaarnttmhawgyhelstsnmereoootooiavrdtglenofg'ddaoeanwniwuStsit,oe'do,odtflusrhugodoryonyodtcrivokehdnfDiseetcnl'bofaasutamlbgehlpeeroetmeedsgnannsar,wuhephrehwirm,iboanduheetvostraereostt,HoaayshirbetechiihizetrhtmthlcbovldwtfcreDdedohtredzs-elhhwkewshanr,edpHnmiaalojsie1eoeiavteoeiopolwlursieephSstn0vysml-siwdylpepdasgsh,Gprtoaeaiaipseterui.,atadephbudnofer,aupraoehcl,mrnsluodlatneerwosDrofootrnaoeasada'nGy;gdfesypsslrtvfenucrnoteo.t-gedigprtsto,eersietwtbddehhehf1kcbrtliiiworTrefdodnnrfe1Seatese.ecosobvcaoerfchaoru-gtlynlheoiiolubmeyela--hniafeneacooyntsyGdcycirerdriisdsAncu.rptsblsbresroashe.omleeriesdeahoarlosl-oavdopAwvsat-siiiBraaraioro;eevtodtreasdlaino5bnnhvaoemeardotule.trrerynyd4oddiy-dnheeser-,fr.tf.t dGsR`2oeri,mNdo4livg-voeDeeter'sre.ep.yvvlMaeennraayssnbvyotcoedonwynatiulvsrlrcoeesisiotdiadouyitsunhlhtgyedomoianaeoi*srr,Dbsoatehnrtenoder po-aIZthnnefeedtdwldiltuoesiioroanusbumntbarTltdiecteieohlrlssi)alhn,im-afktulooetsi(o2inftokC,eco4nnlraC-u.dmDvdoWeiiuentsnnsrhpghltrayyttaaut,h'ymsreaifngGwhgCFoariartoonthodhvrdeiwoeefnruursengstt,l oatirhnopuoupttuhCnrTesedaaihlisvnelncadengimnsesinhoooDtaonifmfekifeicosarroantehrRwdsgetinueCdudsmglnaeeastthncs,eortteetapolsselvcadtewohnrvurdeoernlirutslsdigkueiah.csrs.t FctaPafornuoorooctprdhmeteerosocft-rrrtpiioytOoim,tetnhhrsweeetAghihndegoiUvcienssohn.yp'Slcsvsuyi.tente.edDmEdAtuet'nnshrspvdniotaniolrrkfugpetotmewinictoths,m'ensein;cfmeatlnfaeiibnctaroaiaysrgllf,t eedaculisuffebbcOfDNrCthntpslierotJdriuueabinamucueayleorcroeoeraolsrnCvaiwraarorAateBfmxtsqpulerbueeeisccovn.tnonaycrinsnudegbe,hgpyddtkbosicivo,eofiiy-trliealmo.pouabcnyyctaelmr-aamgotoobnlolnrptsaonrselctoinlieacdeuoylvdltore'nuachirliyuhldoostgepcnsfneaurrraynahoisredmyasaaiwrndtrm,toorttalr2tstuifsly,mthyhyeiepfdo.,dovfht-,mceaea4mbueechneiesrtiaitmafnwRri-ctrrbsghtfaphnscoojee-nDoe.eaoeluhoeewehciheinonsrndfhalrrsnrtnmeroms-Teuy,w,meidoavPwchsdmunfrmkilprqholfiiia2eaeinaibetdleevgoictmerdmiudepnrct,stonepalciruear4shueiieslytpvstaforifsreolcue-dbvrensr.aitlerlDnnkfrachuooyoteexetyasataayfaeturie,ener.rorT-anftln,onetwen.Nysioeiynfmbuddncdeti,gofnfndtsltleosFtga,ohycchpulleahaeainaisretaeseoreivtslteamthulganesyreespd.mthwmnralercrnerfds,pltewmpsiiuenpihaTataweshcovfsrocarrieenneerueilaneeaeeihaoniinrnnsekrstslloaacltcdgsnased-k-o-ye,ht-:s-s.f TadU2acbWhp-rft(cocispraOsp9hsWeignea,oinouoaari6olfnn4oaradluolanoA"nnlmwinguWadeli-lstfnaTliosdtSdpvaulIDtgslnnohg,csyaepmneiiemteauotebtohhidselclaledh'Wlol'trlrdlcrtasenirtiaiiilsomcssaoestonvs,lyagt,niaeieyrhrtempmsonngt.angaeoaeeylsdsn2yaperuk.ttloqcrdauoaifaruotc,ro-eimesv4nsdeuogubEocvlcsobnopeitlC2e-ginrriasgokhealxmuprdwDcerWva,weeaystaeeoy4tnlis,pfeim.ntetCepdsdealuai-keoashrlnipdt.iuGsDeoarcr.eoanennnshy"srmdtins-robcriudoniCJtioi,:",antlsovymmpyoon-wihibiIoboasrteamBorn'Olnthntelssdlmaanolhnlnnyeioricne-ldiscutStbf,ecmdi'tlGsofeOlsfooqkaetuaoewaoonsnaWr,depuncdborurcbccotfr6nuhvoe.peewilnnheoheartfifny5hhimiagurlshtaopel,nrlceiogyoot,-otnl7ocifupmteAbmimdu,s-wuoCrntam0ag,laiOgdyietosasamtirtlmb0rhuiirerric.i)ne'metremSsocloum,s.oesdaehd0nElslYniaettugarlieBus.otd0naiePflioonllnboaoscooyocolt0eoyuIin,Andsnyduednnh"naarff-rt-,tt. blccushhehiUPaMcbbNoditEOp1isnorotqtaoaeetonrnerrPro9aa'.oinhnzoourtIr""etuOkASpsBbt8hPbanbapsescfbafNni2sUnselenrloe.'i'e1eoarelpiloe.sa,Bg,cdlcodeisdynxsntr4n-e"uuywesiissmwito'rskaaddtnil-idntuiosi9eunrafevclthcmDn,dege,erbceors.sd0dsnbtioeneeo5sCptidajauioeeeesbewrr,em0dsuoreyipctopc.xsnfwanaenctaw"stnl.wshtiaeoypthasvettt,saEteaCnleeaieeobday,ihCri,tssnee,dibadtrmhlslgMsoctnieawpdnvsraueeseoehatstiioeinlr'aatoeannrEoarctoieeasoreplgtngoafhffwraee.vautckmfref.yreenfeitrfggoal,ianeoecnTdemfdl2oMuivcppeiekcsosrtys;hse,onsenesbdeerpOcri4tr-eneAaesietoronefaeetoird-t,rsccsre'ro.radttDncUlfveeswalBkecetthnauvottsiepSletshhdsnPinasae.ocertniartl,deehsicsiSnhsihenl^tdngvurseneceiin.Wtiaarshcno-ebDtrehulsnfdettf,ta.Eranasrseidarhia,iase.ivsoatsoefnPrrmaiminchnneooyeimemtpnstoiiAhndy'nedsa'sstssrsft,-t Continued on Page A6 Q 24U Randal Paul Mott was sentenced The two life sentences will run C hem ical w e e d in g"age A6, - Tillamook, Ore., Wed., April 28,1993 Headlight-Herald cfZa-mttwadowedHifCoucupceadaeaaBicsohhHmosfrnrVi2soCrmpnarnnelwnricseanmasinaeeoahhoeaaufeugaoagnuprse,ngomoderarteushrgnyB"os4ZonomsMsmsmeTbtnhaulEadtcoteE.o.n"detd`usaTstaatitsmsc,n.a-NhoIseamaetbutngpschhugtTatigiaPEvpawfrfD-aeeifS.dohgtiuarhedndr-tudgelnf"derhanekfakorA.CteuemPhininaitterimensimolieler'ldysweuenoithnoirdbscfiescbtAas2,eltbdInpshqNllnsafe2dhroneyoorhhacfEdali"sdral,,yoyeie'aeuttiago'era'seK,dlo4nneomawselCnsfioeAsrohPsiu4nysNsgtlernhmnjNetfso-eallxhgeydnsgWAeutftah-pIelsyarlnDredotipbt[rbrdphloeeyDeeydttgeahnerpmanpteoyinNa5t2hl-ohe1dpdinooennmr.gNsaetpaichstesfohprtnmso0tm5f-seien,y,aptpseedheoga-CrrcueaTievooapilaa4tichCrpphHeoprtrfgolaas,.sedhotdmwanmmtpyeptnNvPlosphraeaoIr"eiih-oinehsrnaIetuepnrtevtme]noegphtaulwseDaeieicritoaueoryoCosnenclclcteacamgidlaglrrorhrronp1eOmdeehursfsnnsetcietrs,crs'ieenayItlgeodlsmcof5ed5xolsybtetensoCsroatotcaeyrceapvfnortyashwEneukrahe0a;pirp,tAecdsrunisstteoncooinaaaeecca,fdtoesidtoi,NPooueeiia1ppt,r-miwtooiwntolkmrngitptgsean-bcenymdhoteswAssmludritNDrsriienta'hhnoaeeraecfnsoudh,pohgsvegnnnssdeootibrtertp2adaberd.mhcdrnoiCreh,ratdepty-er.iCdmclwilrcetdlhesse,erhdeeoaeemeleiitA-eiso,lasy4aeirIohaOs.nSdcan"haeeefietdndahsayrtnnzost'Im-ae'nmnisornehtiitvnskbsojewunDikcoOrefateohetolntosShidvdtehcrofeeiimiesnitpolsnednwarhiua-tolcccc2prarnhoehiigulhi.'nfgtoehonpwalveNNeodBwogtoani,ligdtroo.tatsiddesocwp4d.oagtufwienoilpOotduhnaauttwrro-iuteerowiomoalrwuh-nmetrioidtuirceelebrihygnlicorsne.DnsvtawoInsennlsrsyaanmya'd"aneaeedpeneeeiyoss-tdsttt-aeen-,,-etslr.s,-,, cssoasotirbvtttthftpsvsetiwiwjyrwsbnrcattwruihascorhieehcfoioinmgyyolifyuahiotexiyhtunoeioreonhvcesrhsewaoexnaagoensl.evbgrsnoeper"naodotZnrtmellEieyseoig"niytM"ntryiaeeplreis"Svserfirn.IrulrMcnesmhmdeclWto"tiskic2savaetssdlas.ldewdiEauiotiei-hmunsteaip-.getuouhlna.yidmhetr.c,dariaoafoicnsotcfsePnayatd4eeaerdonnrcrnasdratsliBrmhoic,nhtrwooUEvstslorAeeepsd.nta-teao"advuh,igiiidlhaaiecc,itueecli-tdauDnfmPnr,tltrlasdpneneosoerhddshetsfeoheoabeisntrty"sAdgotarrto-ndcliilunsordtiooercpsyetobaeinacnicoieiv.ghlnstixgccoraoln;'cdnstaonfsaistthdlytutldvoacmteee/oeooohserinthieoaeatuaieogsy,mp/ademtlocstitsntaedritvnr.mfnf.ctthptsmdsorseeruntyhusrc.montutreehernseeaeampitvn-SeoehpnesxuttZphgaarseretoiriine,dreohosNsyaapesmnnti'rcsaot.idattcqanrsaseutashcrseceeyctolnratrlde2gimrnaauiuchoa.sohple2esiielososmahierbvutidolstuinoy,fvcrn'sicelnnlvtyageermn,atctenn4lBreurlaahyco,o4esoeichrigsomesi-teieatedmiotgsnisl-ccttbaelikpn-uHkevg.seiglsdnrhrDZhneynEnDairgpmdrwieasrdtymtites2aiietwecx-eieuoiod"eoaoinnPrtsof2ngoibtnncyt,niehpwostaTshsimdoetth-t4ighAdpwnoe,aytegscihsssmeeietttamat-sZd4moge1arshe-hneethao,a-e,anoopaautanaDc9b-tdnkEsEanecanalcliasss2httrrsbexobbrweeDmc8uapnreohhvtiyeteiePPtcni.scsy,elyxpchoniummnt7rpboririli4cemelghsAAotcdy'eriah.omnsmleiucoes.ar'isinen-bsa-rrcsim,ninaacipdtmuglgttgDmbean"StdLrtmntiomw.ataantiumcit'fielitchsnhqbltausdeudosewdonrusdaoss.lltitgfyOmiiuouuttoud"oesblsghennhsuiaeetnucnadcncategmygaitnrnbtrhtammifaheotelhiy,sbuckterseikehcaghrarerns"aehsyo-e'-enieitey-ser,ytse,serrtt cMpgocdgatsama`pMClrtdpwffboRahoeaanreflrilnfraaeooesybatainlriyeidyeosdgaieltlTcacaT"mecspoF"ere,dtheuraw-tissuTWynhcwhtrlrhorpiehnumnntaho-srosistcaeoherlomtanenrdiheseteorlholefnoseerslgedelueaseoiawwekeeaueathntseVseolperefslbcstTygcatprsndceienaimlen'xhisaanoutttshpedortiyelrpii,ohiiastnaegcaiganitlroobemwneo-aimrnlrlsatany.ewvuroetnniir`taff.gybdtescdrcstafees`nlsfeemDa,oO!s"hme'ofnthh.iomissdsl"hiovdwaK`eaoiOiitrSocAeieimp-IgiianTremieadtneiilnmroteUrSssrshlriechiteyatpisilekfeslkUiocnfcav'ne,rtliiwsweslslfehaoseaoatadntpelaiarao.vmlill'eenlorctrvdliimttdnodfhcdfoeItteneahipeaaodecrtspophrec.pttdnosnplti'acyerorhrwltseeitoecnialmuhoboeonetekasIiemtdribwhgndresgetigdmoodfrvaessyieialeeruluisiileoinnpitt-ilpascersndxp.setiwshhndogl'sapmrnalvtntivgarkeieiwreuv.etaaoralosenaceyo,ianotn1tpaprT,"omlijmesehi,cwockpwu9ststpepmtshlnehhiloiiwb7t.rhoeocyoErnaionnceea.oeuou4tisistri,snkgdndgnnhssla-",ltt.t,t dcoTmWtWmtwwoaaaub(nahirvunafpiysokoohdeerleaeldpcel"onB"-oeinsceaAsructltROWaontoudesishmivuihslpoccyesng,oeloiSewtt"aepocnefttghdhnlUaeotrelhoaesougiaioeloc-lgrxsoaoarmk,-tlstfueclcdeotlTpslnnesrheocyutestCoinepwilifhndsea.upefpleuorooeSRelgo,hlihnnahrancfrnulimHueteetsxbmsdionoa2ostranlugtueowetltefds,plodyniy-Di4nobti.a.foopoo.sw-toarottotnt)nDoTktnthechr,hahna'siasehaehRsntaalitl9nSssieheounttntaJG2soepia'fmcdgoasinx,usurdossalb0yonhigh.apstirlgOoy0ninpeeceeyssvnithc0zfrnlrahashuoegevooeeoWtaraolgrtrsgmtirDrsallahfptynMeebeocicejiaspgl-tiziihnrrussnlarstcyslewei.taletedasiaetrsapwitvardtymoiegotnrhgHerbcnheesapdnoniedaedstidn'esesse.,t. i rt j-*r i 4 FOREST N E IG H B O R S - Members of the Grover spraying is going on. Shown above, I. to r.: Debra, David family stand in their yard, which borders forest land to Sr., Sensaira, David Jr., with Aaron in front. be sprayed with 2,4-D between Tillamook and Netarts. The Grovers plan to move away temporarily while the Tim(H-H photo by Sills) sAaaiclm.tS"ueta.altley,ofwOe rtergyonnodtoteosnu'tseseteheimt thaet TFsLLlagfapycuoiaabrlribbrlaaee"LdaehlhyslWelmas,.aailbtniirireo,stnWthtg'.o'sfedsawekshn"jroeou.htAee!nDfsnxiefsi2ctitisshc,alCl4wtiecocrk-aicenthDewcvooegiteatkrieialondn,safllhifysasnsbfaTnagoceyifoinhroolettevlehobu,as"cemesmtaorerfesipemoroarc3pvlyoatlmle0fooslkio.r0cwe"McrSaf,ne0rttcotiatra0hohetrmt0inekees ctfDnbkTtcyaoioneeleoanhrerocsvcTT""utee"a.m,awoiIY'dhIhdrudo'mtbaaejom'swsnGuobttgeeur3ytybngnreef2onsteuoeihaiv-ktfrortaruays'aaesentrswmtacenvraa.pos.oadoshnaaarwruuyritnae-cpfeelcops,deredfthilpvohr,ddboyadwmeebtarmluhrnfuioeeaacontaetsnnttugcbtash.iaouhogmroetmeiaehsnuurnoniml,tmrl-fa'vyatafleiriaepicleoentcldla-l,plyeras"lsietsmriwtespohhshaphcanaoaeenooo.tvsylrndorrr.ieestI doatbcpl`hiDtoiulokrergmritto.eGhshyhulneoelrygyeoo-hsiydvnacalehtamadooornaunfephdlwtdtp.Chot'eiaierdmalmityvezcheloehnioonnbeeubhe-mstssrlahetiapmhrvetleiiiolisotoaryfcnuuohsspgsrmoeehrdntsiotihmstonr.anegtirTettophiiwhagvmeoneiho.rlydpel stcfiiahootinhn"ldeWsirrneetsnhba.naye"etfsoe.cdr"eoTtmowheaegtesbcttaoaacmrltklemtohbaneakciiuknnsgfo,o"ndrmeotchuaier Town hall meetings lineari cur Monteiion icnoor ?POINO /?LO%OM -wir v sh b National Network To Prevent Birth Defects Box 15309, Southeast Station, Washington, D.C. 20003, 202 543-5450 THE MEDICAL ECONOMIC, AND ENVIRONMENTAL IMPACT OF 2,4-D Prepared by Erik Jansson F e b r u a r y 2, 1987 {H TS I THE MEDICAL, ECONOMIC, AND ENVIRONMENTAL IMPACT OF 2,4-D Prepared by Erik Jansson F e b r u a r y 2, 1987 iftH irZ National Network To Prevent Birth D efects Box 15309, Southeast Station, Washington, D.C. 20003, 202 543-5450 THE MEDICAL, ECONOMIC, AND ENVIRONMEHTL IMPACT OF 2,4-D Prepared by Erik Jansson F e b r u a r y 2, 1987 TABLE OF CONTENTS Page THE CASE OF 2,4-D: WHEN HUMAN STUDIES BECOME AVAILABLE CANCER AND 2,4-D Non-Hodgkin's Lymphoma in Kansas Farmers Linked to 2,4-D Animal Studies on Cancer Immune System and Cancers MUTATION AND 2,4-D BIRTH DEFECTS, SPONTANEOUS ABORTIONS, REPRODUCTIVE PROBLEMS AND 2,4-D Laboratory Findings About Developmental Toxicity Farm Animal Studies and Reports NEUROLOGICAL EFFECTS OF 2,4-D IN ADULTS Loss of Nerve Conduction Velocity in Adults Laboratory Studies LEARNING DISABILITIES AND 2,4-D The Dioxin and Liver Enzyme Issue Microneuronal Hypoplasia OTHER HEALTH ISSUES AND FIELD SURVEYS Heart Disease and Stroke Field Studies Dioxins Damage to Crops and the Environment CONCLUSION Appendices ' Bibliography 1 2 3 5 6 9 10 13 14 15 16 17 18 20 20 22-26 27 Chemicals that challenge the health will be unprofitable to the nation, and will detract from the national productivity and growth. One reaches this conclusion because the health costs are simply so much larger than any other economic gain that a chemical could produce. For example, the United States spends 10.7 percent of the entire Gross National Product, or $387 billion per year in 1984, for medical care. It is an expenditure that dwarfs the total sales of all agriculture, forestry, and fisheries, which in 1982 accounted for $84 billion in national product. It dwarfs synthetic organic pesticide sales,) which were only $4.7 billion in 1981, despite high federal research subsidies and direct subsidies. Diseases of the aging process are America's most expensive medical problems. Rice and collegues estimated that the medical and economic costs of cancer in 1980 totaled $51 billion per year. The American Heart Association estimates heart disease, stroke, and arteriosclerosis to cost the nation $51 billion a year in 1982, and the National Institute of Health estimates senility to cost $40 bil l i o n a year. In 1982, Americans over the age of 65 were spending $106 billion a year for hospital care. Childhood diseases are also expensive. We estimate birth defect medical costs to total $14 billion a year, as of 1980. Learning disabililities and mental retardation cost the nation considerably more than $14 billion a year, if economic productivity costs are also included - in an age where education and working smart are essential. Alternatives to Pesticides The economic justification of taking health risks with pesticides diminishes even further in face of the widespread bankruptcy of farmers, and the need to cut back on chemical inputs to reduce costs, maintain competitiveness, and increase profit margi Based on the results of years of research into alternative farming methods such as integrated pest management, many experts conclude that a large pe r c e n t a g e (50 percent or m o r e ) of the use of synthetic organic pesticides represents economic waste to the nation because it increases farm costs without bringing farming advantages such as better control of pests. In the case of homeowners and other users, exposure rates to hazardous pesticides can pose major health problems. Furthermore little national product is produced by cosmetic spraying of home plantings, and there are good alternatives. For example, the lawn is believed to be the easiest home planting to manage without any herbicide by experts who research alternatives. T H E C A S E OF 2,4-D; W H E N H U M A N S T U D I E S `B E C O M E A V A I L A B L E As human studies become available on the health effects of various toxic substances, it is generally a c knowledged that it 1 ? 7 iTiT RHr# becomes less necessary to rely on animal experiments to judge the safety of the chemical. Indeed, when significant and adverse health effects are found in people due to exposure to a pesticide, it means that the regulatory process which was designed to prevent human injury has failed to do its job. Sufficient human studies as well as case studies are available for 2,4-D to be certain that the herbicide can cause serious health injuries after routine exposures. These human studies are in many cases reinforced by laboratory results with similar findings, but not in all cases. Differing human metabolism and inability to query laboratory animals about some symptoms produces some divergence in human and laboratory studies. As Ruth Shearer wrote in 1981 about some of the acute effects of 2,4-D in humans: "Acute effects of 2,4-D in human include headache, weakness and rapid fatigue, nausea and vomiting, diarrhea, burning eyes, sore throat with burning in the chest, and impaired senses of taste and smell. Delayed effects of acute exposure include numbness and pain in hands and feet, occasionally progressing to limb paralysis, and visual problems including diplopia. Residual effects include continued numbness and pain in limbs, chronic respiratory impairment, bleeding tendency including menstrual problems, concentration and memory problems, and hypersensitivity to non-physiologic chemicals. All of these have lasted for years and have been reported in cases of bystander exposure as well as user exposure. Nearly all of these human symptoms are undetectable in laboratory rodents. Bleeding is detectable, however, and has been demonstrated in animals given high doses of 2,4-D and in fetal rats whose mother was given very low doses. Humans would be far more susceptible to such capillary injuries resulting from depletion of tissue ascorbic acid content because the test animals can synthesize ascorbic acid (Vitamin C) while human cannot. Research has shown that ascorbic acid is used up in the detoxification of organochlorine pesticides, and other studies have demonstrated that a 2,4-D family injury found at very lose dose in rodents is depletion of ascorbic acid in spite of the fact that they are capable of replacing it by synthesis." (Belova and Sokolova, 1971) The large number of laboratory studies showing internal bleeding in the animal and fetus are particularly important because of the many human reports complaining about the*same problem. We will come back to this issue in looking at birth defects and abortions. CANCER AND 2,4-D In the Unit e d States, 22 p e r c e n t of all deaths w e r e from cancer in 1982, costing approximately $51 billion a year. In a two step process of initiation and promotion, it really makes l i t t l e d i f f e r e n c e f r o m the v i e w p o i n t of' m e d i c a l c o s t s w h e t h e r the cancer is generated by initiation or promotion. Americans are already exposed to a wide range of initiators. A health approach that aims to reduce the medical costs of exposure to chemicals will look at the initiation and promotion of cancer as equals. A good example of how expensive cancer promotion can be is indicated by Blumer and Reich's paper on lead exposure to Swiss residents from gasoline. Removal of lead by EDTA chelation in high blood lead cases was found to reduce cancer deaths from 17 percent of the population to only 1.7 percent. In other words, at high dosages lead permits the full expression of latent cancers. Farmers are also exposed to a wide range of cancer initiators, ranging from pesticides, to fertilizers, to viruses. Strange and Krupicka in 1984 noted the possibility that nitrogen fertilizers and the nitroso compounds generated from them, might explain some of the higher leukemia rates in mid-western farmers. Obviously, adding cancer promoters to such a situation will lead to problems. The literature suggests that 2,4-D is both an initiator and promoter of cancer. Non-Hodgkin's Lymphoma in Kansas Farmers Linked to 2,4-D The recently published NCI study of Kansas farmers (Hoar et al), and their cancers and pesticide use, is only the last of a series of human surveys linking 2,4-D and other chlorophenols to higher cancer rates. In this case, a higher rate of non-Hodgkin's Lymphoma was found after 2,4-D exposure. It was significant that rates keyed to length of exposure and use of protective equipment. Farmers reporting exposure to 2,4-D for more than 20 days in any year had a 7.6 times greater risk of developing NHL as did nonfarmers. See t a b l e 1. Previous human studies, largely from Scandinavia, have focused on soft tissue sarcoma, malignant lymphoma (including Hodgkin's Disease), nasal and nasopharyngeal cancer, with colon cancer u s e d as a c o m p a r i s o n . T h e s e are s u m m a r i z e d in t a b l e 2. B a l a r a j a n and Acheson in a 1984 survey of soft tissue sarcomas Tn Britain, found that these sarcomas concentrate only in the category of farmer, farm manager, and market gardener, with a relative risk of 1.4. We know from numerous studies of farmers that exposures to chemicals and to livestock and poultry will elevate cancers. Farmers tend to smoke and drink less than the population, which means that it is essential to be specific in comparing cancer fates with the general population, since lung cancer rates will be less - which accounts for such a large portion of cancerideaths. What is most instructive about the Swedish and other phenoxy studies is that they key to cancer types that are relatively rare in the general population. Sharp elevation of rates in these rare cancers makes the case much stronger that 2,4-D does cause cancer in humans and probably initiates these cancers. {^ 7 ^ 7 P anel 1 II )-D and Non-Hodgkin's jjymphoma I Table *11 . -Non-Hodgkin's Lymphoma in Relation to Duration, Frequency, and Latency of 2,4-Dichlorophenoxyacetic Acid Use No. of Cases No. of Controls Odds Ratio (95% Confidence Interval) Never farmed Duration of use,* y 1-5 6-15 16-25 26 X fo r trend P (one-tailed) Frequency of use.t d /y 1-2 3-5 6-10 11-20 21 37 3 7 8 6 3.560 .0002 6 4 4 4 5 286 16 22 15 17 . . .. . 17 16 .16 9 6 1.0 1.3 (0.3, 5.1) 2.5 (0.9, 6.8) 3.9 (1.4. 10.9) 2.3 (0.7. 6.8) -. 2.7 (0.9. 8.1) 1.6 (0.4. 5.7) 1.9 (0.5, 6.7) 3.0 (0.7. 11.8) 7.6 (1.8. 32.3) X *or trend P (one-tailed) First year of use* 1966 or later 1956-1965 1946-1955 Before 1946 X fo r trend P (one-tailed) 3.733 .0001 5 9 8 2 3.561 .0002 . . ..a 21 23 24 2 * eea 1.9 (0.6, 6.0) 2.9 (1.1. 7.2) 2.1 (0.8, 5.6) 6.2 (0.6. 65.3) *.> ' Five controls had missing data. fO n e patient and ten controls had unknown frequency of exposure. First available for use in 1942. (Hoar et al) Phenoxy Herbicides and Cancers Table 2. Risk Ratios (RR) in Cases Exposed to Phenoxy Acids or CP in Swedish Case-Control Studies Referred to in the Text Cancer Type Exposure - Phenoxy High-grade Acids Chlorophenols Reference Soft-Tissue Sarcoma Northern Sweden Southern Sweden Malignant Lymphomab Hodgkin's Disease' Nasal, Nasopharyngeal Cancer Colon Cancer 5.3 6.8 4.8 25..10d 1.3d 6.6 3.3' 8.4 6.5 6.7 1.8d 4 5 7 9 10 12 'p < 0 .0 1 bAn association was found with exposure lo organic solvents, RR equals 3 .1 `Organic solvents, RR equals 3.0 dNot significant. For all other RR, p^O.OOI. (Aihiflnl from Hiinldl") (O'Brien) I c 7 5 ~ 3 > It is of particular concern in the case of 2,4-D, that the chemical is being used in the home and urban setting, as on the lawn. This exposes a much larger population, most of whom are not using protective equipment. In the Hoar study, excess cancer rates were found in farmers who used 2,4-D for even 1-2 d a y s p e r year. (Table 1) \ Animal Studies on Cancer The laboratory studies are suggestive that 2,4-D has significant promotional capacity. For example, Archipov and Kozlova in 1974, reported 2,4-D to be a promoter of skin cancer in mice. Shearer notes that chlorinated catechols, a second-level degradation product, is also a co-carcinogen. Shearer points out that the high incidence of tumors in the c o n t r o l animals of the A m e r i c a n studies of 2,4-D, (that is the Hansen and Bionetic studies), makes it difficult to determine whether the higher cancer in 2,4-D treated animals was due to initiation or promotion. Reuber's analysis of both studies show higher cancer rates, with the lymphoreticular system most sensitive to 2,4-D cancer in mice and rats, but other organs also showing increases. Shearer suggests that there may have been some cancer initiators in the testing laboratories, such as nitrosomines in the feed, that might explain the cancer rates in the control animals. Only a small amount of initiator is needed where there is a strong p r omoter. In June 1986, the Environmental Protection Agency disclosed that 2,4-D had p r o d u c e d a ra r e b r a i n t u m o r at h i g h d o s e (40 mg/kg) in male rats. Immune System and Cancers Hardell suggested that the association between phenoxyacetic acid herbicides and Non-Hodgkin's Lymphoma might have biologic plausibility through the relationship between dioxin contaminants and the immune system. Cancer promotional properties of chemicals probably have immune system aspects in general, though the study of the immune system is still in its infancy. For example, available case studies show that the termite poison chlordane sharply reduces the numbers of natural killer cells, similarly to radiation, leading to higher rates of leukemia just like radiation. Very little information is available concerning the impact of 2,4-D and its associated dioxins, other contaminants, and breakdown products on the immune system. It has long been known that the TCDD dioxin can cause thymus atrophy in all mammalian species studied, and cause immunosuppression at levels too low to produce clinical or pathological changes, with the greatest impact from perinatal exposure. The recent findings at the Quail Run Mobile Home Park in /<? Gray Summit, Missouri that exposures to TCDD depresses immune response in humans confirms these laboratory studies. But, even here the entire range of immune response was not measured, such as natural killer cell levels. The Quail Run findings would suggest higher eventual rates of infection and auto-immune disease among the exposed population, as similar immune system depressions have produced in other populations. Less is known about the significance of abnormal T-cell ratios and loss of T-cell functioning to ca n c e r rates. (See panel 2.) For 2,4-D we will have to wait until adequate studies are completed. MUTATION AND 2,4-D The capacity of chemicals to cause mutation bears upon their capacity to initiate cancers or cause genetic based birth defects. Shearer concludes in 1981 from the literature at that time: "2,4-D causes point mutations in animal cells without liver activation, damages DNA in a manner similar to ionizing radiation, and stimulates mitosis. It does not cause chromosome breakage or nondisjunction." Newer work changes this conclusion somewhat. A 1985 article by Turkula and Jalal finds that 2,4-D in cultured human lymphocytes causes a highly significant increase in sister chromatid exchanges at a 50 ug/ml dosage. Dosages of 100 and 250 ug/ml elevated SCE, but not significantly. Thaubmlean3alny.maRlypastheiaossncoodyffte5esais0sctechexerpltlrcosehsfaerotdormmtteohanet2ti),dc4o-enDxtcr(hoblaansegdesoinn Concentration /ig/ml Mean no. SCE per cell DMSO 50 100 250 t table* F table df F table 7.02 9.8/4.27** 8.32 8.36 2.68 6.11*** 3, 5.42** * *DSuingcnainfi'csatncvealuate,Pw<hic0h.0t5h:e* * * P < 0.001 treatment r value (to the right of the / ) must equal or exceed to be statisti cally significant * Value from A N O VA of sister chromatid exchanges fro*mF 2t,a4b-Dle treatments value for the corresponding d f The authors suggest that at the dosages higher than 50ug/ml, a high proportion of the cells may be so affected that they do not enter the division phase and fail to survive. They also suggest that the disparities among some of the 2,4-D mutation studies might be explained by Seiler's observation that 2,4-D may metabolize \17, O Panel 2 Some health effects associated with immune system depression t y p i c a l of T C D D d i o x i n e x p o s u r e s_______________________________ __ table 4 .; M ain experimental immunological diseases Spontaneous diseases New Zealand Black (mouse) disease M R L /1 lupus BXSB lupus . Aleutian mink disease obese chicken thyroiditis - v. Inducible diseases experimental allergic encephalomyelitis lymphochoriomeningitis *Howie and Helyer, 1966. Steinberg et al., 1980. `Smith et al.. 1983. "Wick et al.. 1970a; Welch et al.. 1973. Wick e ta l.. 1970b. (Amason et al., 1962; Jankovic and Isvaneski, 1963. Jankovic and Isvaneski, 1963. bRowe et al., 1963. Effect o f neonatal ] Effect o f thymectomy J bursectomy -r- aggravates* prevents* aggravates* not known aggravates1* .i -, prevents* prevents* prevents1" no effect - T A B LE ,5 . Relative dependence o f infections on B and T cell function )7C * Bacterial infections streptococci* staphylococci* pneumococci* Hemophilus influenzae* (0 M ycobacterium tuberculosis Salmonella ' Treponem ab Viral infections Fungal infections Parasite infections enteroviruses (coxsacki)bc togaviruses poliovirus* malaria* trypanosomiasis herpesvirus (herpes simplex, cytomegalovirus, zoster*x) pox virus (vaccine) measles*, mumps, influenza virus C an d id a *, M onilia*, C ryptococcus*-b P n e u m o c y stis carinii*, malaria*, A s pergillus leishmaniasis, Chagas disease Data obtained on the following lines o f evidence: , * relative incidence in children with T or B cell immuno deficiency, or in adults with Hodgkin's disease (T cell deficiency) (Allison, 1972, 1973; Good et al,, 1971). bhigh incidence o f infections in ALS-treated mice (see Chapter 6). protection by antibody (B cells) or sensitized cells (T cells) in mice irradiated or treated with high doses o f cyclophosphamide (Allison, 1973). I97<b/ fQ a c h anri C f r n m l differently, to produce in some cases a herbicide-protein transport complex that is more potent biologically than free 2,4-D, or to produce through hyroxylation inactive metabolites. In 1979, Seiler reported on his findings that 2,4-D and o t h e r p h e n o x y h e r b i c i d e s c a u s e d i n h i b i t i o n of t e s t i c u l a r DNA. synthesis as noted by the table below. 2,4-D at 200 mg/kg produced a 29 percent inhibition, which is relatively mild compared to the MCPA. Seiler called for more cancer tests, based upon these findings. RESULTS and DISCUSSION Of the five phenoxyacids tested four yielded positive results, i.e. they depressed thymidine uptake significantly. Only 2,4-DP was not significantly positive (see Table l). As there exists a high correlation between inhibition of testicular DNA synthesis and carcinogenicity by a chemical agent, the question arises imme diately, whether phenoxyacids should be suspected of carcinogenic activity.'' TABLE 6. Inhibition of testicular DNA synthesis by various phenoxy acids Compound Concentration (mg/kg) 2,4-D 2,4-DP 2,4,5-T-acid 2 ,4 5 -T-isooctylester \ MCPA MCPP * 200 200 200 400 200 100 50 200 200 Inhibition ('}o) 29 14 39 44 31 10 1 54 60 P< 0.05 - 0.05 0.01 0.05 - ' 0.01 0.01 l<j7C,a~ Seiler's review of the literature on the mutation properties of the phenoxies other than 2,4,5-T, in 1978, concluded that the phenoxy acids do influence nucleic acids and their synthesis, are weak mutagens in many different test systems, though there were some negative tests. He concludes that exposure to people handling the material would pose the most risk, noting the findings of Yoder of chromosome breakage in people exposed during the spray season, frank mutations in fruit flies, and increased reports of cancers in workers. Seiler concludes: "Thus these compounds are not the absolutely harmless and innocuous substances as which they have been described..." Like Turkula and Jala, Pilinska;ya in 1974 also found positive results in human lymphocyte cultures, wit h .002 to 50 ug/ml dosages. Only at the lowest levels were no effects found, with no further i n c r e a s e s in d a m a g e n o t e d a b o v e .2 ug/ml. C h r o m a t i d ty p e a b e r r a t i o n prevailed over chromosome at a 4 to 1 ratio. Ahmed's study of SV-40 transformed human fibroblast repair synthesis found 2,4-D to act similarly to radiation. Yoder found chromatid gaps and breaks in workers to follow the spray season in Idaho, with mean number of chromatid breaks rising more than four fold, and also the maximal number of aberrations scored in a single person (25 cells) rising from 3 to 6. 2 , 4 - D and a m i t r o l e w e r e the two m o s t f r e q u e n t l y u s e d h e rbicides. Confirming these studies is a Russian study (Belova and Soklova 1971, showing a loss of fertility in both sexes of rats after r e l a t i v e l y low d o s a g e s of 2 ,4-D b u t y r i c a c i d (a h e r b i c i d e in the 2,4-D family). Impaired fertility was also found in the first generation progeny. In the third generation, there was a 12 percent incidence of h a i r l e s s and a 15 p e r c e n t i n c i d e n c e of d w a r f y o u n g a m o n g the newborn rats, indicating; induction of recessive mutations in the germ cells of the treated grandparents. B I R T H DEFECTS, SPONTANEOUS ABORTIONS, REPRODUCTIVE PROBLEMS A N D 2,4-D________________________________ ________ In August 1979, a group of women from Tidewater, Oregon wrote a letter to the Environmental Protection Agency to complain about a series of miscarriages, after the U.S. Forest Service sprayed 2,4-D and Tordon 101 (2,4-D and picloram), by aerial application. There were some other symptoms: "...Between May 25 and June 2, three of the only five women known to be pregnant in the valley had spontaneous abortions. All three women were treated by physicians and were in the first trimester of pregnancy. The two surviving pregnancies were in the later stages of gestation... All three women live within one mile of heavily sprayed units m 63 Since May 12, the health of the population of our valley has undergone profound and disturbing changes. Chief among these has been the incidence of respiratory illness and intestinal disorders in almost every household. Several women experience uterine hemorrhaging not associated with pregnancy. Children and adults suffered bleeding gums, bloody noses, and a number oi women suffered from bacterial vaginal infections. Ten children and three adults have suffered an undiagnosed illness characterized chiefly by high fever; two children and two adults had undiagnosed rashes that doctors were unable to explain, and on July 9 occurred one near-fatal case of meningococcal menengitis in a two-year-old who is still hospitalized..." Numerous other cases of spontaneous abortion associated with 2,4~D exposure were reported, as well as other similar symptoms such as bleeding. In April 1980, a group of women from Ashford, W a s h i n g t o n for examp l e , a l s o w r o t e to E.P.A. as n o t e d in P a n e l 3. I A group of factory reports note similar symptoms such as bleeding among workers. R u t h Shearer, as a l r e a d y noted,) a t t r i b u t e s the b leeding to vitamin C depletion related to the metabolism of 2,4-D, which happens also in numerous laboratory animal studies despite the capacity of these animals to manufacturer their own ascorbic acid. Depletion of vitamins can also be a source of birth defects such as neural tube defects. Smithell and collegues in three human studies find that depletion of folate, vitamin C and riboflaven is associated with mothers who have given birth to neural tube deformed children, and that simple vitamin supplementation can reduce future neural tube rates from 5 percent to 1 percent. 2,4,5-T has been shown to cause neural tube birth defects, but little seems to be known about 2,4-D and human pregnancies outside of the many reports that have been received. The Environmental Protection Agency undertook the Five Rivers Health Study to investigate the reports of human fetal abortions in Oregon, but never issued a report. Correspondence presented in the courtcase, Merrell vs. Block, suggests government awareness of a problem. Dr. Barbara Wood of the Health Department of Lincoln C requested a delay in fall aerial spray due to the preliminary results of the Five River Health Study that noted health histories confirming the symptoms of bleeding and abortions. The ban on herbicide use by federal agencies in Oregon and aerial spray of herbicides nationally has reduced exposures to 2,4-D in spray areas where there are significant populations, and reduced the number of adverse health reports. Laboratory Findings About Developmental Toxicology Shearer reviewed the few studies 'available on developmental toxicity, and concluded that 2,4-D does cause malformation, malfunction particularly through internal bleeding, growth retardatic and lethality. Panel 4 summarizes her conclusions in 1980. 2,4-D easily crosses the placenta. [Q rir w Panel 3 Letter to E.P.A. from Ashford, Washington Complaining About H e a l t h E f f e c t s f r o m 2 , 4 - D S p r a y Drift, A p r i l 1980_____________ ____ "In early autumn of 1979, Ashford had eight pregnant women, a ninth lived thirteen miles away but traveled the common road through Ashford, and a tenth pregnant woman was a roadside mail handler... From Sept. 1979 through March 11, 1980, eight of these ten women suffered miscarriages... Two of the miscarriages were determined to most closely resemble a hydatidiform mole, although one of these two was atypical of a true mole. (The lab at Duke University was not 100% certain, as it met one of the three criteria but not fully the other two). A third miscarriage was a deformed fetus, and the others were lost too early to determine any- deformation if it existed..." The women noted similar effects in animals of the area, and attributed the health problems to timber and highway spraying with 2,4-D. Worker Reports With Similar Medical Problems AU Elina VA \ AA Ufim. Inst. G i g . P r o f z a b o l . , U f a , U SSR ---" ' ; TX Effect of products of organochlorine herbicide production on sCpAe/c0i8f7i/c1 0 6f u1n8c4 Zt i o n s of - th: e f emale bodyy- ; . ,. LASO Gig. Khim. Tr. Pr o Sostoy m-sti. an ; i1e9 7 S9-p. I1e8t7s -i9f0i ch . e s k i k h F u n k t s . Rab. ' Heftekhim. Russ AB C B A C ; C O P Y R I G H T 5 C H E M ABS W o r k e r s of o r g a n o c h l o r i n e h e r b i c i d e prodn. of the 2,4-D family, are exp osed to chlorinated hydrocarbons in concns. exceeding max. admissible c o n c n s . (MAC). (94-75-7 2,4-D) Substantial impairment of menstrual and c hi ld -b ea ri ng funct ion arise man ifested as higher rate of miscarriages, premature births, toxicosis of second half of pregnancy, and the menace of miscarriages during whole pregnancy period. Sanitary-hygienic recommendations are discussed. 79-2080. Bezuglyi, V. P.; Fokina, K. V.; Komarova, L. I.; Sivitskaia, I. I.; Il'ina, V. I.; Gorskaia, N. Z. (Inst. Toxicol. & Hyg. Pestic. Polym. & Plast., Kiev, USSR) Klinika ot- dalennykh posledstvii ostrogo otravlcniia 2,4-dikhloro fenok- ! jsiuksusnoi kislotoi. [Clinical manifestations of long-term se- Gig. Tr. Prof. ZaboLquels of acute poisoning with 2,4-dichloro phenoxyacetic ! acid.] (3): 47-48; 1979. (Russian) A group of 11 female field workers who had deve loped symptoms of acute poisoning after exposure to the her bicide 2,4-dichloro pheoxyacetic acid (2,4-D). were fol- j lowed-for 2 yr. A t the initial examination the patients ! complained of periodic headache, vertigo (7), fatigue, numb- i ness and pain in legs and arms, irritability (5) and partial amnesia (2). All patients had cardiac pain, six patients fea tured palpitation and five had marked dyspnea. Within 1-1.5 mo of poisoning 9 /1 1 patients devclojred oligomenorrhea (in 7 women the menstrual cycle normalized within 5-6 mo). Six patients had mono- and lymphocytosis, while all patients had statistically significant decreases in the activity of a series of oxidative enzymes of the peripheral blood leukocytes. Two patients had chronic toxic hepatitis, 9 developed encaphalopolyncuritis, myocardiodystrophy and vascular dystonia, and 8 patients had chronic conjunctivitis. i ' ! i ! (EPA Pesticide Abstracts, Voi. 12, No. 9, Sept. 1979) ,197 S - tts# sharer's Conclusions About 2,4-D and D e v e l o p m e n t a l Toxicity 2 Conclusions The four manifestations of developmental toxicity have all been demonstrated in animals treated with 2,4-D or its esters or amines. M a l f o r m a t i o n : skeleta l at high do s e (60 m g / k g / d a y or above), p e r i p h e r a l c i r c u l a t o r y s y s t e m d i s t e n d e d at low dose (0 . 1 m g / k g / d a y ) a nd after s i n g l e hi g h d o s e (1 / 2 L D 5 0 ) , eye an o m a l i e s at 1 0 0 m g / k g / d a y . Malfunction: subcutaneous edema at 12.5 mg/kg/day and above, h e m o r r h a g e into soft tissues and b o d y c a v i t i e s from 50 m g / k g / d a y to ..0 a 0 .5 mg/kg/day. ' v ;,\ ; -cr. Growth retardation: prenatal at 0.5 mg/kg/day and above. Post natal after 50 mg/kg/day or when treatment continued during lactation. j;Lethality: pre-implantation not reported. 1 0 0 mg/kg/day and above, or after a single high Postnatal in progeny of rats fed 150 mg/kg/day, ppm. ... . Post-implantation at , dose (1 / 2 L D 5 0 ) . -. or in a pig fed 500 ' T h e above summary includes both oral and intraperitoneal treatment. 2,4-D is rapidly and completely absorbed from the g a s t r o intest i n al tract and is not m e t a b o l i z e d in animals, so the serum c o n centrations should be similar by the two routes. Erne, 1966, has demonstrated the ease of placental transfer of 2,4-D in the pig. 2.4-D a l s o r a p i d l y penetr a t e s the p l a c e n t a in rats; 24 h o u r s after a single dose, 16.8% of that dose remains in the uterus, placentas, fetuses, and amniotic fluid (Fedorova and Belova, 1974). The effect of 2,4-D on the circulatory system was synergistic with that of its microbial breakdown product, 2 ,4-dichlorophenol. W h e n the c u s t o m a r y 100-fold safety factor is applied to the e ffective d o s e (Wilson, 1973, p. 156), the a c c e p t a b l e tolerance is e q u i v a l e n t to a 50 kg woman drinking 40 ml of treated water (2.5 ppm) daily during early pregnancy at a time when 50% of the 2,4-D has been degraded to 2 . 4 - dichlorophenol. The situation is not quite that simple, however, because breakdown continues to other untested compounds, and part of / the 2,4-D would be degraded in plants where 2,4-dichlorpphenol is not part of that pathway (Ashton and Crafts, 1973). M a n y of the studies reported here were done in other countries, raising the question of the similarity of synthesis and contaminants. No studies indicated that the synthesis and purity of these products is d i fferent elsewhere. 2,4-D caused developmental toxicity in all four s p e c i e s tested, including stud i e s done in four count r i e s . It is interesting to note that the hemorrhaging found in all of the Russian rat studies using low doses was not found in any of the high dose American studies. This may be a strain difference in rats, or a dif ference in the protocols of observation. Shearer, 1980 -23- 19 7 C C , m ? 1) The Environmental Protection Agency summary of the literature is particularly interesting in showing the same internal bleeding (edema) and hemorrhaging problem in many laboratory animal experiments where 2,4-D was the pesticide study. under One of the more interesting studies is that of Konstantinova in 1976, showing a synergistic interaction of 2,4-D and its microbial breakdown product, 2,4-Dichlorophenol. Significant e f f e c t s w e r e s h o w n at a d o s a g e of on l y .1 m g / k g / d a y . "...the action of 2,4-D alone in the highest dose tested (50 mg/kg) produced an increase in the overall number of defective f e t u s e s ... for the most part embryos with hemorrhages of varing degree and localization (primarily in the thoracic and abdominal cavities, liver and soft tissue...)... The administration of 2,4-Dph (breakdown product of 2,4-D) alone to the pregnant rats in the highest of the tested doses (1 mg/kg) also increased the total number of defective fetuses... due entirely to hemo rr ha gi ng in the organs and tissues... At the same time, the combined administration of the lowest dose of 2,4-D and 2,4-Dph (.1 and .1 mg/kg) which did not produce an effect when administered separately, increased the number of fetuses with hemorrhaging cavities, organs, and soft tissues..." The laboratory animals are bleeding, just like the humans who have complained in spray areas, and there appears to be birth defects by a mechanical type of action and membrane damage. Doses are very low in the combined test. Schw-etz et al in 1971 found that internal b l e e d i n g in fetal rats occured at 12.5 mg/kg/day with 2,4-D. Shearer notes that with a factor of 100 for safety, a pregnant woman would have to drink only 1/6 cup a day from a lake treated for weeks with 2,4-D. As already noted, frank mutations were shown by Belova and Soklova to occur in laboratory animals after exposure to 2,4-D butyric acid. A number of studies show skeletal and eye defects to occur where dosages are close to maternal toxicity. But, malfunction of the circulatory system is seen after very low dosages. Finally, Diane Courtney's 1975 study of CD-I mice showed that 2,4-D could produce cleft palates, as well as affecting fetal weight and prenatal development. It was found that: "In general the greatest effects of 2,4-D were produced by low doses administer over long time periods." When 2,4-D was administered with corn oil, the major effect was on fetal weight, and when administered with DSMO, fetal mortality increased. Farm Animal Studies and Reports Similar effects and also adverse effects on fertility have been reported to use in goats, horses, and other farm animals. '776/ There is at least one farm animal study, showing increases in spontaneous abortion, sterility, and decrease of fertility of male sheep grazed on 2,4-D sprayed pastures. We are told that farmers are advised not to graze right after spray with 2,4-D because of these problems. "...As a result of our farm experiments, it was established that butyl 2,4-D had a p a rt ic ul ar ly harmful effect on animals (sheep) grazed on spray pastures on consuming feed from these pastures during the first ten days after spraying with this herbicide. This effect manifested itself in spontaneous abortions, mummification of the fetuses, high sterility, a large number of stillborn lambs, and a decrease in the sexual activity of the males and the quality of the sperm. Therefore, in order to prevent the harmful effect on the reproductive functions of animals, the grazing of all species of animals on pastures sprayed with herbicides should be prohibited during the first 20 days after spraying, with an increase in the quarantine period to 45 days for the suckling offspring." (Sadykov, 1972) NEUROLOGICAL EFFECTS OF 2,4-D IN ADULTS Agents that have adverse effects on the neurology of adults often have even more severe effects on the fetus and infant. We will look at the issue of learning disabilities and retardation later. A series of cases of severe peripheral neuropathy due to skin exposure to 2,4-D led to a Hazard Alert being issued by the California Department of Health Services in June 1980. A number of other cases has also been reported. The Department notes that "a number of points favor the role of 2,4-D as a primary neurotoxin". 1It was noted that the mechanism w a s not known, t h o u g h m a n y n e u r o t o x i n s i n t e r f e r e w i t h an essent.icil nutrient such as Vitamin B6. The Department recommended a change in the label of 2,4-D, including the words: "Permanent Nerve Damage May Result After Skin Contact". Possible linkage of 2,4-D with cropduster crashes in the middle West was noted by Mounce and Savage in 1973. In severe cases of exposure to 2,4-D as in suicide, demyelination of the nerves were noted. Loss of Nerve Conduction Velocity in Adults Of even greater concern than the number of extreme cases is the report of Raymond Singer et al in 1982, concerning the loss of n e r v e v e l o c i t y in 56 w o r k e r s e m p l o y e d in the m a n u f a c t u r e of 2,4,5-T and 2,4-D. As the table below shows, there was a slowing of conduction in median motor, median sensory, and sural nerves - a change that held up after controlling for alcohol and other neurotoxic agents. Duration of employment was significantly correlated. /9 7 > e ' f ' H S V - The sural nerve has a long fiber length, less inyelination, and small diameter, and has been shown by other studies to be susceptible to disruption of normal nervous tissue function and metabolism. NCV A N D EXPOSURE TO PHENOXY HERBICIDE Mean N erve Conduction Velo TABLE cities of S7tu!dy Versus Control G r ou ps'1 Nerve Group Mean AT Z value SD t Prob, t (one-tailed) Median motor Study Control 44 25 0.11 0.92 1.17 1.02 2.29 0.01 Median sensory Study 44 -0 .2 3 Control 23 0.04 1.06 0.81 1.01 0.15 , Sural Study 41 -2 .1 1 Control 20 -0 .5 2 1.17 1.62 4.58 0.0001 " Based upon Z values which represent the velocity expected on the basis o f age subtracted from the temperature corrected observed velocity, divided by the standard deviation. Nine subjects with possibly significant previous exposure to neurotoxic agents were removed. It was noted by the authors that although dioxins were involved here, the significant findings may also be due to 2,4-D. The study suggests that exposures to 2,4-D that do not involve gross neuropathies can produce a general loss of vitality of an exposed population and loss of a range of nerve function. While Dow maintains that their laboratory studies do not show neuropathy in laboratory animals, when so many human example are available, we really do not have to guess anymore about the problem. Laboratory Studies There are a number of interesting laboratory findings. Elo et al reported that 2,4-D exposure impaired the functioning of the blood-brain barrier in rats during poisoning, in that blood cells appear in the cerebrospinal fluid as a result of capillary injuries. Desi et al reports that several effects occur in laboratory rats, cats, and dogs: 1. There is an inhibition of cerebral electrical a c ti vi ty in acute and chronic 2,4-D exposures, with severe damage to higher nervous activity occuring, as measured by conditioned reflex experiments; 2. T h i s o c c u r s w i t h o u t o b v i o u s s t r u c t u r a l c h a n g e s in n e r v e cells; I<77 6, 3. Spinal cord damage m a y be responsible for paralysis in extremities; 4. It must be assumed that human subjects may suffer mi ld er disturbances from smaller doses in function of the nervous system. In summary, it needs to be pointed out that chemicals that cause a debilitation of nervous system response in adults and a loss of vitality will have some significantly adverse economic effects for the nation. LEARNING DISABILITIES AND 2,4-D It has long been known that the phenoxy acids interfere with the turnover rate and distribution of thyroid hormones (Florsheim et a l f 1963). 2,4-D is known to enhance the incorporation of radioiodine into the thyroid gland (Kiltgaard et al, 1951 and Florsheim and Velcoff, 1962) and competes with thyroxine for binding to plasma carrier proteins. Chemical exposures that cause hyper- or hypo-thyroidism have been shown to lead to learning disabilities and in extreme cases to mental retardation, where exposure to that chemical takes place either during pregnancy or during early childhood. For example, as Sjoden and Soderberg noted: "...It is, therefore, obvious that all procedures that induce endocrine disturbances (of hormone levels, distribution or tissue response) in uttero or sh ortly after bi rt h may be followed by p e rm an en t defects in physiological parameters and behavior. Such effects are easily overlook by classical t e r a t o l o g i s t s ." Sjoden and Soderberg's experiments found that the phenoxy herbicide 2,4,5-T had some significant effects on thyroid function "...However, we are already justified in claiming that 2,4,5-T has permanent effects on the thyroid, inducing increased thyroid activity at birth; alth ou gh a steeper fall in activity is ob s e r v e d with advancing age in treated than in control animals... In this way, treated animals develop hypothyroidism, and 2,4,5-T thus accelerates the rate of aging of this physiological function. Aging of the thyroid system has also been found in man. (Wahlin et al, 1975) The effects of 2,4,5-T on thyroid activity shows a sexual dimorphism, having a stronger reaction in females than in the males. This is of interest in v i ew of the well-known excess morbidity among women in relation to thyroid and to manic-depressive diseases." The authors' laboratory studies found the following effects: 1. b e h a v i o r a l t e r a t o l o g y in rats f r o m a s i n g l e p r e n a t a l e x p o s u r e to 2,4,5-T towards the first week of pregnancy - leading to a long-term change in behavioral and learning functions well into adult age of the offspring, as measured by swimming maze tests and conditioning active avoidance tests; (Dose was 100 mg/kg on the 8th day), 2. s t r o n g e f f e c t on t a s t e a v e r s i o n at d o s a g e s above 15 mg/kg, and higher order conditioning of taste aversion; 3. t r a n s i e n t i n h i b i t i o n of food and w a t e r intake and w i d e s p r e a d change in electrolyte distribution, with strongest effect on b r a i n and kidney; 4. e n h a n c e m e n t of the t r a n s p o r t of t r y p t o p h a n e into the brain; 5. o f f s p r i n g of 2 , 4 , 5 - T t r e a t e d a n i m a l s s h o w i n g changes in weight development, thyroid activity, and brain serotonin, which correlated with behavioral changes. In summary, while exhaustive testing of this nature has not been done for 2,4-D, we can expect in view of its thyroid activity and similar chemical structure to be a strong candidate as a learning disability agent in animals and humans. The Dioxin and Liver Enzyme Issue In our review of the literature, we have found that chemicals that induce liver enzymes as a class appear to produce learning disabilities. For example, TCDD dioxin is a strong liver enzyme inducer, and also has been shown to cause hypothyroidism. (Rozman shows t h a t t h e w a s t i n g s y n d r o m e is m o d u l a t e d by t he thyroid.) P B B 's cause liver enzyme induction and hypothyroidism as another example. The 2,4-D dioxins may act similarly on liver induction. Alcohol and phnobarbital are examples of liver enzyme inducers that have been shown to cause learning disabilities in human children exposed in utero, as is PCB's. Furthermore, induction of liver enzymes during pregnancy has been shown to cause infertility in the offspring. A good example is phnobarbital, used in epilepsy treatment, which causes both learning disabilities and infertility in both male and female animals. The learning disabilities are confirmed in human c h i l d r e n and t h e r e are i n d i c a t i o n s of, i n f e r t i l i t y in h u ma n s as a result of phnobarbital exposure in utero. Microneuronal Hypoplasia Joseph Altman has looked at one of the mechanisms of learning disabilities, which is depletion of the microneurons, when exposure to a substance takes place late in pregnancy or early childhood as through contaminated milk. In contrast, early toxic exposures that deplete the macro or meso-neurons can lead to profound retardation and motor difficulties. Hypo- and hyper-thyroidism and liver enzyme inducers can produce these neuron deficits. And in summary, 2,4-D is a strong candidate as a chemical that will produce learning disabilities where exposure takes place during pregnancy or in early childhood. Furthermore, thyroid malfunctioning ca affect the myelination of the brain in children. Dudley in 1972, reported extensive demyelination of the brain in the case of a man who died from ingested 2,4-D - a case that resembled multiple schlerosis. As is so often the case, where serious neurological problems are found in the adult, similar effects may be found in the child at much lower dosaqes. i< m / OTHER HEALTH ISSUES AND FIELD SURVEYS Heart Disease and Stroke Little information seems available concerning the effect of 2,4-D on heart disease and stroke. The capacity of the chemical to damage the capillaries and cause internal bleeding would make it a candidate for stroke. PCB's w i t h its dioxins and dibenzofurans is known to elevate blood pressure and increase cholesterol levels - making that chemical a heart disease candidate. Possibly the dioxins and furan: in general may have similar effects. Field Studies Besides the reports from Alsea, Oregon and Ashford, Washington we have also two acute health effects surveys from Canada and North Carolina. As is noted on the next page, farmers in Saskatchev found 2,4-D to be their most difficult chemical from the viewpoint of health, with cumulative symptoms from one season to the next leading farmers to stop spraying and contracting out. Nausea to skin rashes were reported as can be seen. A just completed study from North Carolina looks at the symptoms of 85 people exposed to 2,4-D and Tordon 101 spray drift from Boise Cascade timber tracts. A statistically significant increase in respiratory problems was found among people receiving the spray drift, along with a number of other symptoms presented in the table. Adjustments for age, sex, race, smoking status and education did not alter these findings, and the symptoms were also associated with increase exposure, in that the reactors remained in the spray drift area for a longer time. S Dioxins s The production of chemicals contaminated with dioxins needs to be discouraged, even if the dioxins are ostensibly removed to some degree by the manufacture process. The manufacturer still has to destroy the dioxins removed from the chemical, and there is an additional problem of dioxin production during the distributi and use phase. For example, burning of sprayed areas will generate dioxins. It appears that most Americans now have dioxins in their fat at time of death, and human milk has become increasingly contaminati with dioxins, as has fish and some other food products. The dioxin issue is sufficient cause by itself to discontinue the production of 2,4-D. The enclosed summary of the dioxin issue with regard to 2,4-D by Pollution Probe of Ottawa is enclosed. Panel 5 Most Americans become exposed to dioxins during their life. Table 8 . --Comparison of the Levels of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (Parts per Trillion) in Adipose Tissue of Exposed and Control Groups Variable N Arithmetic-mean Median Range Geometric mean Mean age, y (SD) % Men Controls 57 7.4 6.4 1.4-20.2 6.4 52.6 (15.7) 35.1 Total 39 79.7 17.0 2.8-750 21.8 44.3 (13.7) 61.5 Exposed Recreational Residential 8 16 90.8 21.1 23.5 14.5 5.0-577 2.8-59.1 24.8 15.3 42.1 (14.7) 39.7 (14.9) 37.5 43.8 Occupational 15 136.2 24.7 3.0-750 29.8 50.3 (9.8) 93.3 9Table -Comparison of the Adipose Tissue Concentrations of TCDD in Populations With No Known TCDD Exposure* Source of Specimens Mean, Parts Range, Parts N per Trillion per Trillion Present study: elective surgical patients in Missouri 57 6.41 1.4-20.2 Autopsy specimens from Ohio'1 6 ... 5-12 Autopsy specimens from St Louis'* and Canada7 and adipose from veterans'3 61* 7.5 1-15 Autopsy specimens from sudden deaths in St Louis'4 35 7 .2 | Autopsy specimens from Georgia and Utah'5 35 7.1 f 2.7-19.0 *TCDD indicates 2,3.7.8'tetrachk>rodibenzo`p-dk>xin. f Geometrie mean, : 7$Combination of results from references , 12, and 13. Three results from persons known to have had exposure to 2,4.5-trichloropbenol were excluded. Dioxin Levels--Patterson et a! ,<57 7 3 Damage to Other Crops and the Environment Numerous problems with 2,4-D drift and vegetation damage have been presented. The case of serious damage to grapes in Washington State after long distance drift from wheat fields in Oregon is an unsolved issue. It is fair to say that grapes are a more expensive crop than wheat, and we can expect that 2,4-D probably diminishes the total agricultural product in this case. Damage to sunflowers and cotton are other examples. Damage to aquatic weeds from herbicide runoff in the Chesapeake Bay has proven to be a serious problem, and causes a significant decline in fishing resources and the prosperity of the fishing industry. Here is another example of a reduction of economic produce from drift and run-off. Dioxin and PCB's contamination of the rockfish of the Chesapeake Bay is believed to be a major factor in the sharp decline in populations - leading to fishing moratoriums of recent years. m CONCLUSION While our judgement must be qualitative at this time, there is very good reason to conclude that 2,4-D is probably a net loser to the national economy in view of the significant health and environmental problems associated with the herbicide. One could presume against the further use of 2,4-D solely on the basis of it being a precursor and source of dioxins, since Americans have become so contaminated with dioxins over the past years. However, even without this issue of dioxins, we think that there are sufficient adverse health and environmental effects of 2,4-D, even in a form purified of dioxins, to conclude that the national economy is probably made poorer because of the chemical. 1977V *. APPENDIX VII.0 ; : -333- ' . ' \Z . `: * . H E A L T H E F F E C T S QF 2 ,4-D /' The following letter, reprinted hre for the information a n d i n t e r e s t of the rea de r, was s u p p l i e d to the panel in repl y to a request for information on health effects of phenoxy herbicides. P22R2A0 ILRoImEe SINt,SRTeIgTinUa,TSEaskOatFcheEwNanV.IRONMENTAL HEALTH S4P 2M7 .November 15, 1976 -i ,V ' rbMr.UJ.feM WJ-fe4J 'HEALTH EFFECTS OF 2,4-D 1. A s far as 1 a m aware there are no reliable statistics relating to " t h e health effects of 2,4-D usage in Saskatchewan, where, in 1971 i t was estimated that 70% of the cultivated acreage of the province was sprayed with the herbicide in a year. 2. A small unidentified number of persons, mainly children, have been ` h o s p i t a l i s e d 'with acute poisoning, circumstances unknown. 3. Because o f the widespread use of the herbicide 2,4-D and because no mechanism existed in Saskatchewan which identified agricultural chemical poisoning, a general question was included in a questionaire used in 1969,1970 as part of a field survey of respiratory diseases and effects amongst farmers and grain elevator operators Q. 78. Have you ever had any ill effects from working with any agricultural chemical IF YES specify the chemical product ___________ ' describe the circumstances ___________ what were the effects . , _________ yes no aa 20% of 3,300 farmers and grain elevator operators surveyed, responded yes to the question. Whilst the question was a general one, certain conclusions were drawn from it a) farmers found 2,4-D the most troublesome chemical they used (it is also the most widely used) b) symptoms were confined to the season (or time) of spraying and were, similar amongst farmers who complained of health effects 1) nausea, loss of appetite, loss o f weight, occasional vomiting' during the spraying season. 2) a skin rash in a small number >f persons. I 3) the symptons of one year often worse than the' C dyea r before leading to a significant number of farmers having top spraying themselves and contracting the spraying out. 5. Th e conclusions drawn from the questionaire- are supported whenever health and safety problems are identified and discussed at farmep/rural meetings _ _ . .. . 6. The significance of these observations in relation to long term .effects is unknown; it appears to me that some farmers develop a sensitivity to the effects of 2,4-D (not necessarily the same thing as an allergy) and that this sensitivity id enhanced with repeated exposure over time. * C. A. R. Dennis I? 77-5^ . Symptoms of North Carolina Residents Injured by 2,4-D and Tordon 101 Spray Drift, (Tolbert) T a b l e 1 5 . A s s o c i a t i o n o-f E a c h Symptom Q u e r i e d w i t h E x p o s u r e : R e s u l t s o-f C r u d e A n a l y s i s ( C o n t i n u e d ) Symptom Fatigue Breaking fin g e rn a ils Headaches Chest pain Asthma H air loss Swollen eyes $ Lack of a p p e tite Blood in u rin e B l e e d i n g gums B u rn in g on b r e a t h i n g Easy b ru isin g F a in tin g B u rn i ng on u r i n a t i o n Aching jo in t s Sei zures Observed Among Expgsed_ .9 5 10 4 2 To 6 5 3 2 1 1 1 1 0 RR 2. 1 3. 1 1.9 3. 7 9.3 5.6 2 .2 r? t 2.8 3. 7 5 .6 5. 6 5.6 5.6 0.8 ---- 957. C l <0 . 8 , 5 . 2 ) (0. 8, 12.7) <0 . 8 , 4 . 3 ) (0.7, 20. 0) (0.4 , 191.6) (0 . 6 , 53.1) (0.7, 7.1) (0. 6 , 8.5) (0. 5, 16.5) . <0 . 3 , 4 0 . 7 ) (0 . 2 , 135.5) (0. 2 , 135.5) (0 . 2 , 135.5) (0. 2 , 135.5) <0.3, 2.4) P -V a lu e 0.089 0 . 100 0. 109 0. 113 0 . 120 0. 123 0 . 141 0. 165 0.231 0. 279 0.348 0. 348 0.348 0. 348 0. 494 Ta b l e 15. A s s o c i a t i o n of Each Sympt om Queried with Exposure: R esults of Crude Analyses Symptom Observed Among Exposed_ _RR_ Cough D iffic u lty breathing 13 13 12 .2 12.2 Sinus congestion 10 * 6 .2 Runny nose 9 8.4 Swollen glands . 6 11.2 Skin p eeling Wheezing 4 16. 7 6 5. 6 Di zz i ness 6 5. 6 Blurred vision Nausea 9 2.8 7 3. 3 Hay fe v e r 4 7. 5 C onstipation - 4 7. 5 Vomi t t i ng Skin rash 5 4. 7 9 2.4 Burning eyes 8 2. 5 Upset stomach 7 2.6 Preci sion-Based _____9 5 % _ C I ______ Fi sh er'5 Exact Test _ P - V a l _ u e __ (2 . 8 , 52.6) 0.000 <2 . 8 , 5 2 . 6 ) 0 . 000 <1 . 8 , 2 2 . 0 ) 0.002 < 1 . 9 , 3 8 . 1) 0 . 002 <1.4, 91.7) 0 . 008 <0 . 9 , 3 0 7 . 3 ) 0.014 ( 1 . 2 , 27.2) 0.023 <1 . 2 , 2 7 . 2 ) 0. 023 ( 1 . 0, 7.6) 0.036 <1 . 0 , 1 0 .9 ) 0.045 (0. 8 , 65.9) 0.051 <0 . 8 , 6 5 . 9 ) 0.051 <0.9, 23.6) <0.9, 6 . 2 ) 0.052 0.059 <0. 9, 7 . 0 ) 0.068 <0.9, 8 . 0) 0,077 i24--D "Eight out of nine esters and four/oiiV bf''seven' a m i n e ; l :..<*v pc w prp found to c o n t a in n i * t r i - . and t e t r a - c n l n r n d i benZft-D~' ;:":;V-: , -y:;:^ ; ; ^ d3i*o x' i_n . c_ o. r_K *er t'r_la>ti_o ^L ' ' 'a ' rv ` '.. \ i ,'*;;,'rwasf'fo u n d ijih e highest' concentration speci es repofJtS . . * - <'":rf,;?tS v ^ ^ } \ 2 ,7-(o r 2 , 8 - ) 'dioxi n r ' '" 'M.: ".-';' r,-v V >: 'v '"V'-vv' /'>.' ;v...'y-v'~' ' '"''V/-' ^ "-'v `v-'v'`-""-` 0 s;^c- " " causes "defects in the ;heart muse!e of rats at the '1ow dose level ,V 1-2 mg/kg (Khera 'and Ruddick, 1 9 7 3 ) . V; - - " :. : . y'- ';v ' : . > ' ; :n) Summary: There Is enough vidence.on dioxin contain!nation, of ,, '- . * ' - . - : ..\ -'.'Z V ' ".i ; c , V.v. .,v ': i i ~.*. ' :i- / ;i--t-:' :-.v""... ^^ 2^4---D^ or ' form^ f>..H;:'-;;"r -<-V *nr * - v f V - / s'jV:*-/ >."/. y ;/*. : , . .' , ' v . , rom '2 , 4--D??t o indicate cons1c!er abl e caution vi7 - -r;'^ ' ' W . i '-':-'.^ ; ^ S - 3 tsuse'!::'^The"*ciiemistry of the formation o f dioxins under ; 1 :- ' ^ ^ > ^ t^ ia b o ra to ry conditiohs is fa ir ly well understood, but ;.$ .-: v'Vi.v....... ..-- i v ' - V - ' ' -r'' 'r .'J < v~vt\-V^V/i V :X'"''vi: ''\v;--;^-;-;y-''^-:;;^;%^ienvironinenta1 studies of dioxin formation are ju s t beginning. ..'/, : :: ' -^^'vny form o f heating "of 2,4-D, short of high temperature' (greater ^ */-' #.' '' . J` *' ^ '-'rif'ivN".--'.,r- C-t-*..' -< -V.- .<<' : i-N-v*; r '. ^-Ni:- i *; ' ^ ' '*:.' \- *v: >' ` VV: *M*> - * t~v*'<.\;-..i'f--f r . r. V:V`- "CkT.-,T*.??'<V-*'.._*~!V.-'*'x.'*"^**-\ ^ ^ "^'"v '- .' . vr%' :t. ': " : r ' ' than 800C) incineration, should be avoided. Also, dioxins form more rapidly under alkaline condition. ' ' ' V. CONCLUSIONS Increasing concern about the safety of 2,4-D has led to discontinuation of its use in numerous school boards in Ontario and in the cities of Toronto and Ottawa. 2,4-D has been shown to cause birth defects and mutations in animals and is suspected of causing cancer. Occupational exposure of sprayers and farmers has led to a variety of reported symptoms, the most serious being paralysis. Dioxin contamination of commercial products has been shown and in addition, formation of dioxins from 2,4-D Via environmental processes is possible. . . Practises of using herbicides on lawns are primarily cosmetic. While there are serious doubts on the safety of 2,4-D, both for the short and long term health of sprayers and of those who use the parks, the most reasonable course of action is to continue to suspend herbicide use in these areas. Introduction of any alternative herbicide should not be begun without, a thorough safety analysis and public discussion. VI. RECOMMENDATIONS 1. That the City of Ottawa continue its suspension of all herbicide spraying programs. 2. That fertilization, aeration and reseeding programs with hardy grasses be tried in selected areas on an experimental basis, with costs being estimated for large-scale .appl ication. 3. That the quality of lawns be monitored and reported on yearly to the Environmental Advisory Committee. % jqy g o Ahmed, Farid, E. et al, "Pesticide induced D N A damage and it*s repair in cultured hu ma n cells", M u t a t i o n Research, Vol. 42, pp. 161-174, (1977) Altman, Joseph, "An animal model of minimal brain dysfunction: Microneuronal hypoplasia", in Catherine Caldwell Brown, editor, Childhood Learning Disabilities and Pren at al R i s k . Pediatric Round Ta bl e 9, Jo hnson & Johnson, Slcillman, New Jersey, 08558, (1983) ___ Archipov, ~g 7n . and I.N. Kozlova, "Study of the carcinogenic properties of the he rbicide amine salt of 2,4-D", Vo p r o s y Pitaniya, Vol. 5, pp. 83-84, (1974) . Bach, J.F. and T.B. Strom; "The mode of action of immunosuppressive agents", Rese ar ch m o no gr am s on immunology, Vol. 9, Elsevier, N e w York: (1985) Balarajan, R. and Ed Acheson, "Soft tissue sarcomas in agricultural and factory workers", Journal of Epidemiology and Community Health, Vol. 38, pp. 113-6, (1984) Belova, R.S. and L.A. Sokolva, "Toxicolog. Ev al ua ti on of the lier-bicide 2,4-D<!f Butyric Acid from the viewpoint of food sanitation", Gigiena I Sanitariya, Vol. 36, pp. 211-5, (1971) Blaska, David, "U.W. researchers say 2,4,5-T may impair immunity", Capital Times, Aug. 21, 1981 Blumer, W. and Th. Reich, "Leaded gasoline- a cause of cancer", Environment International, Vol. 3, pp. 465-71, (1980) Courtney, K., Diane, "Prenatal effects of herbicides: evaluation of the prenatal development index", Presented in Part at 15th annual meeting of Teratology Society, May 11-15, 1975, Philadelphia. U.S. E.P.A. Research Triangle Park, N.C. Czuczwa, Jeane, and Ronald A. Hites, "Airborne dioxins and dibenzofur ans: sources and fates", Env. Sci. Techn. Vol. 20, No. 2, (1986) Dennis, C.A. R v "Health effect of 2,4-D", Prairie Institute of Environmental Health, Regina, Saskatchewan, Nov. 15, 1976 Desi, I. et al, "Nervous system effects of a chemical herbicide", A r ch iv es of En vi ro n m e n t a l Health, Vol. 4, No. 1, pp. 95-102, (1962) Epidemiological Studies Laboratory, (Hazard Alert System), State of California, Department of Health Services, 2 ,4-Dichlorophenoxy acetic a c i d : Evaluation of hu m a n he al th h a z a r d s . June 16, 1980 Fl or sh ei m et al, "Some effects of 2 ,4-dichlorophenoxy acid in thyroid function in the rat..." Endocrinology, vol. 71, pp. 1-6, (1962) and vol. 72. pp. 327-333, (1963) Grady, Denise, "The He a l t h care crisis", Discover, Vol. 7, No. 5, M a y 1986 Hansen, W.H. et al, "Chronic toxicity of 2,4-D in rats and dogs", Toxicology and Applied Pharmacology", Vol. 20, pp. 122-129, (1971) Hoar, Sheila, et al, "Agricultural herbicide use and risk of lymphoma and soft-t is su e sarcoma", JAMA, Vol. 256, No. 9, Sept. 5, 1986 Hoffman, Richard, E. et al, "Health effects of long-term exposure to 2,3,4,8T e t r a c h l o r o b e n z o - p - D i o x i n " , JAMA, Vol. 255, No. 15, April 18, 1986 Kallen, Bengt, and Gunnar Thorbert, "A study of pregnancy outcome in a small area around a chemical factory and a chemical dump", Env. Research, Vol. 37, pp. 313-19, (1985) Khera, K.D. and J.A. Ruddich, Adv. in Chemistry S e r . , Vol. 120, No. 70, (1973) I*?7 S / 1 # * ^ Kiltgaard, H.M. et al, "Inhibition of thyroxine action by iodinated phenoxy acids", Endocrinology, Vol. 48, pp. 525-533, (1951) Konstantinova, T.K. et a l , "The embryonic effect of the dissociation products of he rb ic id es ba se d on 2,4-D", G i g i e n a I. Sanitariya, No. 11, pp. 102-5, (1976) Mattsson, Joel, L. et al, "Neurotoxicological examination of rats dermally exposed to 2,4-D amine for three weeks", Neurobehavioral Toxicology and Teratology, Vol. 8, pp. 255-63, (1986) Mattson, Joel, L. et al, "Lack of neurop at ho lo gic al consequences of repeated dermal exposure to 2,4,-D acid in rats", Fundamental and Applied Toxicology, Vol. 6, pp. 175-181, (1986) Merrell, Paul vs. J.R. B l o c k et al, U.S. District Court for D i s t r i c t of Oregon, Civil No. 81-6138-E, Memorandum in support of plaintiff. Mounce, M. and E.P. Savage, "The epidemiology of aerial application in the H i g h Plains, 1966-1969", Ag r i c u l t u r a l Aviation, Vol. 15, No. 4, pp. 105-112, (1973) Northwest Coalition for Alternatives to Pesticides, (NCAP), 2 , 4 - D . P.0. Box 1393, Eugene, Oregon 97440, $9 O'Brien, Mary, H. "Those Swedish Studies by Hardell: phenoxy herbicides, chlorophenols, and cancer", NCAP News, Spring 1984 Patterson, Donald, G., Jr., "2,3,7,8-Tetrachlorobenzo-p-dioxin levels in adipose tissues of exposed and control persons in Missouri", JAMA, Vol. 256, No. 19, Nov. 21, 1986 Pesticide and Toxic Chemical News, "2,4-D produces rare brain tumor in male rats, E.P.A. officials note", June 25, 1986 Pitinskaya, M.A., "Cytogenetic effect of the herbicide 2,4-D on human and animal chromosomes", T s i t o l a g i y a i Genetika, Vol. 8, No. 3, pp. 202-6, (1974) Reuber, Melvin, "Preliminary review of some onc.ologenicity studies for 2,4-D", U.S. Senate Judiciary Committee Report on the E.P.A. and Regulation of Pesticides December 1976 Reuber, Melvin, "Re-review of slides of Bionetics study", From E.P.A. Review of the Literature on 2,4-D, (1979) Rice, D.P. et al, "H ea lt h Care Financ. Review, Vol. 7, pp. 61-80, (1985) Rozraan, K. et al, " T hy ro id hormones mo d u l a t e the toxicity of 2 , 3, 7, 8- Te tr achlorodi ox i n - p - D i o x i n (TCDD), Jo urnal of To xi co lo gy and En vi ro n m e n t a l Health, Vol. 16, pp. 481-91, (1985) Sadykov, R.E., "The effect of butyl 2,4-D treatment of pastures on the reproductive functi on in g of sheep", Zh iv ot no vo ds tvo (Animal Breeding), Vol. 34, No. 1, pp. 73-4, (1972) Schumacher, Mary, Catherine, "Farming occupations and mortality from No n- Ho d g k i n s L y mp ho ma in Utah", J. of Oc cu pa ti on al Medicine, Vol. 27, No. 8, Aug. 1985. Schwetz, B.A. et al, "The effect of 2,4-D and esters of 2,4-D on rat embryonal, foetal and neonatal growth and development", Food, Cosmetic Toxicol., Vol. 9, pp. 801-17, (1971) Seiler, J.P., "Phenoxyacids as inhibitors of testicular DNA synthesis in male Mice", Bull. Env. Contam. and Toxicol., Vol. 21, pp. 89-92, (1979) Seiler, J.P., "The genetic toxicology of phenoxy acids other than 2,4,5-T", Mu ta ti on Research, Vol. 55, pp. 197-226, (1978) Shearer, Ruth, W. and M a r k Halter, Li te ra tu re Reviews of Four Selected H e r b i c i d e s ; 2,4-D, dichlorobenil, diquat, and endothal", Muncipality of Metropolitan Seattle, p. 1-34, January 1980 Shearer, Ruth, W. "Toxicology of 2,4-D", Apri l 24, 1981 Shearer, Ruth. W . , Affadavit in Superior Court of Washington for Thurston County, J u ly 2, 1982 Singer, Raymand,. et al, "Nerve co nd uc ti on v e lo ci ty studies of workers employed in the manufacture of phenoxy herbicides", Environmental Research, Vol. 29, pp. 297-31, (1982) Sjoden, P.0, and U. Soderberg, "P he noxyacetic Acids, sublethal effects", in C.Ramel, editor, Chlorinated Phenoxy Acids and Their Dioxins, Ecol. Bull., Vol. 27, pp. 149-164, Stockholm, (1978) Smithells, R.W. et al, Archives of Diseases in Children, Vol. 51, (1976), The Lancet, Feb. 16, 1980, The Lancet, M a y 7, 1983 Strange, Marty and Liz Krupicka, "Farming and Cancer", in Center for Rural Affairs, It's Not All Sunshine and Fresh Air, CRA, Box 405, Walthill, Nebraska 68067, April, 1984, $5 Tolbert, Paige, Elizabeth, "Retrospective cohort study of a community exposed to herbicides - an investigation of perceived health effects", Masters of Sc ience in Public He al th technical report, U. of No rt h Carolina, Chapel Hill, (1986) Turkula, T . E . and S.M. Jalal, "Increased rates of sister chromatid exchanges induced by the herbicide 2,4-D", Journal of Heredity, Vol. 76, pp. 213-4, (1985) U.S. Environmental Protection Agency, Industrial Environmental Research Laboratory, Dioxins, Vol. 1, Sources, Exposure, Transport, and Control. E P A / 600/2-80-1>56, June 1980 U.S. Statistical Abstract U.S. E.P.A., Review of literature on 2,4-D, (1979-80?) Vital Statistics, 1982 Wright, James, S. and V i rg in ia Salares, He a l t h Effects of 2,4-D, Pr es en ta ti on to the City of Ottawa, March 26, 1981, Pollution Probe, Ottawa Yoder, J. et al, M u t a t i o n Research, Vol. 21, pp. 335-40, (1973) Elo, Heikki and Ylitalo, Pauli, "Substantial increase in the levels of chlor o p h e n o xy a c e t i c acids in the CNS of rats as.a r e sult of severe intoxication", Acta Pharmacol, et Toxicol. Vol. 1, PP- 280-1, (1977) tT i * * . A I }/_ UIIIT2S o? a c r m s m s t o d i s c u s s a o v a l u t E I S T OE S C X T I 0? 2 ,U *D AD 2 ,^ ,5 - T C EIK K S S S i 25 April 1563 17.7 i , u u i SD2JST: lilcctca f a osatia held Co diacuso od rvaluatn tbo tesicity of 2,4-D and 2,*f,57 cccrtounds viti porticoLar crpiasis ca use of tbaso satarloIo la allitory cparatioca co hexbicidas. H52s. DATSi FLACZi 1CCO b ear* ' * : 2$ Aprii 15C3 *. . '' V * Coca 2 0 2 , B ld a 3310 (3 > 3 )* Disewood r s e n a l, lia ryla n d ATTSSJrSS: Iris Cea 7. J. Delscre, Ce=sadia<5 Cenerai, C3D Asey, E.A., >id. Col I.L, Daucr, chtirrnn, Director of ied Ras, CDDL, C.., lld, Dr. 3.?. roll a ra, Dir/llad/lea, cr'JL, E.A., ili Or* J.3. Tburstoa, Ltiica of Secretar? os Defesse, Vaah., D.C. ' Dr. J.3. De:..*itt, ?ctussr.t Vildlifc ?jss Center, Laurei, !& Dr. >?.C. ihav, U3 S-cpt c Arricultturrs, F.cltrville, li. Dr. U.E. Susscr-son, Cief Sclcatiat, CS;; A.3C7 , E* A., id. Dr. C.Z. l'Lnarik, Fort Detric'.;, Irodericb, ,'id. Dr. J.3. Lear?, Cd -ree of -risultare, Leltrvillc, I-3d Dr. tf. Kaxthiasd, Arsy r<*3 C-sxica, Ariir.r,tcs all. Ve. Dr. 2.J. Crtcn,_An Casa Proructa, Ine.* .'-caler, /a, Dr. V,K. Fave, bev Uiumica Co., :./e;slr-."cx Dr. 5.Silver, Scicneiiie Dirc.-ettor, CiDL, I.A., Sid. Dr. H.?. Averill, Velicolo-r? Dlv, Dix/Isd/Fas, CFDL, E.A., Kd. Dr. John C. Atainaca, Staciaticiaa, Dir/'.:ed/I *, CEDI, S.A.,2'<d. LE Col D,C. Dica, Eq CCii /-c-acy, 2. A., rii. Capi 3 .A. Hsrrtra, ella-Dea DI?, CfDL, IJ.,, I*/d. Hr. Frank J. Vacci, Cb, 2ssic Con Sr, CIDI, ,A, Sid. Dr. Karold d. He'.-srland, lazlctoa Labs, Falla Cliurch, Va. t e , Eartha A. Linosa, Jceaosrepher, Ics Si?, CIOL, &.A., Ili. I 17 7 & ^ v r i *ijc*e- >A r*1 4 eetia;; vos callad to crder b7 Che Chaimea* Col Sanar, vbc <:osaeated Chas vastt eraas o tha tronico and canicropiea ara covursd \aj densa g ro vtts o traca shmbs, etc* Depsndeet upen cirscretoacas thia ver,stative r.rotrrd cover haa la tina3 p?st besa a prcblea to fcsalth (calarla control, sarao tupius alea central), a acarea o snfcuaeaes, en obstruccin o Unas o lira, observacin, trsasportetica ecs She Cfcairm n stated th a t these in ettosdcnca could be fa s iilia ria c d v i t h th e a c ta a 1 use os c e r t a in h e rb ic id e s l a V ic e Saa d u rin g th e pose tv o T e a rs lie s ta te d th a t th e c u r.itt-fo r end o f th e noetic? ; vae a g e n e ra l statesmans about dose ls v e la and heccrda to h e a lth o f ra n and d e s a s tic m i s z i s Ir o n 2 ,t - D end 2 ,U ,5 - 7 h.-sed on th e r a d ic a l l it a r a t u r a cad tsrpubllchail data c f-va rio u s research lab o ra to rie s H :o C o m itte e v&s nsl-cd to e v a lu a te te e t o n i c i t y o f a n ic tu r e Icas-vn as 'T u r p l e : T e l? r i r t u r a c o n sists o f ^C-i ncru e l b u ty l 2 ,* i-D , 3 -. c o rra l b u ty l 2r h ,3 - 7 * end 1 0 ; is c b u ty l 2 ,1 ;,5 - 1 ilte C h rirra a fu r th e r sta te d th a t the C e rs itte e should also review th ia in tc re a tio n in li^ h t o f cctual e ra o f th e se no s e r ia ls ca n i l i t a r y h c ra ic i-'o s in V i e t >Ccs sad ecasacc aa to vh ctiier h e a lth heserda vero engendered by such o p e ration al uaa .i - |(? 7 9 f c ' ~ui..jfciaiUMSUHHK: Cot -Ufc 0 9 0 eulacioaii yvidaairaelroaauDlsrato*o]|as *U#c^.*sis* 22^. Dr,-- - -:ts. -. f t p , vcreirtec<rasl' .s,i : feafc tbi; addition -* t^j^a^:'`oss#fiaai tassa __ chronic. : 'cxsaaS ^ ___ _ r V .'r-'&'S'&i'i p -v General F . J . Balnora presented a bcrbiode3 ia m ilita r y operations. D r * W*C* ts v described the use expenditure sad contact v ith the rasa o p e r a to r s . ILLs rcm riua arc attached, B r C *S , 'lin e rib presented assn body splash ei^osurca ia ncnurreturin 7 i c t t i i a . Ha carmen tad fu r char th a t po*ares ts thana ccaaoxsda there uure C ol F * L * ta u a r presented an aval o u t oso to eaa o f harbicicea 3 tto-; c u la tio n e are attached as Appendix 3 , D r . 3 .? , lic'-lanara pm aentad d c t- va rio u a a n ir a i species* These rrsari- vas also m aticned cast tha sealcal 3 hare to xic e ffe c ts possibly vera a t: O r * y * Ilorrhlaad ciseusscd the i p o s s ib ly due to exposure to 2 ,h -D pui Jeans and Broun end the fo u rth rub L i; la c . Jicd. :;o . 3 , 12 2, 15^3. / O r * H .I 7 . Ib rn Ta rla rd coarse ted or la c ta tio n o f not lean than cfOO es c: cna can invested rr; or 2 ,1-D per p e rc e p tib le e ffe c ts * The sp e c ific r; pass 2 p , 1>"^2 D r * J . S , L e a r y d escribe d the Dec r i t e r i a f o r use o r h e rb ic id e s and pv e ra as ' f c l l o u s : th e c i r t c r i a f o r c: th a t th e y trust t * , by rsvyslaticr., no: f larrrnbla* c ra ila b ia in lr.rrs c te n ti a d d itio n , c p e r s t io u s liy , the Dapsrcrt: eonstent c o n tro l ia areas users the i D r * J . 3 * Bc'.' i t t sta te d chat te and 2 ,b ,5 - T v e re added to the ci<C3 < senses o f jrtc-'tfc, tin ccniirr.ad th a t c h ro n ic and a c u ta t o n i c i t y * The cal- crease in sq-yLevin*;; o f a n lla rd duck 2 *h -D and/or 2 ,^ 7 a t a dcse le v e l hand, Che q u a il produced a larger th. the t c : t r - r i e d . r-'*-"T T ot A.* I Dr* V.Z* Dave stated that the oraltable tonicity data are adequate for the prediction of ccnie doses* tic bbscd thin ca ecrcriaental evi* anca, as vail as on field eopLicatia.rs Us esplaiaed coat there vaa a nuisance factor involved ia that people have cecplaincd of a harsh taste is the drinking vatnr. Sr* R.J* Cttes stated hla erporicncea os the use of herbicides ia practical field a-plicacioae* tla consented chat hi3 firs ha a rusher of contrasts with industrial first cartas these ecnticoua field applications ever very lar^a areas* even thourh tiiousaada of people vere involved in these operations, shin sensitisation vaa the sssnrca effect produced* this vna noted in probably oaa out of a thousand persons* Dr* IScDasara surtssrinsd the and LZ51 data for oral, intra tracheal, iacraperitoneal, cud percutaneous routes on several species of anirals* Zassd upon all data presented, the Ccneitteo. decided to adopt as acute tonicity standards the figures viiich are cited in the coaclusicn of this report* The Ccnraittee adopted the following observation end conclusions: C?sr?vVATIs;>^ Da^cd upon the data revieved and presented, the Ccraittce rcccrrcnuod acceptance of chose ii-.turen for acute tonicity of purple datura. . Vua dcscittea further noted that these vere complied free* several animl specie3, Chat ta::ieit7 ata t*cr slid.1s t fxca species Co suec c b , and that the occasional eases of accidental poisoning and/or atterpeed suicide in sen report even higher figures* Oral and intrr.^eritonesl rentes - rsTev.faneou-s ror.trq .. (ID>0 JCC-1COO nz/lcg (ISL - 1CO-333 i=3/itc (1250 - lcCC-CC9 vrzi'<z (LSI - Cco-icca CG/^S CC.rrr~nC:?3 - The Coccitfcee stated 'in#sumary sad after careful review of tcuicoio;:Lcai data relat-d to S.L-O and ,L,5*~ ?lu3 cha Knouleir.d as to the uanner chose racerloia cave been used for do* foiiaticn. in nilitsry situations In Scucbusst Asia, the Comic toe con* eluded that no health hnenrd is or vis involved to can or ccnestie aaicals iron the mounts or caancr those netariais v e m used ia the aforementioned essreis** Additional inforsntion pertinent ta this Ejecting ora attached as Appendices D, I, and F. j l lc? 7 ' ? ? fcgZitJ t* 6 on . .*o1C*0irlwrrHtOmt* *R.HHpu1* u r& . i-Vt*PfMH1`r?iubBp(Cc?u*iJ. .HB . . 0Cl3lJ 0rt Bu & n 3 ( I . * A F P 2 3 I X JL a jPresentation & r . V . C . Sfcsv * l ? 7 "?0 o A m m di n A. I'w U . U - tW 4t ~ J 'ri Cto Thenoxyacctata herbicides Arts' used to co n tro l vecds In vh aat, oats, barlay. Tics, aepara-{.us, 6u?.nTcaaa, com, aad other eroos* Ih7 are also used to control veeiis cad trash in svarpLands cad pastaros, soso croplands, undesirable harevoed.tress in conifer forests, on otilit7 ris/nts-of---mys, industrial aad nilitary sites aad nilitary operations These ccrpcuada arc asplied sc rates of 1/15 to ItO pounds/ acre depending ea the vesacatioa to bo controlled sad nathod of application* d a hexbieidal properties of these chested* uera reported in . and their ccmareial rauufecture bs^aa in boat 19 ^ * since 19^7 tare than 3CO cillicn psunda hare been produced end uued to eaatrol vegetation on r e than CO nillioa acres of lend* The- annual production of the phencuyaeeiata herbicides is cstiuafced to exceed 50 nil lien pounds aad they a m used on about 30 cilliea acres of lead each year* H a a herbicides aro registered by the U.S. Departnent of A.vricnlture and tl:sir use for need control in sod crops is pemitted vith a tolerance of 3 P?3 on apples, asparagus, and other edible crops* * Sorias the 15 years those herbicides have beta used extensively in the 0*5,, the Dept cl Agriculture records shov that the Dcrartnant baa not recaivcd a single ccrol&iat of injury to bunsna, livestosh, vildlifc, cr soils iron the phenosy herbicides, In addition, the teaJor ESKufccturcrs of the phenony herbicides have certified that ncaa of the vorl-ctsn in their factories have com any 11 effects, Apprcndnatelj 200 scientists conduct research t/ith those evsnsunds each year* l.'ot a ainsla cate of injury, illness, or irritation cf any bind has ever been reported* *' '. ` . 1979/ * FF223IX Z ' 'a evaluation o Feasible Sitia Fall*Out Cose to Usa Prasentod by .Col ? L* 2sasr J*_' PfWS^P "M JJli'J" > w 1*9>7 7i5juii-ijiim.. o Ascendls.3 --f-t i -- ---T---- -- --- 'i'i --- \ __ f? gsdv ATsa a 50 hf,# 1 5 7 entire ter tail (110 lbs 2 in) heras tea a total body area of 1.5 cetera or lb*2 sq ft ?oc purpose of coaputatioa, it is assured that a esaisun or 1/2 of the body area caa bo cade available Co fall-out, i.c, 6 sq. ft Zsood ure a v a i l dseaassitad studies, Che fall-out ratio bettvetsi V X on the creicsd aad oa a heraa la various positions averages 1:075* itiarcfoxc, the theoretical rasiraa all-cut raid yesitioa ea a bean body veuiu- be 6 aq ft 2p0 eg per sq ft 2 X 0 x 075 (V^corrcctiaa)* lgSO c s total body .-- 1500 cs/5Q m 50 cs/bs body voisbt It is also taioua frea V S caaoriarnta that 1-2 layers o elothias provide b to IC-ioiu pzoccaeire n^aloat fall-cut slsia daeoaitisa. li the hvraaa subject usa assured to be pC-;i covered by cay tors os elochins, thea cazisaa theoretical bedy dcpcsifcica is Id cs/fcj body velvet /?7?3 o APPSSZS C Toricity of Herbicides in Variotic Attisai Species * . Presented B y ' Br* B. P. licBcsaxa 1 9 7 9 1 /. AflOf*r>dix C - Considerable data can be found la the literature oa phccomyacetata*. ilcvcver, cost of this indorsation concerns the parent acids or salts. Although, cur intareats are in Che butyl escera ei 2 fbyS and 2 ,b,5*^* thn indorsation on the parent acids and ealts are pertinent because there are definite relationships between the parent cocpocsds and the esters. A s data in Table 1 indicate a low order of toxicity for all of tha ccrpcusda mentioned in the various cnisal speciaa for tha routes of administration shown. There era eo sinniiicaat differences in the tori* cities of the various types or compounds by the intrareritones1 end intrar.aatric routes or odainistration. */ these routes of aaainiatration the toxicity of *purple* la similar to that of the other cot-sounds mentioned. 7 percutaneous application, purple-' is less toxic than by t%ha intrapsritoneal, iatrssastric or intratracheal administration routes. The information on the toxicity of the parent phanoryaectates in do^s is sparse. These data Indicate Lkac cops ara sore sensitive than other opeciaa to the toxic effects oi pkansxvecatates. However, la doss `-purple'' appears to be lass comic than tha parent compounds. Tha data shown in Table 1 refers to the tS*30 values. Table 2 gives tile predicted dose irrr/ls;) of the rr.rcnt itat.is which sight cause uoath in 1..?, G.ly end O.Gl.i of a population. r*c-sas which, might produce one death in a copulation of 1C,COG are considerably higher than the maximum dcia -0 rv/k-) i.-hich could have been c ivsred in the Viet h'an operations. It would be expected that tha loth. , osc for ''purple1 would be similar to thoso shown in Table 2. A summary of the aveliable data froa toxicity ntudicj n w in progress are shown in Table Thaae data indicate that ``purple1' will be as core toxic that predictions froa information contained in Tables 1 and 2. This suggests that it is very unlikely that purple" vuuld pro duce any fatalities as used ia tee operations in Viet Ilam. '/ Icf7`}i " f c f *1 * ' T ' " " T ' I l 'I, -- - ' Appendix C * Tabi I ' ruru t o x i c inr o f riiFJiomcEtMi Speciaj * Kouto Acid Salt Eat ` ip *3 it pc pc Fbbit It ip is ' It pc C Dog /, ip is . it pc 315(1) S M I ? ) 1 1(i io (a) 0oo(2) ', f 1CC(J) TJJO :t /-r O*V*hi,?-T - . Mis:c.:i Cat * Acid - v-nr C:;toi* Purple (*> 620(1) ,5(l) itfMi) 0 *8l(l) 36 WiO 55 teco > i:>c o 718(1) f130 :-C;o 559 1339 m 0 100(5) % 353 505 >1250 OU3 ip 369(2)->i2(a) is 3CC(l) 375(1) 70(1) 3C9(i) iod) Cutnri ? ip is 567i2)-rco(2) W 9 ( l ) 591(1 J-loco() C'iO(l) 5,71(1) Chlcls i 5'.l(i) rcc3(i) 319(1) (a )J) rewis & Kycas, Aia J. Vat Ved, Vol XV, -r'o. ')(, p I & 2 , L51*. Hill t Carlisle. J Ind Kyg 2c Tex* O S 1?V7. t*\ Urli . Klmi-vk.t. Arch Ind llyji Occt:p lied, 7*^1. 1953* 750(1) rUa A TrsQnl'z C l a b i a 2 t: . i . LETH A L D0323 ? C I PHZSOSSAfiSt&tSS ' Speeles t iasa Pis usa .t .t -use Pis linea Pis niSC Peut *3 . c a A ai n u La ; ip ip ip iS ls is is 72 43 . 2=0 SO l5 . 18 50 13*0 ES/JtS IDI ISQ.l cs/ks =3/*S 3 .4-0 512 5$0 369 223 2?^ 2=3 37 630 4S I 557 2to 23I 350 237 173 235 1^5 120 ITO 375 05 2 .4 .5- T I T O .01 = S 7*S PefercRces . 138 155 ito * nm, Hill, Hill, i<A7 1587 Fitziiush . 133 130 3to 185 H i l l (r^ron?,.) Pav ritshysh(a Ha ve , l y >2 Slave, l54 V . ' r is is to 527 co 3 5 9 25 230 232 220 155 Cove, I534 155 C o v a , 155^ is 2 7 3 T3 13 118 53 P x v s , 1954 : V ^iPBSiig ? 7 C7 7 52ss 'khbl f I i i "Tl *f' * :} ( .i t i i i i P * (e lo bed) 5*12,500 Eu t 4i t IW O JNVEftiOFED p JQC4 ..iTORlED & F! En HJh - y 15ST Technical Note Number 62-68 THE PRESENT STATUS OP CHEMICAL CONTROL OP VEGETATION IN RELATION TO MILITARY NEEDS J. H. COATES I. M. SHARPE H. POLLACK flM Institute fo r Defense Analyses Research and Engineering Support Division i?7 77 TECHNICAL NOTE 62-68 OHE PRESENT STATUS OF CHEMICAL CONTROL OF VEGETATION IN RELATION TO M ILITARY NEEDS December 1962 Submitted by: L . M. Sharpe H . Pollack Approved by: i / 'f:V e.W A A ^ f D i'. S . S . Penner. D ire c to r, IDA/RESD 3S T IIU T E FOR DEFENSE 'ANALYSES RESEAR! AND ENGINEERING SUPPORT D IV IS IO N C ontract SD-50 Project AGILE L^'r I e? $ 0 0 The authors wish to express th e ir ap pre ciatio n to M r. S . J . Deitchman of the In s titu te fo r Defense Analyses f o r h is many v a lu a b le suggestions and a d vic e . TABLE OF CONTENTS Page In tro d u c tio n Recommendations 1 . Short-range Problem 2 . Interm ediate-range Solution 3 . Longer-range Problems 4 . Advisory Panel 5 . System atic Botany 6 . Phytotoxic Su sc e p tib ility 7 . Program Management D is c u s s io n I. H. H I. IV . V. V I. VH. V IH . IX . The Problem Commercial Agents Immediately App licable in tiie F ie ld In d u s tria l Chemicals a t the DevelopmentalStage Fundamental Studies Proper Function of F o rt D etrick in the A n ti- V e g e tative Program Other Government E ffo r ts in P la n t Chemistry In du strial Liaison M anufacturing C a p a b ility to Respond to M ilita r y Requirements Botany 1 2 2 2 3 4 4 4 5 6 7 10 12 14 IS 17 19 24 25 Appendix 26 INTRODUCTION Under P r o je c t A G I L E , a subtask was undertaken t o p ro v id e "te c h n ic a l advice on the s ta te -o f-th e -a rt in the United S ta te s , both governmental and n o n -g o ve rn m e n ta l," on chemical means f o r c o n tr o llin g v e g e ta tio n . The problem was broken down i n t o th e fo llo w in g c a te g o rie s : 1 . Commercially a v a ila b le agents which could be a p p lie d in m ilita ry operations w ith in s ix months. 2 . Chemicals in commercial production or la b o ra to ry development which could be brought to the o p e ra tio n a l statu s w ith in 18 months. 3 . Fundamental studies on p la n t physiology re le v a n t to these short and interm ediate range problem s. 4 . Botanical studies in re la tio n to the ta sk . 5 . The proper fu n c tio n and d is t r ib u tio n o f in tra m u ra l e ffo r t a t F o rt D etrick in re la tio n to these o b je c tive s. 6 . Relevancy of n o n -m ilita ry government e ffo r ts to the p ro b lem . 7 . L ia is o n , p ro p rie ta ry r ig h t s , and c o n tra c tu ra l arrangements in fa c ilita tin g th is program. 4 RECOMMENDATIONS Short-range Problem a . The evaluation o f commercially a va ila b le a g ric u ltu ra l chemicals along the lin e s o f h e rb ic id e -h e rb ic id e , h e rb ic id e - d e fo lia n t, herbicide-desiccant m ixtures has the g re a te st promise fo r developing operational agents in the next s ix months. Fo rm u la tio n s must be in v e s tig a te d as a key p a r t o f these e v a lu a tio n s . The p a r t ic u la r choice o f agents can p ro b a b ly be b e s t made by F o r t D e tr ic k w ith th e USDA i n c o n s u lta tio n w ith - representatives from in d u s try , or by the panel discussed below. b . The i n i t i a l e v a lu a tio n s can be b e st conducted i n i n d u s t r i a l la b o ra to rie s , second choices are the USDA f a c i l i t i e s and F o r t D etrick. c . The fie ld evaluation fo r tro p ic a l areas prelim in ary to o p e ra tio n a l te s tin g can be c a rrie d o u t im m ediately a t th e fa c ilit ie s a va ila b le to several of the ia rg e r companies. A good second choice i s th e P u e rto Rican Commonwealth A g r i c u l t u r a l S ta tio n . Independent USDA supervised f a c i l i t i e s would have to be s e t up and manned; F o r t D e tr ic k su p e rvise d s ite s cou ld be used i f the others were u n a v a ila b le . Interm ediate-range Solution a . In d u s tria l labo rato rie s are the best source o f candidate chemicals f o r p h y to to xic e v a lu a tio n . Th is should be implemented through 8 to 12 modest ($100,000) synthesis and screening contracts The c o n tra c to r should be g iv e n maximum l a t i t u d e i n p u rs u in g th e program ; prim ary and secondary screening should be t h e i r responsib ility. 2 c . Closer in te ra c tio n is required between those responsible fo r designing d e liv e ry equipment and those preparing the chemical agent regardless of th e ir S e rvic e . d . F o r t D e tric k should u t i l i z e a wide range o f con sultan ts from in d u s try , the u n iv e rs itie s , research fo u n d a tio n s, and the fe d e r a l, s t a t e , and commonwealth a g r i c u l t u r a l s t a t i o n s , re p re s e n tin g divergent points of view . Advisory Panel An advisory panel on the a n ti-v e g e ta tiv e program could p la y a c r it i c a l ro le in meeting the present d if f ic u lt ie s and la y in g out an e ffe c tiv e plan fo r the fu tu r e . In a d d itio n to the required s ta tu to ry re p re s e n ta tio n , i t should include both m ilita r y and c iv ilia n re pre sen ta tio n from th e A i r Force and N a vy. I t would be d e s ira b le t o have a re p re s e n ta tiv e o f th e O f f i c e o f th e A s s is ta n t S e c re ta ry o f th e Army f o r R&D and th e O f f i c e o f th e C h ie f o f Research and Developm ent, Department o f th e Army also re pre sen te d. The panel should fr e e ly u t i l i z e con sultan ts as suggested in Paragraph 3 (d ) above. System atic Botany An immediate e f f o r t should be made t o com pile a b o ta n n ic a l r e g is te r , from a q u a lita tiv e and q u a n tita tiv e p o in t o f vie w , fo r S o u th e a st A s ia . A corresponding e f f o r t should be s ta r te d f o r other p o te n tia l trouble spots. Fhytotoxic Susceptibility The re la tio n s h ip between p h y to to xic s u s c e p tib ility and phylogenetic s t r a in should be s tu d ie d . Program Management I t would be an in tru s io n o f an unnecessary a d m in is tra tiv e la y e r to have some i n s t i t u t i o n such as S ta n fo rd Research I n s t i t u t e o r Armour undertake a supervisory fu n c tio n in the expanding a n ti v e g e ta tio n program . .The s u p e rvis io n o f the a n ti-v e g e ta tio n program as i t applies to the m ilita r y r ig h tly belongs to F o r t D etrick. 5 06 DISCUSSION The consensus i n and o u t o f governm ent, w ith which we con cur, i s th a t th e Crops D iv is io n o f the U .S . Army B io lo g ic a l La b o ra to ry a t F o r t D e tric k has responded sp lend id ly to the present operational m ilita ry requirem ents. In view o f th e ir h is to ry of budgetary caprice, intram ural r e s is ta n c e , and la c k o f s u p p o rt by th e m i l it a r y command, a f a r le s s e ffe c t iv e response could have been e xp e c te d . Now t h a t th e a n t i ve ge tation program a t F o r t D e tric k is being re -fu n d e d , i t is appropriate to review th e fu n c tio n s o f th e expanded s t a f f in terms o f the s h o rt and longer range o b je c tiv e s . Conclusions based on discussions w ith govern ment and in d u s tr ia l contacts on th e proper fu n c tio n o f F o r t D e tric k are presented below. I t was made e v id e n t by o u r i n d u s t r i a l contacts t h a t ra p p o rt w ith the a n ti-v e g e ta tiv e program va rie d from s a tis fa c to ry to a n ta g o n is tic . Most companies appeared t o be confused as t o o b je c tiv e s and i t was e v id e n t t h a t th e r e la tio n s h ip was r e c ip r o c a lly u n re sp o n sive . Since no s a t is fa c t o r y u t i l i z a t i o n o f th e i n d u s t r i a l c a p a b ility can be made w itho u t improved ra p p o rt, th is problem also w i l l be discussed. U n like many o th e r te c h n ic a l f i e l d s , i n which th e p r in c ip a l e x p e rtis e and com petence l i e s i n tiie m i l i t a r y , th e developm ent o f new a n ti-v e g e ta tio n chemicals is fundam entally an a c t iv it y o f the commercial chemical in d u s tr y . The m ilita r y a p p lic a tio n s are p e rip h e ra l t o , and d e riv a tiv e o f , tiie i n d u s t r i a l com petence. In d u s tr y must be u t i l i z e d t o a much g r e a te r e x te n t i f a more e f f e c t i v e a n ti-v e g e ta tio n program i s to be developed 6 W 07 From a b o ta n ica l p o in t of vie w , the above problem includes various aqu atic p la n ts , mangrove, and a wide range o f grasse s, fe r n s , palms, p alm e tto s, tr e e s , and herbaceous p la n ts throughout South Vietnam . Although time did not perm it an exhaustive search, conversations with a number o f know ledgeable in d iv id u a ls make i t appear u n lik e ly th a t th e re e x is ts an adequate b o ta n ic a l c o lla tio n o f th is area from e ith e r the q u a lita tive or q u an titative p oin t of view. Our in fo rm a tio n in d ic a te s th a t mangrove i s c o n tro lla b le . However, there is a p a u c ity o f in fo rm a tio n on the r e la tiv e s u s c e p tib ility of the va rio u s o th e r species to h e rb ic id e s . I t is known t h a t: 1 . There are no ra in fo re s ts in the area of m ilita ry in te re s t. 2 . The upland area has a d ry season in the w in te r in which th e re is le s s than one inch o f r a in . The tre e species there are la rg e ly non-deciduous broadleafs. 3 . In the v irg in fo re s t, the p rin cip a l obstruction to visio n re q u irin g d e fo lia tio n is the broadleaf evergreens which grow up to a h e ig h t o f 100 f e e t . The ground has r e la tiv e ly lit t le cover. 4 . There is a tr o p ic a l scrub growth c o n sistin g la rg e ly of such f lo r a as broadleaf evergreens which are o fte n mingled w ith bamboo (ru n n in g up t o 40 f e e t i n h e ig h t) and im perata g ra s s . T h is t r o p ic a l scrub appears to be ty p ic a l o f those areas in which c i v i l i z a t i o n has in tru d e d . The above categories do not c la r ify f u l ly the ta c tic a l objective o f th e m i l i t a r y d e f o l i a t i o n program . The chem icals now i n o p e ra tio n a l . 8 t r i a l s , as o f November 1962, are e ffe c tiv e against a l l o f the categories described above to a g re ate r o r le sse r e x te n t. The ta c tic a l problem to which research must be d ire c te d i s the development o f agents which a tta c k a broader range o f b o ta n ic a l species more r a p i d l y . The agents must be a p p lic a b le by a i r o r ground spray d e v ic e s . They should be n o n -to x ic to the troops using i t , to the natives in or passing through the area tr e a te d , and harmless to t h e ir liv e s to c k . C e r ta in ly , acute e ffe c ts must be guarded a g a in s t and th e lik e lih o o d o f chro n ic e f f e c t m in im ize d . S in c e any agent w i l l , i n most a re a s , be used once, o r a t most a few tim e s , i t is not necessary to conform to the high sa fe ty standards re q u ire d by the Food and Drug A d m in is tra tio n f o r commercial a g r ic u ltu r e . I t is im portant' also to guard against cosmetic e ffe c ts , however tra n s ie n t, because o f the propaganda va lu e . There appears t o be a d iffe re n c e between the m i l it a r y and com m e rcia l te rm in o lo g y. The term " d e fo lia n t" appears to be used by the m i l i t a r y t o mean an agent which causes th e le a ve s to drop whether i t k i l l s the p la n t o r n o t. In commercial term inology an agent which ki l l s a p la n t is a h e rb ic id e , whereas "d e fo lia n ts " are e xc lu s ive ly non -herbicidf agents which cause the leaves to drop from a commercial crop p la n t in o rd e r t o f a c i l i t a t e h a r v e s tin g . D esic can t appears t o have th e same meaning f o r the m ilita r y and in d u s try ; nam ely, *an agent which.causes the dehydration of leaves and th e ir w ith e rin g but not n ec e ssarily causing them to drop from the p la n t. Another category o f agen t, the s o il s te r ila n t is recognized commercially as an agent which p ro h ib its the growth o f a l l flo r a in an area whether tem porarily o r perm anently. 9 Iq f o ? There was some confusion among o u r in d u s tr y c o n tacts as t o whether tiie m ilita ry wanted, d id n 't w ant, o r d id n 't care whether the agents o ffe re d were h e rb ic id a l o r s o il s t e r i l i z i n g . T h is needs c la r i f i c a t i o n . In our understanding, s te rila n ts have a d e fin ite place in roadside clearance whereas they might b rin g about erosion problems i n the fo r e s t proper. S e v e ra l companies which b id on th e two re c e n tly granted c o n tra c ts had o n ly a vague understanding as to what the m ilita r y o b je c tive s a re . T h is la c k o f c l a r i t y undoubtedly hampered some i n th e p re p a ra tio n o f a s a tis fa c to r y p ro p o s a l. More s p e c ific in fo rm a tio n on th e now c la s s ifie d aspects o f m ilita r y requirem ents would a s s is t th e bidders in sub m ittin g more responsive p ro p o sa ls. I I . Commercial Agents Im m ediately A p p lic a b le in the F ie ld The most prom ising source o f new o p e r a tio n a l agents f o r use i n tiie n e x t s ix months l ie s in th e com bination o f com m ercially a v a ila b le h erb icid es, d e fo lia n ts, and/or desiccants. Form ulation is the key to the successful fie ld ap plication of such agents. The U n ited S ta te s Department o f A g ric u ltu re appears to be aware of the performance c a p a b ilitie s o f a l l commercially a va ila b le h e rb ic id e s , d e fo lia n ts , d e sic c an ts, and s o il s t e r il a n t s . They are fa m ilia r w ith the published lite r a tu r e as w e ll as th e re s u lts from the s e ve ra l sta te agencies. In a d d itio n , they have an extensive research program of th e ir own. I t is not clear th a t the able but overworked s ta ff a t F o r t D e t r i c k , since the a rre s t o f th e ir e ffo r ts in 1958 and i t s resumption 10 l^glo in 19 6 1 , have been able to apprise themselves o f th e performance capa b il i t i e s o f a l l marketed agents. I t is iro n ic th a t the F o r t D e tric k a n ti-v e g e ta tio n program was ab orted i n 1958 since t h i s i s approxim ately th e tim e th a t a number .of new agents re p re s e n tin g d i f f e r e n t chem ical typ e s became a v a ila b le . The ready a v a i l a b i l i t y o f th e components o f th e agent used and the g e n e ra lly re co g n ize d range o f e ffe c tiv e n e s s made i t the lo g ic a l f i r s t contender. Our c o n tac ts i n in d u s tr y were unable to suggest any agent as prom is in g as those being te ste d o p e ra tio n a lly f o r two reasons: 1 . They had not been given the m ilita r y requirem ents s p e c ific a lly in terms o f the s itu a tio n in Vietnam ; and 2 . They had no r e lia b le , comprehensive, organized body of data on the e ffe c ts of th e ir chemicals in tro p ic a l environ m ents. We make no s p e c ific suggestions as t o com m ercially a v a ila b le agents which should be in v e s tig a te d i n th e f i e l d . We d o , how ever, recommend t h a t m ixtu re s o f one o r more d i f f e r e n t h e rb ic id e s e it h e r w ith c u r r e n tly used agents o r in vario u s com binations, such as d in itro p h e n o ls and 2 ,4 ,5 - T , should be t r i e d . T h is ty p e o f com bination should b rin g about ra p id le a f drop and subsequent k i l l . One would expect th a t a d e fo lia n t ( i n t h e commercial sense) by i t s e l f would be o f m ilit a r y in te r e s t o nly i n c e rta in t a c t ic a l s itu a tio n s since growth in a few months would undo i t s short-term e ffe c t. A combination o f d e fo lia n t and h e rb ic id e , how ever, presents problems which c a ll f o r s p e c ific experim ental work. One a n tic ip a te s th a t i f le a f-d ro p should occur to o r a p id ly , the h e rb ic id e may n o t have tim e t o be absorbed and b r in g about a subsequent T1 k i l l . S im ila r ly , combinations of herbicides and desiccants also should be e va lu a te d . The th ir d aspect of th e u t il i z a t i o n o f cu rre n t m aterials lie s in fo rm u latio n . The la tte r is the a d d itio n of a d d itiv e s , so lve n ts, e m u ls ifie rs , e t c ., to basic agents in order to enhance th e ir e ffe c tiv e ness. E ffe c tiv e fo rm u latio n requires an in d iv id u a l w ith long experience and a knack bordering on a r t . T h is competence i s best embodied i n a few p r iv a te c o n s u lta n ts and some i n d u s t r i a l la b o r a t o r ie s . I t is our opinion th a t the recommendation o f the commercial agents t o be in v e s tig a te d can be b e s t made by F o r t D e t r ic k and 11SDA a t B e l t s v i ll e in c o n s u lta tio n w ith some o f th e la r g e r c o rp o ra tio n s such as American Cyanamid, Dow, M onsanto, S h e l l , Amchem P ro d u c ts , and G ie g y Chem ical C o rp o ra tio n . We b e lie v e t h a t th e fo rm u la tio n and i n i t i a l e v a lu a tio n of these m ixtures can be most r a p id ly , e f f e c t iv e ly , and econom ically accomplished through in d u s tr ia l c o n tra c ts , whereas F o r t D e tric k ' s major c o n tr ib u tio n should be i n la rg e -s c a le f i e l d e v a lu a tio n . H I . In d u s tr ia l Chemicals a t the Developm ental Stage In the interm ediate and long-range e ffo r ts of the a n ti-v e g e ta tiv e program, the accumulated la b o ra to ry and screening data as w e ll as the current developmental a c tiv itie s o f the herbicide manufacturers could be p r o fit a b ly a p p lie d to th e program . In any te c h n ic a lly o rie n te d b ig business, such as a g ric u ltu ra l chemicals, there is a bu ild-u p of unused te c h n ic a l inform ation available o n ly to company em ployees. I n w a rtim e , i n th e name o f p a tr io tis m and n atio n al defense, the b arrie rs o f in d u s tria l se c u rity are lowered. In 12 a cold war, demands of proprietary self-interest are still dominant. In peacetime in d u s tr y , by and la r g e , is re lu c ta n t to give to the m ilita r y p ro p rie ta ry in fo rm a tio n which has been accumulated a t gre at expense. I n th e h e r b ic id e -d e fo lia n t f i e l d , a sm all company e a s ily can accumulate d a ta on 200 to 300 p o t e n t ia l a g r ic u ltu r a l chemicals in a y e a r . A la rg e company can accumulate d a ta on t h a t many i n a m onth. A v a n is h in g ly sm all percentage o f th e compounds i n i t i a l l y screened f o r h e rb icid e a c t i v i t y , because o f un favorable economics, t o x i c i t y , o r an in a p p ro p ria te spectrum o f b io lo g ic a l a c t i v i t y , i s e ve r com m e r c ia lly d e ve lo p e d . I t s t i l l may be t o th e company's in t e r e s t t o keep th e perform ance d a ta on these u n s u c c e s s fu l compounds s e c re t to avoid aiding it s com petitors. The Food and Drug A d m in is tra tio n requirem ents which must be met by agents t h a t are to be a p p lie d t o crops make th e development o f a crop chem ical exceedingly expensive - ranging from $250,000 to $ 2,000,000. This expense is incurred la rg e ly in animal feeding stu d ie s, fie ld e va lu a tio n s , residue determ inations, and in ve s tig a tio n s of the m etabolic d is p o s itio n of the chemical in the p la n t. Such expensive studies probably are not necessary fo r a m ilita ry agent. S e ve ra l o f th e la r g e r companies in d ic a te d th a t they d id h a ve , o r m ight h a v e , agents in th e ir accumulated f i l e s which they would be w illin g t o make a v a ila b le t o th e m i l i t a r y i f th e y were approached w ith a s p e c ific o b je c tiv e . I t should be p o in te d o u t th a t th e s t a ff s o f t h e s ta te and fe d e ra l a g ric u ltu ra l agencies also are la rg e ly uninformed of the behavior o f these te s t chemicals because o f in d u s tr ia l s e c u rity . 13 IS313 Chemicals under developmnt present a d e lic a te problem to in d u s try . The re v e la tio n o f performance c h a ra c te ris tic s might reduce a company' s le a d tim e o ve r i t s com petitors by s e v e ra l y e a r s . The o p in io n was expressed fre q u e n tly th a t a s p e c ific m ilita ry request, coupled w ith a b e tte r safeguard of the companies p ro p rie ta ry r ig h t s , would induce them to re v e a l d a ta on prom ising compounds. An a d d itio n a l inducement would be to g iv e the companies more r e s p o n s ib ility than i s p re s e n tly the case f o r the screening and e va lu a tio n of th e ir compounds. I V . Fundamental Studies There is a slow but accelerating production of fundamental studies on p h y to to x ic a c tio n . In s p ite o f more than IS years o f in v e s tig a tio n , th e re i s no d e f i n i t i v e account o f th e mode o f a c tio n o f 2 ,4 - D , th e o ld e st o f the commercial organic h e rb ic id e s . In c o n tra s t, the re has been marked success in in v e s tig a tin g th e mode o f a c tio n o f s e v e ra l o f the newer h e rb ic id e s . Monuron, chlorophenyldim ethylurea, has been shown by Todd and o th e rs to i n t e r f e r e w ith th e H i l l re a c tio n i n photo s y n th e s is . H i l t o n o f DuPont and o th e rs o f B e l t s v i l l e have shown t h a t Dalapon, s a lts o f 2 ,2 -d ic h lo ro p ro p io n ic a c id , and other chloro-acids compete f o r pantoate in th e enzyme in vo lve d in pantothenate s y n th e s is . There a lso has been in c re asin g a c t iv it y in the study o f ab sorp tion and tra n slo c a tio n of p hyto -active chemicals. These b a s ic advances are being made la r g e ly in th e u n iv e r s itie s and the USDA f a c i l i t i e s in the U n ited S tates and by a group o f workers in England. 14 Fundamental studies a t present are la rg e ly irre le v a n t to the short and interm ediate range problem s. In the long p u l l , these studies present the g re a te s t promise since they are the foun dation upon which o ur u n d erstan d in g o f p h y t o t o x ic it y re s ts and t h is knowledge could be c r u c ia l i n th e s e le c tio n o f compounds to be stu d ie d i n th e f u t u r e . A t one tim e , F o r t D e tr ic k was a c e n te r o f fundm ental s tu d ie s . I t i s no more an d , in our o p in io n , i t should n o t b e . Fundamental work is best conducted in an un in h ib ite d environment of fre e exchange such as e x is ts a t th e u n iv e r s itie s . In our o p in io n , th e re fo re , the m i l i t a r y should p ro v id e su p p ort f o r b a s ic re s e a rc h . We b e lie v e , a ls o , th a t F o r t D e tric k should be give n the o p p o rtu n ity to take f u l l advantage of th is inform ation by the appointment of consultants representing disparate points of view . V . Proper Fu n ctio n o f F o r t D e tric k in the A n ti-V e g e ta tive Program As pointed out above, the m ilita ry a p p lica tio n s o f d e fo lia n ts are a r e la tiv e ly minor but sp ecialized aspect of the general technology o f p la n t c h e m is try . 'Die m ilit a r y have s p e c ific problems p e c u lia r to t h e ir needs, b ut the p rin c ip a l resources to solve them are located in in d u s try . F o r t D e tric k should, th e re fo re , play the primary ro le in fo rm u la tin g these unique problems and in developing the appropriate technology to solve them. To do t h i s , they need a c a p a b ility which ranges from b asic research to ap plied te c h n o lo g y. One o f the key problems is to achieve the proper balance o f these a c t i v i t i e s . The F o r t D e tric k operation should go in to the fundamental aspects of p la n t chem istry o n ly f a r enough to m aintain a competence a t the in s t a lla t io n 15 which w i l l enable i t to in te rp re t fundamental research re po rts from a l l sources. On the o t h e r hand, fundamental studies in p la n t chem istry are c u rre n tly under-funded a t the u n iv e rs itie s and the Department of Defense would do w e ll to support th is a c t i v i t y . The second a c t i v i t y , t h a t o f e v a lu a tin g new a g e n ts , can be d iv id e d i n t o two p a rts - syn th e sis o f new a g e n ts , and t h e i r sc ree n in g * By th e very nature of organic synthesis, small in s ta lla tio n s cannot have a f u l l spectrum of syn th e tic c a p a b ility . Fundam entally, in d s u try and, t o a le s s e r e x t e n t , th e u n iv e r s it ie s should be th e source o f new c h e m ic a ls. The syn th e sis o f these new compounds can be b e s t done on a c o n tra c t basis and these la b o ra to rie s should be give n wide la t it u d e t o in v e s tig a te new chem ical s tr u c tu r e s . How ever, F o r t D e tr ic k must have s u ffic ie n t synth etic organic chemical c a p a b ility to perm it i t to fo llo w up prom ising s y n th e tic leads where an in-house e f f o r t is d e s ira b le . The o th e r aspect o f new agent e v a lu a tio n i s p rim ary scree nin g to s e le c t those chemicals which have he s lig h te s t promise o f phytochem ical a c t i v i t y . Whenever p o s s ib le , screening should be the r e s p o n s ib ility o f th e o rg a n iza tio n s y n th e s izin g th e compounds i n o rd e r to p ro v id e a h ig h ra te of feedback o f the re su lts to the synthetic program. In th is way, in t e r e s t i n the research would be heightened and economies i n both tim e and money e ffe c te d . T h ir d ly , the a p p lica tio n o f p la n t chemicals fo r m ilita r y purposes should be the strong p r in t o f th e F o r t D e tric k o p e ra tio n , i . e . , problems connected w ith modes o f d e liv e r y as w e ll as o p e ra tio n a l e v a lu a tio n s , and 16 large-scale testing in those environments of military interest. In summary, the use o f p hytochem ically a c tiv e agents i s p rim a rily a s p e c ia l fa c e t o f a much la r g e r te c h n o lo g y . F o r t D e tr ic k needs a f u l l range o f c a p a b ility to stay abreast o f developments but i t s emphasis should be overw helm ingly on those aspects which are p e c u lia r to m ilita ry applications. V I . O ther Government E ffo r t s in P la n t Chem istry The p rin c ip a l focus of n o n -m ilita ry fe d e ra l government a c tiv ity in phytotoxic agents is the U n ited States Department of A g ric u ltu re ; comparable agencies e x is t a t th e s ta te le v e ls . T h e ir in te re s ts range from the improvement o f a g r ic u ltu r a l y ie ld s w itho u t im p airin g the wholesomeness o f fo o d , c o n tro l o f u n d e sira b le p la n ts in wooded lands to h e lp th e lum bering i n d u s t r y , c o n tr o l o f growth alon g r ig h ts o f way used f o r power transm ission lin e s and tra n s p o rta tio n , to c o n tro l of weeds i n n avig ab le w aters and a q u a tic s p o rts a re a s . These agencies conduct extensive e va lu a tio n programs a t the applied l e v e l which are designed p r im a r ily t o measure th e e ffe c tiv e n e s s o f new agents in th e ir various fie ld s o f in te r e s t. The s ta te and fe d e ra l agencies u su a lly are given o n ly those m ate rials which the manufacturer has d e c id e d , on th e b a sis o f h is own e v a lu a tio n s , have a good chance o f being commercially successful. Thu s, the governmental agencies' f o r t e is the knowledge o f th e e ffe c tiv e n e s s o f commercial chemicals being marketed o r being o ffe re d f o r commercial developm ent. T h e ir weakness is a lack o f in fo rm a tio n w ith respect to the f a r g re a te r number of m aterials re je c te d by the m anufacturer f o r com m ercialization. 17 mi 7 Fo r the current m ilita ry needs, th e re fo re , the a g ric u ltu ra l stations, i n p a r t ic u la r th e USDA , are i n a k e y p o s itio n t o recommend to F o r t D e tr ic k those com m ercially a v a ila b le agents which should be brought immediately to operational e va lu a tio n . On the le v e l o f secondary p lo t s ize screening, the U . S . Department o f A g ric u ltu re and the s ta te a g r ic u ltu r a l s ta tio n s have conducted f i e l d e v a lu a tio n s f o r many y e a r s , e s p e c ia lly i n tem perate zo n e s . They do n o t have th e manpower, which can be a p p lie d im m ediately t o th e s h o rt and interm ediate range m ilita ry problem s' In d u s try w ith i t s lo n g e xp e rien c e i n fo rm u la tio n must be u t i l i z e d to th e maximum. The p ro p e r fu n c tio n o f F o r t D e tr ic k i s t o coordin ate these two competences and to channel t h e ir e ffo r t s in to a p ro d u c tiv e , e f f i c i e n t program. P a r tic u la r a tte n tio n should be give n to the Puerto R ic a n Commonwealth A g r i c u l t u r a l s t a t i o n which has a c lim a te s im ila r to t h a t o f South east A s i a . The f l o r a may n o t be comparable i n t h e i r reactions to the phytotoxic agents. The Fo re s t Service i s , in g e n e ra l, in te re s te d in removing undesirable tre e s from those areas which are commercially s ig n ific a n t, f o r example, the selective k illin g of scrub oak in pine fo re s ts . R ap idity of response, a m ilita ry n ece ssity, has not been a Fo re s t Service requirem ent. Secondly, th e ir in te re s t is d ire cte d toward s e le c tiv ity or s p e c ific ity of a c t i o n . T h i r d l y , many o f t h e i r t r e e - k i l l i n g techn iques such as f r i l l i n g (p ry in g a rin g o f wedges o f b ark away from the tre e and ap plyin g the _ chem ical to the wound) are m i l it a r i l y im p ra c tic a l. 18 I n summary, due c o n s id e ra tio n and emphasis should be g ive n to the various aspects of the development program. The prime re s p o n s ib ility f o r fo rm u la tio n and i t s associated screening should be assigned to in d u s try , d ire c tly or in d ir e c tly . The f a c ilit ie s fo r p lo t-s ize screening are most fre q u e n tly found in the s t a t e , commonwealth, and fe d e ra l agricultural stations. V H . In du strial Liaison I t became apparent e a r ly i n o u r in v e s t ig a t io n t h a t th e p r in c ip a l focus of phytochem ical technology lie s in in d u s try . The m ilita ry has not been re ce ivin g f u l l advantage o f th is technology because o f a fa ilu r e to communicate i t s unique problem s, and in d u s tr y 's fe a r o f lo s in g i t s proprietary rig h ts . Economic D if fic u lt ie s - Contact a fte r contact in the in d u s tria l la b o r a to r ie s made th e p o in t t h a t th e a g r i c u l t u r a l chem ical business is h ig h ly c o m p e titive . An awareness by the com petition o f the performance o f a developm ental chem ical o r even th e g e n e ra l tre n d o f new re s e a rc h , can mean la rg e d o l l a r lo s s e s . When d a ta i s sub m itted t o th e v a rio u s governm ent a g e n c ie s , i t i s w ith th e un d erstan din g t h a t secrecy w i l l be m aintained on p ro p rie ta ry in fo rm a tio n . In a few re g re tta b le instances, t h i s confidence has been v i o l a t e d , causing th e s u p p lie rs to become o v e r -c a u tio u s . Most o f o u r c o n ta c ts agreed th a t th e in d iv id u a ls t o whom tiie in fo rm a tio n is given i n i t i a l l y a c t in good f a i t h . Two e ffe c ts act to undercut th e ir good in te n tio n s . One i s a r e la t iv e ly ra p id tu rn over 19 o f personnel and the o th e r appears to be a needlessly broad dissem ination o f in fo rm a tio n t o th o se who have no r e a l "n e e d -to -k n o w ." O th e r d i f f i c u ltie s are th e f a i l u r e to c l a r i f y and p u b lic iz e in d u s tr y ' s o p p o rtu n ity t o r e t a in commercial r ig h t s and concern t h a t an agent m ight be c la s s ifie d "se cre t" thus preventin g the development o f a p aten t p o s itio n . In sp ite of these adverse re a ctio n s, the in d u s tria l representatives expressed a d e s ire t o serve th e c o u n tr y , even a t some r i s k t o p ro p r ie ta r y in te re s t, provided: 1 . The problems were made e x p l i c i t p re fe r a b ly th rou gh fa c e -to -fa c e con tact; and 2 . There is an o p p o rtu n ity to earn a f a i r p r o f i t . The s a lie n t fe a tu re s o f th e l a s t p o in t are the fir m guarantee o f com m ercial rig h ts to any agent developed in a government program, and the opportunity to tu rn previous lab o rato ry in ve stig a tio n s to p r o fit by d e ve lo p in g m i l i t a r y uses f o r agents which th e company had p re v io u s ly re je c te d f o r c o m m e rc ia liza tio n . In th is manner th ey w i l l be able to r e t r ie v e some o f t h e i r research e x p e n d itu re s . s Cost Sharing - In connection w ith the g ra n tin g o f two recent co n tra c ts by F o r t D e tric k which went to Penn S a lt and Monsanto, r e s p e c t iv e ly , a number o f com plaints were made w ith re s p e c t to c o s t sh a rin g . In th is arrangement, the contractor absorbs p a rt of the program' s cost presumably because h is commercial in te re s ts are being aided by th e c o n tr a c t. C o st s h a rin g tends t o be promoted by those who w i l l gain the most through fe d e ra l subsidy, whereas cost 'sharing tends t o be discouraged o r n o t engaged i n by those who have th e le a s t to ga in b u t th e most t o g iv e t o th e fe d e r a l e f f o r t . A company w ith no g re a t 20 commitment i n a f i e l d may undertake a g re a t d e a l o f c o s t s h a r in g , th us p ro v id in g f o r i t s e l f an o p p o rtu n ity to break i n t o a new f i e l d . I n e f f e c t , r a th e r th a n s u b s id izin g a fe d e r a l e f f o r t , i t i s u t i l i z i n g fe d e r a l money t o s u b s id ize i t s own i n t e r e s t s . I n c o n tra s t t o t h i s , th e la rg e company w ith a tremendous backlog o f in fo rm a tio n and te c h n o lo g y , when asked to engage in c ost sh a rin g , is su b s id izin g the fe d e ra l e f f o r t . The i n d u s t r i a l re a c tio n to c o s t s h a rin g , i n most c a se s, was u n fa vo ra b le . Th is a ttitu d e is based on the fe a r th a t in sane cases purchase p ric e may ta k e precedence o ve r q u a li t y o f re s e a rc h . Communication Problem - The fa ilu r e to communicate adequately the m ilita r y needs to In d u stry has been a major fa c to r in re ta rd in g response. We w i l l d isc u ss th e problem i n terms o f (a ) th e I n d u s t r ia l L ia is o n O f f i c e which was o rg a n ize d o f f i c i a l l y to b rin g new chem icals in t o th e m i l i t a r y program , and (b ) the handling o f the two re ce n t F o r t D e tric k con trac ts as s p e c ific examples o f d i f f i c u l t i e s . (a ) In d u s tria l Lia is o n O ffic e - The general a ttitu d e toward the effectiveness of the In d u s tria l Lia is o n O ffic e varied a ll the way from ,:vexy fa vo ra b le " to " in e ffe c t iv e ." There is a tendency f o r th o se companies who are a c tiv e p a r tic ip a n ts o r who have a lo n g standing h is to ry o f involvem ent in m ilita r y programs to consider tiie In d u s tr ia l Lia is o n O ffic e e ffe c t iv e . Instances were reported where companies were re c ru ite d in to the program by s p e c ific contacts w ith D r . M e tc a lf, the Chairm an. A t th e o th e r extrem e, th e companies which had r e la tiv e ly few dealings w ith th e m ilita r y f e l t th a t the I n d u s t r i a l L ia is o n O f f ic e was n o t d o in g a good j o b . They tended to lo o k upon the a c q u is itio n program as in d isc rim in a te and in e ffe c tiv e . 21 With respect to the h erb icid e s, the opinion generally expressed was t h a t th e s ig n if ic a n t m anufacturers a lre a d y had screened most o f th e compounds b e fo re th e y subm itted them to th e I n d u s t r i a l L ia is o n O f f i c e . They f e l t th a t tile m ilita r y should n ot be conducting a redundant e ffo r t in screening these chemicals but ra th e r should be c o n s u ltin g more c lo s e ly w ith th e s y n th e s iz e r w ith re fe re n c e to th e p h y t o - a c t i v i t y o f th e compounds. More im p o rta n t was th e s ta te ment t h a t th e compounds subm itted t o th e I n d u s t r i a l L ia is o n O f f i c e were " h ig h ly f i l t e r e d ." I t was s a id t h a t o n ly those compounds which were e it h e r known t o be o f low a c t i v i t y o r f o r which th e re had been establish ed a firm p a te n t p o s itio n were subm itted. The most in te r e s tin g c r itic is m o f a l l came from one company which has subm itted th e names o f hundreds o f compounds i n th e re c e n t p a s t and has received no request f o r e v a lu a tio n sam ples. The con c lu s io n drawn by t h i s s u p p lie r was t h a t n o t even th e m i l i t a r y i s interested in the In d u s tria l Lia iso n O ffic e a cqu isition program. A contrast to these criticism s re la tin g to herbicides is the awareness by in d u stry o f m ilita r y in te r e s t in h ig h ly to x ic m a te ria ls. Almost w ithout exception, industry has cooperated by subm itting samples o f new compounds f o r te s ts where th e p re lim in a ry d a ta was suggestive. (b ) Negotiation of Contracts - Our in d u s tria l contacts showed spontaneous in te r e s t i n d iscu ssin g th e va rio u s aspects o f sub m itting proposals f o r an a n ti-v e g e ta tio n research c o n tra c t w ith F o r t D e tr ic k . While none o f the remarks below could be said to re p re s e n t th e o p in io n o f a l l th e i n d u s t r i a l com panies, th e re was s u ffic ie n t consensus to m e rit p re s e n ta tio n . 22 The b id d e rs ' conference seems t o have l e f t some c o n tra c to rs confused on o b je c tiv e s . A request f o r bids fo r the synthesis of phosphorus, a c e ty le n ic and o th e r compounds was made. Many i n t e r p re te d th e re que st to mean to o heavy emphasis on th e f i r s t two c a te g o rie s . A ls o , th e re was a g re a t d e a l o f c r it ic is m o f th e lim ite d screening requested o f th e c o n tr a c to r * The l a t t e r was to screen th e new compounds a g a in s t one p la n t and F o r t D e tr ic k was to screen them a g a in s t a d d itio n a l o n e s. One p la n t was n o t regarded as a s in g u la rly s ig n ific a n t f o r d ia g n o s is . Our contacts g e n era lly b e lie ve d i t was much more econom ical and e f f i c i e n t t o p e rm it th e c o n tra c to r to conduct th e prim ary and p o ssib ly secondary screening. We b e lie ve th e c o n tra c t work would be more e f f i c i e n t and e ffe c tiv e were the c o n tra c to r in vo lve d i n g o a l p la n n in g , s y n th e s is fo rm u la tio n , prim ary and secondary screening, and f i e l d e v a lu a tio n s . A l s o , many o f th e la rg e c o rp o ra tio n s and some o f ih e s m a lle r ones have t r o p i c a l and s u b tro p ic a l e v a lu a tio n f a c i l i t i e s i n o p e ra tio n o r a v a ila b le t o them which could respond alm ost im m e diate ly t o th e m ilita r y requirements f o r secondary and f i e l d scree n in g . Such a systems approach could be most e ffe c tiv e ly c a rrie d o u t in dealing w ith the la rg e r companies such as Dow, S h e ll, D uPon t, American Cyanamid, Monsanto, e tc . Some o f th e i n d u s t r i a l co n ta c ts were s u f f i c i e n t l y in te re s te d in the m ilita r y program th a t they wished to i n i t i a t e u n s o lic ite d c o n tra c t p ro p o s a ls . A p p a re n tly th e o p p o rtu n ity and th e mechanism f o r doing t h i s was n o t made c le a r to them a t th e b id d e r s ' m eeting. 23 1 ^ * 3 a 3 V I I I . M anufacturing C a p a b ility to Respond to M ilita r y Requirements An im portan t question is th e a b i l i t y of the m anufacturer to produce la rg e q u a n titite s o f a new chem ical i n response t o m i l i t a r y requirem ents. T h is problem has two im p o rta n t aspects - m anufacturing f a c i l i t i e s and the cost of the products. F o r p rim ary screening p u rp o se s, a few grams o f m a te ria l are q u ite adequate and are th e sc a le on which a s y n th e tic program i s and' should be conducted. F ie l d o r p lo t screening e v a lu a tio n m ight c a ll f o r one pound q u a n t it ie s . I n alm ost a l l c a s e s , i t was f e l t by th e m anufacturers th a t they could respond to such a requirem ent w ith in a month. Should an agent be s u c c e s s fu l a t t h a t tim e th e re p ro b a b ly would be a need f o r q u a n titie s i n th e range o f 20 t o 25 pounds f o r a la r g e -s c a le f i e l d e v a lu a tio n . The response tim e in th is case p robably would not exceed three months. A p p lic a tio n o f a new agent a t th e o p e ra tio n a l l e v e l m ight in v o lv e s yn th e s is o f 50,000 t o one m i l li o n pounds p e r y e a r . The la r g e r manu fa c tu re rs w ere, by and la r g e , c o n fid e n t th a t such a need could be met p ro vid e d f a i r l y broad l a t i t u d e i n c o s t was allow ed i n o rd e r to cover the e x tr a expenses in h e re n t i n th e la r g e -s c a le p ro d u c tio n o f a new chem ical. I t i s o u r b e l i e f t h a t i n lo o k in g f o r t h i s new m i l i t a r y a g e n t, one could j u s t i f y , i n i t i a l l y , s e v e ra l-fo ld higher costs than th a t allowable f o r an e s ta b lis h e d com m ercial a g e n t. We b e lie v e t h a t i f in d u s tr y were e x p l i c i t l y inform ed t h a t such an o p p o rtu n ity e x i s t s , i t would be g r e a tly s tim u la te d i n i t s search f o r new phytochem ical a g e n ts . 24 l<?f a-4- I X . Botany Our observations indicate th a t there is s ig n ific a n t lite ra tu re a v a ila b le on the botany o f the Indo-Chinese p e n in su la . 3his is not w e ll organized nor is i t a va ila b le conveniently in the English language. We b e lie v e t h a t some taxonom ic botany would be most h e lp fu l to those attem pting to develop improved h e rb icid e s and d e fo lia n ts . The objectives should be: 1 . To gain a d e a r understanding of the re la tiv e m ilita ry importance o f the s p e c ific species; 2 . To explore the re la tio n s h ip s between chemical s e n s itiv ity and taxonomy in tem perate and tr o p ic a l re g io n s . Our prelim inary in ve s tig a tio n s suggest th a t considerable p ertin en t in fo rm a tio n i s s c a tte re d among th e v a rio u s companies which have p la n ta tio n s o r commercial in te re s ts in the tro p ic s : these are p rim a rily the ru b b e r, c o ffe e , banana, and cocoa grow ers. A taxonom ist w ith a chemical o rie n ta tio n undoubtedly could perform a u se fu l service in c o lle c tin g and c o d ify in g th is in fo rm a tio n . O f p a rtic u la r note is M aurice Schm id, a Frenchm an, hose E n g li s h , we u n d e rsta n d , i s e x c e lle n t and who i s con sidered t o be th e o u tsta n d in g , a u th o r ity on th e botany o f Vietnam . 25 APPENDIX The fo llo w in g o rg a n iza tio n s and in d iv id u a ls have been contacted in our attem pt to evaluate the current state o f the a rt of v e g e ta tio n c o n tr o l by means o f chem icals: 1 . Biology Department, Harvard U n ive rsity Cambridge, Massachusetts a . D r . Duncan Clement b . D r . Kenneth Thimann 2 . U n ite d F r u i t Company Boston, Massachusetts D r . N . C . Thornton 3 . Colonel K . C . Emerson O ffic e o f the Secretary of the Army(R&D), Pentagon 4 . Smithsonian In s titu tio n Washington, D . C . a . M r. Morton b . D r . F . A . McClure 5 . Esso Research Center L in d e n , New Je rs e y D r. H . H . Yow ell 6 . Vi. R . Grace S> Company C la r k s v ille , Maryland D r . W. K . Lo u g h lin , D ire c to r o f Research 7 . Fo rt Detrick Fredericksbu rg, Maryland a . D r.M in e ric k b . D r . Brown c . D r . Darrow d . D r. Xingsolver 26 [^ * 5 P & 8 . U . S . Department of A g ric u ltu re Washington, D . C . a . Fo re st S e rvic e , D r. Donald Lynch b . A g ric u ltu ra l Research Center D r. D . C. H aller Assistant Director c .. P la n t In d u strie s S ta tio n , B e lts v ille , Maryland ( 1 ) D r . W. D . M cClellan (2 ) D r . D . L . Xlingman (3 ) D r . Shaw 9 . American Cyanaaid P r in c e to n , New Je rs e y N a . D r. Frank Stark b . D r. John King 1 0 . S t a u f f e r Chemical Company, New Y o rk C i t y a . D r . Chester Arnold Vice Presiden t in Charge o f Research b . D r . Donald Mast i c k , Assistant to the Vice President c . D r . D . Dorman Associate D ire c to r of B io lo g ica l Laboratories d . M r. Obrecht Research D ire c to r, Chemical D iv is io n 1 1 . Boyce Thompson I n s t it u t e Y o n k e rs , New Y o rk D r . George McNew, Research D ire c to r 1 2 . Dupont Chemical Company W ilm ington, Delaware D r . Max G o e be l, D ir e c to r o f Research 1 3 . Texaco Research Center Beacon, New Y o rk D r . C . L . W. Swanson 1 4 . Pennsylvania State U n ive rs ity U n ive rs ity Park, Pennsylvania D r . Donald Fre a r 1 5 . N ational Geographic Society W ashington, D . C.. 16 . E th y l Corporation D e t r o it and Baton Rouge a. Dr. E llis R ifkin b . Mr. J . D . Lib b y, J r . 1 7 . S h e ll Development E m e ry v ille and M odesto, C a lifo r n ia a. D r. R. G . Larsen, D ire c to r o f A g ric u ltu ra l Research b . D r . J . Van Overbeak c . O th e r s t a f f members 18 . Standard O il of C a lifo rn ia Richmond, C a lifo rn ia a . D r. B . F . Quisenberry b . D r. I . Levine c . D r.L . R . Gardiner, D ire c to r of A g ric u ltu ra l Research d . O th e r s t a f f members 19 . University of C alifornia D avis, California D r. A . S . Crafts 20. C a lifo rn ia State Department of Fo re s try Sacramento, C a lifo rn ia D r . L . Burcham 2 1 . Dow Chemical M idland, Michigan a . D r . W. P . Schambra, Defense Lia is o n and Planning b . D r. X . C . Barrons, Plant Scientist c . D r. L . C . Cham berlain, A ssista n t to the D ire c to r o f Research 22 Chemagro Kansas C it y , Kansas D r . vonRumker oc onsanto' wc--location--^honc)________D . R . Bishop : M a y 11, 1983 `-cct : "Removing the hysteria from dioxin" 'CftCNCC 0 : J. F. Hussey As you know, Dow is currently engaged in a major effort to try to "take the hysteria out of dioxin." They have two-man teams of scientists, recently trained in media interview techniques, traveling throughout the country in a media blitz. Dow also hired Hill & Knowlton to aid them in this effort. Their motives are two-fold: 1) to refute charges that they have seriously c o m p r o m i s e d health and the environment in the Midl a n d area and 2) to articulate their position vis-a-vis the Agent Orange lawsuit. Obviously, we could put together our own road show, employing basically the same techniques. We do have the Suskind mortality study to point to and hopefully, soon, the morbidity study which we're currently restrained by the court from exploiting. In my opinion, Dow's efforts and, indeed, ours if we choose to emulate them, will do little more than give our management the proverbial "nice warm feeling." In the case of dioxin, we've got two very major things w o r k i n g against us: 1) dioxin is a compl e t e l y worthless, highly toxic, unwanted contaminant, i.e., it's impossible to defend it on any logical grounds, and 2) we have virtually no credibility on this subject because of the lawsuits, i.e., the news media and the public say "What would you expect a company that is being sued for billions of dollars to say about dioxin?" ` If any real progress is to ever be made in the battle to bring a sense of reason to the dioxin health debate, it is m y belief that it must come from independent scientists, prestigious technical organizations like the National Science Academy and the Congressional Office of Science and Technology and the regulatory community, e.g., EPA, CDC, NIOSH, etc. Not many people are going to believe the extreme ends of this highly polar i z e d bo d y of experts (M o n s a n t o / D o w versus Epstein, et al). It's these so-called independent scientists and government experts who can make a difference -- if a way can be found to motivate them and that's a b i g IF! C07154 What's clearly need e d is a "truce." This si t u a t i o n is very much out of control. A major scientific symposium might be an appropriate mechanism to bring all interested parties together. It should be jointly sponsored by organizations like the AMA, CMA, NSF, NRDC, possibly the WHO, etc. I don't pretend to have all the answers on how this could be orchestrated, assuming it makes sense. It might be an appropriate agenda item for the Environmental Policy Committee to address -- or perhaps the CMA's Executive Committee under Lou Fernandez's leadership could take it on. In my view, the analogy to AN in Dick Mahoney's note is inappropriate: 50,000 Vietnam Vets aren't suing anyone over exposure to AN. The CDC never said 1 ppb of AN is a health hazard. The government isn't buying out any towns contaminated with AN. AN is a highly beneficial product of commerce, notwithstanding its potential hazards. These are my thoughts. Hope they are helpful. DRB:ec an R. B i s h o p C07155 RS30 le sb i FE D E R A L G O V E R N M E N T EXPRESSION OF CONCERN March 5, 1971, Meeting With U.S. Producers " 'P e n ta ' Is A Useful Preservative For W ood." "Unless Pentachlorophenol Can Be Cleaned U p, We Will Probably Lose It." "T h e Subject O f Dioxins Is P retty Explosive Ahd Could Blow Up A t A ny T im e ." CO IN C ID EN TS A T T R IB U T E D TO N O N -P H EN O LIC IM PURITIES IN P O L Y C H L O R IN A T E D P H E N O L P R O D U C T S SUBJECT TO PROTECTIVE ORDER. G o v e r n m e n t Hearings O n 2 , 4 , 5 - T H e r b i c i d e s ................................................4 - 1 4 - 7 0 K i m m i g & S c h u l t z .......................................................................................................................1 9 5 7 C o o k , F . D . A . - R e p o r t T o 1 9 7 0 I . U . P . A . C ......................................................... 1 9 7 0 P o l a n d , et a l.............................................................................................................................................1 9 7 0 C h i c k E d e m a D i s e a s e ......................................................................................... PROCTER & GAMBLE (Cantrell, et al.) F.D.A. (Firestone, Campbell) U.S.D.A. (Kearney, Woolson) SWEDISH ENVIRONMENT PROTECTION BOARD - JENSEN 1958-1972 Thom as Whiteside Articles In The " N e w Y o r k e r " 1970 BULK COMPOSITION OF PENTACHLOROPHENOL P E N T A C H L O R O P H E N O L ........................... 90%a TETRACHLO RO PHENO L . . . . . . 8%a T R IC H L O R O P H E N O L ................................. 0.1%a H IG H M O LEC U LA R W E IG H T PHENOLS . 1%b NON-PHENOLIC COMPONENTS . . . . 0.5%c a Determ ined by infra-red spectroscopy and gas-liquid chrom atography fo r major and minor components. Precision = + 0.5% r.s.d. b Determined by gas-liquid chromatography of trimethylsilyl-derivatives and extraction from caustic solution and ion-exchange chrom atography c betermined by ion-exchange chromatography o Oh oh? ~hS'&L>I EXAMPLE OF A POTENTIAL ROUTE TO FORM ATION OF NON-PHENOLIC IMPURITIES IN COMMERCIAL PENTACHLOROPHENOL C l Cl + HCI subject t o SOIECTIVE O R D E R -drJuTTT3 C19: TOXICOLOGY OF 2,3,7,8-TETRACH LORODIBENZO-p-DIOXIN CM CM 05 3 Acute Lethality -:>> Single Oral LD5Q -- 0.6 mg/kg - 115 mg/kg ' It s g > Acnegenic Response -- Positive Response A t 0.04 mg/ml Chicle Edema Factor -- Positive A t 1 And 10 v f mg/kg/Day. No Effect Dose Level, 0.1 mg/ kg/Day Embryotoxicity -- Positive A t 0.6 mg/kg/Day O * yegb 1 TOXICOLOGY OF HEXACHLORODIBENZQ-p-DIOXIN Acute Lethality -- Not Documented As Y et Acnegenic Response -- Positive A t 10 - 50 mg/ml Chick Edema Factor -- Positive A t 10 And 100 mg/kg/Day o Em bryotoxicity -- Positive A t 10 m g/kg/D ay Teratogenicity -- Positive A t Dose Level Of 100 mg/kg/Day tv tv o* o r- -> TOXICOLOGY OF OCTACHLORODIBENZO-p-DIOXIN CM CT> O Acute Lethality n NOT LETHAL TO FEMALE RATS, ORAL DOSES OF 1 g/kg NOT LETHAL TO MALL MICE, ORAL DOSES OF 4 g/kg o Acnegenicity-- Negative o Teratogenicity -- Negative A t 500 m g/kg/Day Em bryotoxicity -- Positive A t 500 m g/kg/Day L Q> b I  COMMERCIAL PENTACHLOROPHENOL Monsanto Company IO Ol 05 \ Pentachlorophenol................................. 86.3% Tetrachlorophenol ................................. 4.2% H i g h e r s ................................................... 9.4% t Octachlorodibenzo-p-Dioxin i Hexachlorodibenzo-p-Dioxins . . . . . . . 1550 ppm k- I 18 ppm wI Hi o h Chloracne Response -- Positive ( 0 Un a sse ti RESULTS OF COMPARATIVE TOXICOLOGY STUDIES Ci a> kS COMMERCIAL PENTACHLOROPHENOL, DOWICIDE 7 o Responsible For Chloracne o Responsible For Production Of Chick Edema o Responsible For Histopathological Changes a BLOOD CHEMISTRY CHANGES a GROSS ORGAN CHANGES Is Not Teratogenic But Is Embryotoxic RESULTS OF COMPARATIVE TOXICOLOGY STUDIES rCQ C* Im proved Pentachlorophenol (D ow icide EC -7) A n d Pure P e n ta c h /o ro p h e n o l Do Not Cause Chloracne Do Not Cause Production Of Chick Edema Do Not Cause Histopathological Changes Not Teratogenic But Are Embryotoxic Are Equal In Acute Toxicity Are Equal In Chronic Dietary Feeding Toxicity Studies Qfr&tl lb 8M CONCLUSIONS D ER IVED FROM COM PARATIVE TOXICOLOGY STUDIES Acute Oral Toxicity Of Dowicide EC-7 Is Greater Than Dowicide 7 Dowicide EC-7 Does Not Cause Chloracne, Dowicide 7 Does Dowicide EC-7 Does Not Produce Chick Edema, Dowicide 7 Does Dowicide EC-7 Does Not Cause Histopathological Changes In Chronic Feeding Studies, Dowicide 7 Does Pentachlorophenol, Regardless Of "Grade," Is Not Teratogenic Pentachlorophenol Is Embryotoxic CV* O DOWICIDE EC-7: WHY HAS TOXICITY BEEN IMPROVED? 05 o Total Chlorinated Dioxin (And Furan) Content Has Been Significantly Reduced ( 9 Specification Of 30 ppm. Maximum Octachlorodibenzop-Dioxin Has Been Imposed O Limit Of 1.0 ppm Hexachlorodibenzo-p-Dioxins Assures Absence Of: o CHLOROACNE CAUSING IMPURITIES a CHICK EDEMA FACTOR I a HISTOPATHOLOGICAL CHANGES RESULTING FROM ' TOXIC IMPURITIES ~h&t> I Tfyb I DOW confidential -t-fcr-t-Uui. - i u a j e c r 70 P R O T E C T IV E o r d e r C19231 "tl9232 I * DOWICIDE EC-7, WITH REDUCED CHLORINATED DIBENZO-p-DIOXIN CONTENT, DOES NOT CAUSE: o Chloracne o Chick Edema o Histopafhological Changes In Chronic Feeding Studies ANALYSIS AND SPECIFICATIONS OF DOWICIDE EC-7 PENTACHLOROPHENOL f li r> P E N T A C H L O R O P H E N O L .............................................. T E T R A C H L O R O P H E N O L ......................................................................... T R I C H L O R O P H E N O L ..................................... ..................................... H I G H E R S ............................................................................................................................... D IO XIN S 2 ,2 ,7 ,8 -T E T R A C H LO R O D IB E N Z O p - D I O X I N ........................................................................................... H EXA C H LO R O D IB EN ZO -p -D IO XIN S . . . O C TA C H LO R O D IB EN ZO -p -D IO XIN . . . . 88-93% 12-7% < 0. 1% 0. 1% < 0.05 ppm 1.0 ppm M A X . 30 ppm M A X .  ANTIMICROBIAL EFFICIENCIES (.VI bl CONFIDE TEST FUNGI Trichoderma viride, ATCC No. 8678 Trichoderma sp.. Madison P-42 Ceratocystis pilifera, ATCC No. 15457 Polyporus tulipiferae, ATCC No. 11245 Rhizopus stolonifer, ATCC No. 6227a Lenzites trabea, Madison 617 Ceratocystis ips, ATCC No. 12860 Chaetomium globosum, ATCC No. 6205 Aspergillus niger, ATCC No. 6275 % DOWICIDE EC-7 FOR INHIBITION 0.0025-0.005 0.001-0.0025 0.0005-0.001 < 0.0001 0.0001-0.00025 0.0001-0.00025 0.001-0.0025 0.0001-0.00025 0.001-0.0025 Lb9>b\ ANTIMICROBIAL EFFICIENCIES TEST BACTERIA % DOWICIDE EC-7 FOR INHIBITION Bacillus cereus var. mycoides, ATCC No. 11778 Staphylococcus aureus, ATCC No. 6538 Bacillus subtills, ATCC No. 8473 Escherichia coli, ATCC No. 11229 Salmonella choleraesuis, ATCC No. 10708 Pseudomonas aeruginosa, ATCC No. 15442 Enterobacter aerogenes, ATCC No. 13048 Strbptomyces grlseus, ATCC No. 10137 Flavobacterium arborescens, ATCC No. 4358 0.0005-0.001 0.00025-0.0005 0.005-0.01 0.025-0.05 0.01-0.025 0.1-0.25 0.05-0.1 0.0005-0.001 0.00025-0.0005 eo Ci >-h$kl From The Desk Of LARRY ATKINS (/] <<? * \ i NTIALC O iV F / F ; ^ c r ro p'RjOtTtE.CriVE ORDER u rn jrn a -pep C192 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY BEFORE THE ADMINISTRATOR In re: The Dow Chemical Company, ) ) ) et a l . ) _______ ) FIFRA Docket Nos. 415, et a l . */ DIRECT TESTIMONY OF DR. LENNART HARDELL Scheduled Date of Testimony: September 29, 1980 */ EPA Exhibit No. 762 D o r o t h y E. P a t t o n K e v i n M. L ee P a t r i c i a A. Roberts R i c h a r d P. Bozof T i m o t h y D. B a c k s t r o m Andrew G . Gordon Karl 0. Bayer J o h n W. O ' D o n n e l l Counsel for Respondent U.S. Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY BEFORE THE ADMINISTRATOR In re: The Dow Chemical ) ) ) Company, et a l . ) _____ ) FIFRA Docket Nos. 415, et a l . V DIRECT TESTIMONY OF DR. LENNART HARDELL My name is L e n n a r t Hardell. I r e c e i v e d my medi c a l degree from the University of Uppsala in Sweden and have sub sequently specialized in internal medicine and oncology. I am currently employed by the Department of Oncology at the Regional Hospital in Umea, Sweden. My work at the Department of Oncology includes diagnosis, treatment, and evaluation of possible causes of human cancer. My testimony concerns several epidemiological studies which my colleagues and I recently conducted in Sweden. We examined the r e l a t i o n s h i p b e t w e e n the risk for two for* m* s! of cancer, soft tissue sarcoma and malignant lymphoma, and exposure to phenoxyacetic acid herbicides and chlorophenols (Hardell and Sandstrom 1979, Exhibit 594; Eriksson et al. V EPA Exhibit No. 762 **/ Soft-tissue sarcomas are rare cancers of certain connective tissues, such as m u s c l e and fat. Since c o n n e c t i v e tiss u e s are widely distributed throughout the body, soft-tissue sarcomas are not restricted to a single physiologic site. Lymphomas are cancers of lymphatic tissue. -2 - 1980, Exhibits 763a, 763b; Hardell et a l . 1980, Exhibit 764). We found that exposure to phenoxy acids or to chlorophenols is r e lated to a s i g n i f i c a n t l y e l e v a t e d risk for these types of cancers. I . BACKGROUND My interest in the relationship between exposure to phenoxy acids and soft-tissue sarcoma began when three patients with sarcomas were admitted to the Department of Oncology in Umea in the autumn of 1976. Each of these patients reported substantial occupational exposure to phenoxy herbicides some 10-20 years earlier. Two of these patients were forestry workers who had previously worked with the phenoxy acids 2,4,5-T and 2,4-D and the third patient owned a workshop where large quantities of phenoxy acids had been stored, partly in open buckets. Prompted by these reports, I reviewed the Department of Oncology records for the period of 1970-1976 and found four additional soft-tissue sarcoma patients who reported previous exposure to phenoxy acids. I then brought this series of cases to the attention of the scientific community (Hardell 1977, Exhibit 765a, 765b). Based on these observations, my colleagues and I decided to conduct a formal epidemiologic investigation to determine Vw h e t h e r or not e x p osure to p h e n o x y h e r b i c i d e s increases the risk of developing soft-tissue sarcoma. Because soft-tissue j^/ W e also evalu a t e d the risk a s s o c i a t e d w i t h e x p o s u r e to chlorophenols, which like 2,4,5-T and silvex are known to contain chlorinated dibenzodioxins as impurities. -3 - sarcoma is a rare variety of cancer, it was apparent that a case-control (also called case-referent) study would be the most appropriate epidemiologic method to test our hypothesis. The case-control method is particularly well suited to the study of rare diseases because a case-control study begins with identification of a group of persons who have the disease (cases). After selection of an appropriate comparison group of persons free of the disease (controls), the nature of previous exposure to the suspected causal agent is then compared between the two groups and, with appropriate statistical a na l ys * i * s!, the relative risk can be estimated. for the disease In our initial case-control study (Hardell and Sandstrom 1979, Exhibit 594), which utilized subjects residing in the Department of Oncology admission area in northern Sweden, we found that exposure to phenoxy acids and to chlorophenols was 37 Relative risk is the rate at which a disease develops in exposed persons divided by the rate at which the disease develops in unexposed persons. In the absence of uncontrolled confounding factors or bias (see discussion below at p.6-9, 22-29), a relative risk of 1.0 indicates that a particular exposure is not related to the disease in question. A relative risk significantly greater than 1.0 indicates that exposure increases the risk of developing the disease, while a relative risk significantly less than 1.0 indicates that exposure provides protection against the disease. **/ In contrast, a cohort study compares the incidence of disease in an exposed population directly to the incidence of disease in an unexposed population. In order to yield meaningful data on the risk for a rare type of cancer such as soft-tissue sarcoma, a cohort study would probably have to be large and cover a long period of time. -4associated with a significantly elevated risk for soft-tissue sarcoma. We also employed the case-control method in a subse quent study of soft-tissue sarcoma and exposure to phenoxy acids and chlorophenols in an agricultural region in southern Sweden (Eriksson et al. 1980, Exhibits 763a, 763b). This second study, which was conducted at the request of the Swedish Board of Occupational Safety and Health, corroborated our initial findings in a separate and different population. My interest in the possible relationship between exposure to phenoxy acids and malignant lymphoma began in May, 1978, when a patient with a tumor in the soft-tissue of his left femur was admitted to the Department of Oncology. Although the clinical picture resembled that of a soft-tissue sarcoma, histological examination indicated a malignant lymphoma of the histiocytic type. The patient reported prior exposure to phenoxyacetic acid herbicides. I then questioned seventeen male patients with the same type of tumor admitted to the Department of Oncology between January and September 1978 about their past and present occupation and possible exposure to phenoxyacetic acids or chlorophenols. Fourteen of these seventeen patients reported a current occupation consistent with the possibility of exposure and eleven of these patients reported prior exposure to phenoxy herbicides or chlorophenols (Hardell 1979, Exhibit 766). Prompted by these clinical observations, my colleagues and I conducted a third case-control study (Hardell et al. -5 - 1980, Exhibit 764) in the same geographic region where the first soft-tissue sarcoma study had been conducted. In this study, we found that a significantly elevated relative risk for malignant lymphoma was associated with previous exposure to phenoxy acids and to chlorophenols. In the following section, I will review mthodologie considerations that were important in all three studies. Following that, I will discuss our findings in these studies, some general concerns in interpretation of our findings, and the conclusions that may be drawn from them. I I . METHODOLOGY Each of our three case-control studies was carefuly designed to minimize the likelihood of spurious or misleading results and to enable a meaningful evaluation of the risks associated with the exposures studied. This section discusses some of our basic mthodologie concerns and describes the tech niques we utilized in selection of cases, selection of control subjects, assessment of exposure, and calculation of relative risk. A . Selection of Cases The first step in a case-control study is the selection of a group of subjects who have the disease in question. In our first soft-tissue sarcoma study and our lymphoma study, we identified cases by reviewing the records of patients previously treated at the Department of Oncology in Umea. Cases in the second soft-tissue sarcoma study were obtained from the Cancer -6Registry of the Swedish Social Welfare Board and were sarcoma patients who resided in a particular region of southern Sweden at the time of diagnosis. In all three studies, tumor slides from each patient were examined by pathologists in order to verify the initial histologic diagnosis. In each instance, these pathologists had no information concerning any patient's prior exposure history. B . Selection of Controls After selection of each group of diseased patients, we selected a corresponding group of controls. In general, it is d e s i r a b l e to use a m e t h o d for s e l e c t i n g controls w h i c h is designed to minimize the influence of confounding factors. These are factors that are associated with both the probability of developing the disease and the probability of exposure to the suspect agent. Inadequate attention to confounding factors can produce a misleading estimate of relative risk. For example, consider a hypothetical case-control study of breast cancer and exposure to household cleaners in which the investigators failed to consider sex in selection of control subjects. This oversight could result in a spurious elevation of the relative risk, if the group of cases (subjects with breast cancer) contained a higher proportion of women, who are both more likely to develop breast cancer and to use household cleaners, than the group of controls. In such a study, the sex of the subjects would be a confounding factor. -7- One effective way of controlling for the possible influence of confounding factors is to match cases and controls indivi dually for comparability as to possible confounding factors. For statistical reasons, matching should be limited to a small set of the most likely confounding factors. In each of our studies, we matched two or more controls to each case Von the b a s i s of t h r e e p o s s i b l e c o n f o u n d i n g factors: sex, age, and place of residence. As will be discussed below, we also considered a number of other possible confounding factors in analyzing the results of each study. C . Assessment of Exposure After selection of cases and controls, we investigated the exposure history of each case and control, including information on possible carcinogenic agents to which the subject had previously been exposed and the nature and duration of such exposure. Although adequate exposure information may sometimes be derived from occupational or historical records, such records are often fragmentary or inadequate, especially when exposure is not limited to particular groups in the subject population or the disease in question exhibits a long latency period prior to clinical detection. Accordingly, exposure information in case-control studies is most commonly obtained b y questioning or interviewing the subjects (McMahon and Pugh 1970, Exhibit 767). J7 In addition, d e c e a s e d controls w e r e s e l ected for d e c e a s e d patients and matched for year of death. In each of our studies, exposure information was obtained by written questionnaires and was supplemented by interviews. When exposure information is obtained from the subjects, care must be taken to avoid the possibility that the subjects' attitudes and experiences will introduce bias into the investi gator's ascertainment of exposure (Axelson 1980, Exhibit 597a). One possible source of such bias could be a tendency, conscious or not, for those suffering from a disease to overstate past exposure as compared to healthy controls. In recognition of this potential problem, we designed each of our studies to minimize the possibility of such recall bias. Each subject or next-of-kin of a deceased subject received a questionnaire by mail, which was subsequently supplemented by a telephone interview. Each questionnaire contained a variety of extraneous questions concerning previous and present occupation, conditions in the occupational environment, smoking habits, etc., avoiding any special attention to phenoxyacetic acid or chlorophenol exposure (see Exhibits 768a, 768b). Supplementary interviews were conducted by individuals who did not know whether the subjects were cases or controls. Employers, neighbors, and other individuals who might have special knowledge concerning a subject's past exposure were consulted by questionnaire or telephone to verify and monitor the accuracy of exposure information. In addition, deceased controls were selected for deceased patients, in order to avoid any bias which might -9 - result from differences in recall between live subjects and deceased subjects' next-of-kin. The potential risks associated with use of phenoxy acids, including their possible carcinogenic and teratogenic effects, have been vigorously debated in Sweden. Despite our precautions, we could not completely exclude the possibility that diseased individuals might be inclined to exaggerate their past exposure as compared to healthy controls. Thus, we also analyzed our results for indications of residual observational bias by utilizing a statistical technique recently developed by Dr. O l a v A x e l s o n (Axelson 1980, E x h i b i t 597a). Dr. A x e l s o n is a leading Swedish epidemiologist who has also been conducting an ongoing study of a cohort of railroad workers exposed to phenoxy acids and other herbicides. He provided methodological assistance to my colleagues and me in designing and evaluating all three of our case-control studies. The results of our analyses using Dr. Axelson's technique are described in a later section. They suggest that bias in the observation of exposure, if present at all in our studies, was very slight. After collecting exposure information, we classified each' case and control as exposed or unexposed for each category of substances studied. Phenoxy acid preparations have been used extensively in Swedish forestry and agriculture (Barring 1978, Exhibit 769; G r a n s t r o m 1978, Exhibit 770), and individuals classified as exposed to phenoxy acids generally were or had -10- V been forestry or agricultural workers. Most subjects classified as exposed to phenoxy acids reported they had performed jobs involving application of phenoxy acids, such as knapsack spraying, basal-bark spraying, tractor-mounted spraying, operation of mistblowers, stump painting, and notching. A recent study has documented the presence of 2.4.5- T and 2,4-D residues in the blood and urine of Swedish forestry workers engaged in tractor-mounted spraying of 2.4.5- T and 2,4-D. (Kolmodin-Hedman et a l . 1979, Exhibits 517a, 517b). In our studies, we also classified some subjects as exposed to phenoxy acids who reported wet clothes or skin contact while working on wet ground which had been sprayed with phenoxy acids. Individuals who worked in areas previously sprayed with phenoxy acids but who did not report any wet contact were classified as unexposed. In instances where the reported exposure to phenoxy acids was uncertain or less than one day in duration, subjects were classified as unexposed. D . Calculation of Relative Risk In studies where cases and controls have been individually matched to avoid confounding, different formulas for calculating the relative risk may be used, depending upon whether or not Subjects classified as exposed to chlorophenols consisted primarily of individuals employed in sawmills, (see Levin et al., 1976, R e f e r e n c e 1) p a p e r p u l p operations, or p a i n t i n g with wood preservatives. -li the matching is taken into account. When, as in our studies, each case is a s s i g n e d two or m o r e controls, the c a l c u l a t i o n of relative risk using the matched material is relatively complicated (Miettinen 1970, Reference 2). Calculation of relative risk without matching is considerably simpler. The procedure we followed in each of our studies was to calculate the relative risk both with and without matching in the initial analysis (including all subjects and considering exposure to phenoxy acids and/or chlorophenols). In each study, we found that the matched analysis gave slightly higher values for relative risk than the unmatched method. This indicated to us that the confounding factors we matched for did not bias the result (See Miettinen 1972, Reference 3). Consequently, we were able to greatly simplify the subsequent calculations in each study by dissolving the matching, recognizing that use of the matched material would yield somewhat higher, not lower, estimates of relative risk. III. RESULTS OF OUR RESEARCH A. The First Soft-Tissue Sarcoma Study In our first study (Hardell and Sandstrom 1979, Exhibit 594), the 52 cases consisted of 21 living and 31 deceased male patients with soft-tissue sarcoma, ranging in age from 26 to 80 years, who were treated at the Department of Oncology between 1970 and 1977. We selected four control subjects for each case and matched the cases and controls on the basis of sex, age, place of residence, and vital status. Deceased cases and controls were matched for year of death. -12 - In this study, 19 of the 52 sarcoma patients (36.5%) and 19 of the 206 controls (9.2%) reported previous exposure to phenoxy acids or chlor o p h e n o ls , Of the 19 exposed cases, 12 reported exposure to phenoxy acids, 6 to chlorophenols, and one to both. Of the 19 exposed controls, 13 reported exposure to phenoxy acids, 5 to chlorophenols, and one to both. Among those reporting exposure to phenoxy acids, combined exposure to 2,4,5-T and 2,4-D was by far the most common exposure history (9/13 cases, 8/14 controls). Other subjects reported exposure to 2,4,5-T or 2,4-D separately or to MCPA (4-chloro-2- methyl phenoxyacetic acid). The relative risk for soft-tissue sarcoma associated with exposure to phenoxy acids and/or chlorophenols in the matched */ material was 6.2 (95% confid e n c e interval 3.0 - 12.6, p <0.001). Without matching, the relative risk was 5.7 (95% confidence interval 2.9-11.3, p <0.001). These relative risks suggest that persons occupationally exposed to phenoxy acids and/or chlorophenols are approximately six times more likely to ^_/ T h e 95% c o n f i d e n c e interval indicates the range of values for relative risk in which there is a 95% probability that the actual value lies. The p-value, or level of statistical significance, is the probability that the calculated estimate of relative risk could have arisen solely by random variaton (in this case, less t h a n 1 c h ance in 1,000). P - v a l u e s w e r e determined from the standard chi square test of statistical significance. 95% confidence intervals were calculated by the test-based method of Miettinen (Miettinen 1976, Reference 4). Therefore, if the lower limit of the 95% confidence interval is greater than 1.0, p is less than 0.05. All reported values for our studies are derived from two-tailed tests of significance. -13develop soft-tissue sarcoma than similar persons not exposed to these substances. Since the relative risk by the matched method was slightly greater than by the unmatched method, we concluded that retention of matching was unnecessary and simplified subsequent calculations by dissolving the matching. We determined the relative risk for soft-tissue sarcoma associated with exposure to phenoxy acids alone by excluding all cases and controls reporting exposure to chlorophenols and repeating the analysis. This procedure yielded a relative risk of 5.3 (95% confidence interval 2.4-11.5, p <0.001). When all subjects reporting exposure to phenoxy acids were excluded, the relative risk associated with chlorophenol exposure was 6.6 (95% confidence interval 2.8-15.6, p <0.001). Therefore, we could not attribute the increased risk for exposed individuals either to phenoxy acids or to chlorophenols, as both exposures were independently associated with increased risk. However, we noted that both groups of chemicals contain chlorinated dibenzodioxins as impurities. The inference that the excess risk for soft-tissue sarcoma associated with exposure to phenoxy acids and to chlorophenols may be related to dioxin contamination is consistent with the unexpected occurrence of soft-tissue sarcomas in relatively small cohorts of individuals occupationally exposed to 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD). A single death from a soft-tissue sarcoma was observed in a cohort of 121 individuals -14exposed to TCDD in a 1949 trichlorophenol process accident (Zack and Suskind, 1980, Exhibit 771). Although the investi gators did not draw any conclusion from this observation, they described it as a "rare" event. Moreover, an additional death from a soft-tissue sarcoma has recently been reported in a cohort of only 61 trichlorophenol production workers exposed to TCDD in 1964 (Cook et al. 1980, Exhibit 772). B . The Second Soft-Tissue Sarcoma Study Following completion of the first soft-tissue sarcoma study, we conducted a second soft-tissue sarcoma study in another part of Sweden, using different patients and controls but the same study method (Eriksson et a l . 1980, Exhibits 763a, 763b). The first study, in which the cases were patients treated at the University Hospital in Umea, included subjects residing in the three most northern counties in Sweden. In the first study, subjects exposed to phenoxy acids were primarily workers in forestry. In the second study, we studied patients and controls from an agricultural region in the five most southern counties in Sweden. This new study was initiated partly to determine whether or not the results we observed in the first study could be replicated in a different geographical area, and partly to determine whether or not agricultural exposure to phenoxy herbicides which are not known to contain measurable levels of chlorinated dibenzodioxins (e.g. 2 , 4 , -D, MCPA, mecoprop, dichlorprop) might also be associated with an increased risk for soft-tissue sarcoma. \<VM -15 - In the second study, the 110 cases c o n s i s t e d of 72 living and 38 deceased male patients with soft-tissue sarcomas diagnosed and reported to the Swedish Cancer Registry between 1974 and 1978. Patients ranged in age from 25 to 75 years and were living in the five southernmost counties of Sweden at the time of diagnosis. Two control subjects were selected for each case and matched on the basis of sex, age, place of residence, and vital status. Deceased controls were matched with deceased cases for year of death. Analyses were conducted in the same manner as in the first study. In the second study, 25 of the 110 sarcoma patients (22.7%) and 13 o f the 219 control s (5.9%) r e p o r t e d e x posure to p h e n o x y acids or ch l o r o p h e n o ls . Of the 25 exposed cases, 14 reported exposure to p h e n o x y acids and 11 to c h l o r ophenols. Of the 13 exposed controls, 5 reported exposure to phenoxy acids and 8 to chlorophenols. Among those reporting exposure to phenoxy acids, exposure to 2,4,5-T was less prevalent than in our first study, although combined exposure to 2,4,5-T and 2,4-D was still a common exposure h i s tory (7/14 cases, 1/5 controls). The relative risks associated with exposure to phenoxy herbicides and chlorophenols were essentially comparable to those obtained in the first study. (See Table 1). The relative risk for soft-tissue sarcoma associated with exposure to phenoxy acids and/or chloropehnols in the matched material was 5.1 (95% c o n f i dence interval 2.5-10.4, p <0.001). Since the corresponding relative risk without matching was 4.7 (95% confidence interval 2.6-8.5, p <0.001), matching was dissolved for all subsequent -16- TABLE 1 Relative Risks for Soft-Tissue Sarcoma in Two Case-Control Studies Exposure category Study location Northern Sweden3 Southern Sweden0 Phenoxy acids and/or chlorophenols Phenoxy acids only Chlorophenols only 5.7(6.2)* 5.3 6 .6 4.7(5.1)* 6 .8 3.3** V Estimates in parentheses were calculated from matched material. All others derived from unmatched material. * * / p < 0 .01. For all o the r r e l a t i v e risks, p < 0 .001. Sources: a. Hardell a n d S a n d s t r o m 1979, E x h i b i t 594. b. E r i k s s o n et a l . 1980, E x h i b i t 753a. -17- calculations. When all subjects reporting exposure to chloropenols were excluded, the relative risk for soft-tissue sarcoma associated with exposure to phenoxy acids was 6.8 (95% confidence interval 2.6-17.3, p <0.001). After exclusion of subjects reporting exposure to phenoxy acids, the relative risk associated with chlorophenol exposure was 3.3 (95% confidence interval 1.3-8.1, p <0.01). In the second sarcoma study, we also looked for evidence of a dose-response relationship between exposure to phenoxy acids and the risk for soft-tissue sarcoma by calculating relative risks separately for groups of subjects with different exposure durations. Workers reporting exposure to phenoxy acids for more tha n 30 days had a relative risk of 8.5, w h i l e those reporting exposure for less than 30 days h a d a relative risk of 5.7. Although this difference in relative risk in relation to duration of exposure is not statistically significant, it is consistent with a possible dose-response relationship. Because the second study was conducted in an agri cultural region, sufficient numbers of cases and controls were exposed to phenoxy herbicides not known to be contaminated with dioxin (MCPA, 2,4-D, mecoprop, dichlorprop) to enable a separate analysis of the risk associated with these herbi cides. Exposure to these substances was associated with a significantly elevated relative risk of 4.2 (95% confidence 3 -18 - interval 1.3-13.4, p<0.025). */ This finding raised the possibility that the phenoxy acids themselves, rather than dioxin contaminants, might be responsible for the increased risk for soft-tissue sarcoma. Alternatively, it is possible that these phenoxy acids are contaminated with dioxin at concentra tions below the limit of detection. C . The Lymphoma Study Like the first sarcoma study, our case-control study of malignant lymphoma was initiated in response to clinical obser vations at the Department of Oncology in Umea. Because lymphoma is also a relatively rare disease and our Department records provided a convenient source of cases, we again chose the case-control method of study (Hardell et al. 1980, Exhibit 764). The 169 cases in this study consisted of 107 living and 62 deceased male patients with various types of lymphoma, ranging in age from 25 to 85 years, who were treated at the Department of Oncology in Umea between 1974 and 1978. We selected two control subjects for each case and matched for sex, age, place of residence, and vital status. Deceased controls were matched with deceased cases for year of death. The relative risk for lymphoma associated with exposure to phenoxyacetic acids and/or chlorophenols in the matched jV In contrast, the relative risk for subjects reporting exposure to 2,4,5-T, alone or in combination with other phenoxy acids, was 17.0. -19 - material was 6.0 (95% confidence interval 3.7-9.7, p<0.001). After dissolving the matching, the relative risk was 5.3 (95% confidence interval 3.4-8.3, p<0.001). As in the sarcoma studies, these results indicated that further analysis could be simplified by dissolving the matching. After excluding persons reporting exposure to chlorophenol the relative risk associated with exposure to phenoxy herbi cides (primarily 2,4,5-T and 2,4-D) was 4.8 (95% confidence interval 2.9-8.1, p < 0 .001). Workers reporting exposure to p h e n o x y acids for m o r e th a n 90 days h a d a r e l a t i v e risk of 7.0, w h i l e those r e p o r t i n g exp o s u r e for less t h a n 90 days h a d a relative risk of 4.3. As in the second sarcoma study, this observed difference in relative risk was not statistically significant, but was consistent with a possible dose-response relationship. After excluding subjects reporting exposure to phenoxy acids, exposure to chlorophenols was associated with a relative risk of 4.3 (95% confidence interval 2.7-6.9, P <0.001). These findings were quite similar to those in the two soft-tissue sarcoma studies: a statistically significant increase in the relative risk for lymphoma was associated with exposure to phenoxy acids and to chlorophenols. Because a recent study suggests an increased risk for malignant lymphoma in occupational groups exposed to benzene (Vianna and Polan 1979, Reference 5), and a number of subjects in our study reported exposure to substantial amounts of 5 -2 0 - various organic solvents, we also evaluated the risks associated with exposure to organic solvents. High exposure to organic solvents was associated with a significantly elevated relative risk for lymphoma, which was most pronounced for exposure to certain solvents which are suspected mutagenic or carcinogenic agents (benzene, trichloroethylene, perchloroethylene, and styrene). The relative risk for all individuals reporting exposure to organic solvents, excluding those also reporting exposure to phenoxy acids or chlorophenols, was 2.4 (95% confidence interval 1.5-3.8 P<0.001). An especially strong association with lymphoma was observed in individuals reporting exposure to both organic solvents and phenoxy acids or chloro phenols, who had a relative risk of 8.5 (95% confidence interval 4.2-17.2, p < 0 .001). These results suggest that the association of lymphoma with exposure to phenoxy acids and chlorophenols was not due to confounding by exposure to organic solvents, and that separate increases in risk are attributable to each category of substances. This study indicates that exposure to phenoxy herbicides such as 2,4,5-T or to chlorophenols is a risk factor for mal i g nant lymphoma. The presence of chlorinated dibenzodioxins as impurities in 2,4,5-T and chlorophenols suggests one possible mechanism underlying the observed excess risk for lymphoma. Animal tests indicate that dioxins, particularly 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), suppress cell-mediated immunity (Vos et al. 1973, Reference 6). Defects in cell-mediated immunity b -21in humans have been associated with Hodgkin's lymphoma (Bjorkholm et a l . 1977, Reference 7), and the incidence of histiocytic lymphoma is 350 times greater in kidney transplant patients with deliberately induced immunological deficiencies than in the general population (Penn 1978, Reference 8). Thus, it is possible that the elevated risk for lymphoma associated with exposure to phenoxy herbicides such as 2,4,5-T and to chlorophenols is related to immunologic effects resulting from exposure to dioxin contaminants in these products. The hypothesis that the observed excess risk for lymphoma among individuals reporting exposure to phenoxy herbicides or to chlorophenols is related to dioxin contamination is consistent with other epidemiological evidence of the effects of TCDD exposure. A recent cohort study of mortality among individuals exposed to TCDD in a 1949 trichlorophenol process accident (Zack and Suskind 1980, Exhibit 771) indicates that TCDD-exposed workers have an elevated incidence of lymphatic and hematopoietic cancer. Even though no hypothetical induction or latency period was used in evaluating cancer mortality, 3 deaths from lymphatic and hematopoietic neoplasms were observed as compared to 0.88 deaths expected. All three observed deaths occurred more than 20 years after exposure to TCDD. The investigators did not calculate risk ratios or significance levels for types of mortality with fewer than five observed deaths. However, the excess incidence of lymphatic and hematopoietic cancer would be statistically s i g n i f i c a n t (p <.05) aft e r i n c l u s i o n of any r e a s o n a b l e l a t e n c y period in the analysis. -2 2 - I V . INTERPRETATION OF OUR FINDINGS Proper interpretation of epidemiological data depends in part on assessment of the possible effect of bias or confound ing on the observed results. We designed each of our casecontrol studies to minimize the chance that our results would be influenced by bias or confounding. However, although we were able to control the potential impact of certain factors by application of proper study design techniques, we could not entirely eliminate the possibility of uncontrolled bias or confounding. Thus, we also evaluated the results in each of our studies for evidence of potential problems such as bias in the observation of exposure or confounding by concurrent exposure to causative factors other than phenoxy acids. A. O b s e r v a t i o n a l Bias The possibility of bias in the observation of exposure was an important methodological concern in each of our studies. Accordingly, we utilized a number of techniques to reduce the likelihood of observational bias, including addition of questions regarding extraneous matters, blinding of interviewers to whether a particular subject was a case or control, independent questioning of the subjects' employers and acquaintances, and selection of deceased controls for deceased cases. However, since the potential risks associated with the use of phenoxy acids have been the subject of considerable controversy in Sweden and the ascertainment of exposure in our studies was based primarily on recall, we were still concerned about the <5 -23- possibility that diseased individuals or their next-of-kin might be inclined to overstate exposure as compared to controls or their next-of-kin. Therefore, we also used a statistical technique developed by Dr. Axelson (Axelson 1980, Exhibit 597a) to evaluate the results of our studies for evidence of the presence of observational bias. T a b l e 2, w h i c h is d e r i v e d from the resu l t s o f o ur second Vsarcoma study, p r o v i d e s an e x a mple of the a p p l i c a t i o n o f Dr. Axelson's technique. By dividing the subjects between those employed in occupations where exposure to phenoxy acids is common (agriculture and forestry) and those employed in other occupations, separate relative risks can be calculated for exposed and unexposed workers in agriculture and forestry, as compared to unexposed persons in other occupations. If cases were inclined to substantially exaggerate their exposure, this bias would increase the number of exposed cases in occupations where exposure is common (in this instance, 13), creating an artifical deficit in unexposed cases in these occupations (in this instance, 17). Thus, the presence of substantial recall bias should result in a relative risk considerably below 1.0 when unexposed individuals in agriculture 37 D r . Axelson's observational bias technique had not yet been developed at the time our first sarcoma study was completed. The Swedish version of our second sarcoma study included a separate application of Dr. Axelson's technique in which subjects exposed to chlorophenols were also included. -2 4- TABLE 2 EXPOSURE TO PHENOXY ACIDS IN THE SECOND SARCOMA STUDY DIVIDED BY OCCUPATION Cases Controls Agriculture/forestry Exposed Unexposed 13 17 5 39 Other Occupations Unexposed 68 167 R e l a t i v e Ri sk 6.4 1 .1 (1.0) Source: Eriksson et a l . 1980. Subjects exposed to chlorophenols are excluded. One case and no controls exposed to phenoxy acids were employed in occupations other than agriculture and forestry. TABLE 3 EXPOSURE TO PHENOXY ACIDS IN THE LYMPHOMA STUDY DIVIDED BY OCCUPATION Agriculture/forestry Exposed Unexposed Cases 35 37 Controls 23 114 Relative Risk 4.1 0.9 Other Occupations Unexposed 71 189 (1.0 ) Source: Hardell et a l . 1980. Subjects exposed to chlorophenols are excluded. Six cases and one control exposed to phenoxy acids were employed in occupations other than agriculture and forestry. 25 and forestry are compared to unexposed individuals in other */ occupations. However, in this instance, the relative risk was 1.1. The comparable relative risk for our lymphoma study was 0.9 (see Table 3). These calculations indicate that bias in the observation of exposure to phenoxy acids, if present in either of these studies, did not substantially influence the results. My colleagues and I have recently conducted a new case-control study to obtain further evidence concerning the likely magnitude of observational bias in our soft-tissue sarcoma and lymphoma studies. In this new study, we evaluated the relation between exposure to phenoxy acids and the risk for colon cancer, a type of cancer not previously suspected of being associated with exposure to phenoxy acids. We utilized the same basic study design employed in our first three studies. Discussion of phenoxy acids and their presumed risks in the Swedish media was especially intense during the period when this new study was conducted. Accordingly, any observational bias present in the first three studies should also be present in this study. We have just completed a preliminary 37 In contrast, the presence of an independent risk factor among individuals in agriculture and forestry not also exposed to phenoxy acids could result in a relative risk above 1.0. Thus, it is theoreticaly possible that confounding by an occupational variable which is not closely related to phenoxy acid exposure could compensate for the statistical effect of a possible observational bias. However, since we found no evidence of this type of independent occupational risk factor, such an ad hoc hypothesis is inappropriate. -26- analysis of the data in this new study and will publish our findings soon. B . Confounding Factors In each of our studies, cases were individually matched to controls on the basis of sex, age, place of residence, and year of death. This procedure resulted in a comparable distri bution of these characteristics in the cases and controls, thereby minimizing the influence of these characteristics as possible confounding factors. We also evaluated the possible confounding effect of smoking habits in each study and could detect no apparent difference between cases and controls. Our studies found a higher incidence of soft-tissue sarcoma and of lymphoma in occupations where exposure to phenoxy acids or chlorophenols is common than in other occupations. Thus, we also evaluated the possible confounding influence of other types of occupational exposures, in order to determine whether or not the observed excess risk might be attributable to some occupational factor other than phenoxy acid or chlorophenol exposure. In the first sarcoma study, we studied DDT exposure and exposure to exhaust from motorized sawing and found no significant increase in risk was associated with these exposures. In the second sarcoma study, we analyzed the possible confounding influence of a number of occupational factors, including exposure to organic solvents, DDT, exhaust from motorized sawing, mercury seed dressings, asbestos, glass fiber, and a variety of other pesticides. Although reported exposure -27- to these other occupational factors tended to be somewhat higher among cases than controls (see T a b l e V, Exhibit 763a), no other studied exposure varied nearly as much between cases and controls as exposure to phenoxy acids and to chlorophenols. Moreover, none of the relative risks for soft-tissue sarcoma associated with more common exposures such as organic solvents, DDT, and mercury seed dressings were significantly elevated. The total percentage of subjects who reported exposure to pesticides other than phenoxy acids or chlorophenols was higher among cases (21.8%) than controls (11.0%). However, after excluding subjects who also reported exposure to phenoxy acids or chlorophenols, the per centage of subjects who reported exposure to other pesticides was roughly comparable among cases (9.5%) and controls (8.0%). Thus, the observed difference in exposure to other pesticides between cases and controls was probably due to an incidental occupational relationship between use of phenoxy acids or chlorophenols and use of other pesticides. Each of our soft-tissue sarcoma studies found an association between exposure to phenoxy acids and a significantly elevated cancer risk, although the studies were conducted in different geographic and occupational settings. Phenoxy acid exposures in the first study in northern Sweden occurred primarily in forestry work, while phenoxy acid exposures in the second study in southern Sweden occurred more frequently in agri cultural work. The similar results in each study, despite -2 8 - differences in the occupational context in which phenoxy acid exposure occurred, increased our confidence that the observed association of exposure to phenoxy acids and softtissue sarcoma was not due to occupational confounding. In our lymphoma study, we evaluated the possible confounding effect of a similar series of occupational factors, including exposure to DDT, mercury seed dressings, diesel oil, exhaust from motorized sawing, asbestos, glass fiber, and a variety of other pesticides. Although reported exposure to DDT, mercury seed dressings, asbestos, and glass fiber was somewhat higher among cases than controls, the differences were not nearly as pronounced as those for exposure to phenoxy acids and c h l o r o p h e n o l s (See T a b l e 6, E x h i b i t 764). As in our second sarcoma study, the differences in exposure to these other agents between cases and contols were probably due to an incidental occupational relationship between use of these other agents and use of phenoxy acids or chlorophenols. In general, we found no evidence in any of our studies of any uncontrolled confounding factors which could account for the observed relation between phenoxy acid exposure and an elevated risk for soft-tissue sarcoma and lymphoma. On Vthe other hand, w e could not identify a n y specific p h e n o x y acid or.contaminant as the principal causative factor. jVFor example, exposure to 2,4,5-T was most often reported in combination with exposure to 2,4-D. Thus, the observed excess risk for cancer associated with exposure to 2,4,5-T could be attributable to 2,4,5-T itself, TCDD contamination in the 2,4,5-T, concurrent exposure to 2,4-D, or a combination of these factors. V In addition, it is possible that the observed increases in relative risk were related to some as yet unidentified factor which is closely associated with use of phenoxy acids. Nevertheless, it is most likely that the observed excess risk for human cancer was associated with the phenoxy acids themselves, impurities in the commercial preparations, or a combination of these factors. V. CONCLUSION Two separate case-control studies have demonstrated that occupational exposure to phenoxyacetic acid herbicides (primarily 2.4.5- T and 2,4-D) is associated with a statistically signifi cant fourfold to sevenfold increase in the risk for soft-tissue sarcoma. Exposure to chlorophenols, which like 2,4,5-T are contaminated with chlorinated d i b enzodioxins, is also associated with a significantly elevated risk for soft-tissue sarcoma. However, in one study a significant association was also found between soft-tissue sarcomas and exposure to phenoxy acids which do not contain measurable dioxin. Thus, the excess risk for soft-tissue sarcoma in individuals reporting exposure to 2.4.5- T and 2,4-D may be related to TCDD contamination in the 2.4.5- T, the p r o p e r t i e s of the p h e n o x y h e r b i c i d e s themselves, or a combination of these factors. Another case-control study indicates that exposure to phenoxyacetic acids and to chlorophenols is also associated with a significantly elevated risk for lymphoma. Since lymphomas are known to be more prevalent in individuals -30- wit h d eficient immunological competence, it is possible that the observed increase in relative risk is related to immunologic depression caused by exposure to the dioxin contaminants in 2,4,5-T and chlorophenols. Each of these studies was carefully designed to minimize the likelihood of spurious or misleading results. Cases and controls were individually matched on the basis of a set of potential confounding factors. A number of measures were employed to avoid systematic bias in the ascertainment of the subjects' exposure histories, including questions concerning extraneous variables, interviewers unaware of whether a subject was a case or control, verification of exposure by employers and acquaintances, and selection of deceased controls for deceased patients. In addition to use of appropriate study design techniques, we also evaluated the results of each study for evidence of problems such as confounding by concurrent occupational exposure or residual observational bias. Although exposure to some factors other than phenoxy acids and chlorophenols tended to be higher among cases than controls, exposure to these factors among cases and controls not also exposed to phenoxy acids or chlorophenols was quite similar, indicating an incidental occupational connection. Thus, although we cannot absolutely rule out confounding by some unknown factor related to exposure to phenoxy acids and chlorophenols, we -3 1- found no evidence of any uncontrolled confounding factors which could account for the observed increases in relative risk found in our studies. The potential hazards associated with use of phenoxyacetic acid herbicides have been vigorously debated in Sweden. Thus, d e s p i t e o u r p r e c a u t i o n s , a p o s s i b i l i t y r e m a i n e d that, diseased individuals might be inclined to overstate their past exposure as compared to controls. In recognition of this possibility, we employed a new statistical technique to determine whether or not our findings were substantially influenced by observational bias. Utilizing this technique, We found no evidence of an observational bias sufficiently large to account for the observed increases in relative risk. For each of our major findings, the chances were less than one in a thousand that the observed relative risk could have occurred solely as a result of random variation. Research into the health effects of environmental agents, whether conducted in the laboratory or the clinical setting, is s e ldom c o n c l u s i v e and additional research is n e a r l y always warranted. Nevertheless, in the absence of any evidence that uncontrolled confounding factors or bias seriously distorted these stuies, our findings must be regarded as strong evidence of a causal relationship between exposure to phenoxy herbicides and human cancer. (tib) Lennart Hardell, M.D. -32- EXHIBITS Exhibit No. 5 94 Hardell, L. and A. Sandstrora 1979. C a s e - c o n t r o l study: Soft-tissue sarcomas and exposure to phenoxyacetic acids o r c h l o r o p h e n o l s , Brit. J. C a n c e r 39: 711-717. 597a Axelson, 0. 1980. A note on observational bias in casereferent studies, Scand. J. W o r k Env. H e a l t h 6: 80-82. 763a Eriksson, M., L. Hardell, N. Berg, T. Moller, and 0. A xelson 1980. Soft-tissue sarcomas and exposure to chemical substances: a case-referent study. Br. J. Ind. Med. (in press). 76 3b Table: Type and duration of exposure for cases and referents exposed to phenoxyacetic acids in Eriksson et al. 1980. 764 Hardell, L . , M. Eriksson, P. Lenner, and E. L u n d g r e n 1980. Malignant lymphoma and exposure to chemical substances, especially organic solvents, chlorophenols and p h e n o x y acids. A cas e - c o n t r o l study, Brit. J. Cancer (submitted). 765a Hardell, L. 1977. (In Swedish) M a l i g n a m e s e n k y m a l a tumorer och exposition for fenoxisyror - en klinisk observation, Lak a r t i d n i n ge n 74: 2753-4. 765b EPA translation of Hardell 1977. 766 Hardell, L. 1979. M a l i g n a n t ly m p h o m a o f h i s t i o c y t i c type and exposure to phenoxyacetic acids or chloro phenols, Lancet 1 (8106): 55-56. 76 7 McMahon, B. and T.F. P u g h 1970, " C a s e - C o n t r ol Studies," Chapter XII in Epidemiology: Principles and Methods, Little Brown and Co., at 256-265. 76 8a Questionnaire for living subjects in E r i k s s o n et al. 76 8b E P A t r a n s l a t i o n of Eriksson et al. questionnaire. 76 9 Barring, U.S.M. 1978. T he use o f p h e n o x y h e r b i c i d e s in Swedish forestry: Amounts, types, and modes of applica- tion. In R a m e l , C. (ed.), C h l o r i n a t e d P h e n o x y A c i d s and Their Dioxins, Ecol. Bull. (Stockholm) 27:219-230. -33- 770 Granstrom, B. 1978. The use of p h e n o x y acid h e r b i c i d e s in Swedish agricu l t u r e . In Ramel, C. (ed.), C h l o r i n a t e d Phenoxy Acids and Their Dioxins, Ecol. Bull. (Stockholm) 27: 231-234. 771 Zack, J.A. and R.R. Suskind 1980. The m o rtality experi ence of workers exposed to Tetrachlorodibenzodioxin in a t r i c h l o r o p h en o l p r o c e s s accident. J. Occup. Med. 22: 11. 772 Cook, R.R., J.C. Townsend, M.G. Ott, and L.G. Silverstein 1980. Mortality experience of employees exposed to 2,3,7,8 - T e t r a c h l o r o d i b e n z o - p - d i o x i n (TCDD). J. Occup. Med. (in p r e s s ). REFERENCES No. 1 Levin, J.-O., C. Rappe, and C.-A. N i l s s o n 1976. U s e of c h l o r o p h e n o ls as f u n g i c i d e s in sawmills, Scand. J. Work. Env. H e a l t h 2: 71-81. 2 Miettinen, 0. 1970. E s t i m a t i o n o f r e l a t i v e ri s k from individually matched series, Biometrics 26: 75-86. 3 Miettinen, O. 1972. Components of the crude risk ratio, Am. J. Epid. 96: 168-172. 4 Miettinen, 0. 1976. Estimability and estimation in c a s e - r e f e r e n t studies, Am. J. Epid. 103: 226-235. 5 Vianna, N . J . , and A. Polan 1979. Lymp h o m a s and occupa tional b e n z e n e exposure, L a ncet i: 1394-1395. 6 Vos, J.G., J.A. Moore, and J.G. Zinkl 1973. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the immune system of laboratory animals, Environ. Health Perspectives 5: 149-162 (EPA Exhi b i t 112). 7 Bjorkholm, M., G. Holm, and H. Mellstedt 1977. Immuno logic profile of patients with cured Hodgin's disease. Scand. J. Haematol. 18: 361-368. 8 Penn, I. 1978. T umors arising in o r g a n t r a n s p l a n t recipients, Adv. Cancer Res. 28: 31-61. CERTIFICATE OF SERVICE I hereby certify that copies of the foregoing DIRECT TESTIMONY (AND EXHIBIT*) OF DR. LENNART HARDELL were hand delivered or mailed first class postage prepaid on September 15, 1980 to the following persons. *Edward W. Warren L . Mark Wine R i c h a r d L. McConnell, Jr. Kirkland & Ellis Counsel for Dow Chemical Company 1776 K Street, N.W., 12th Floor Washington, D.C. 20006 * W i l l i a m A. Butler, Esq. J a c q u e l i n e M. W a rren, Esq. Counsel for Environmental Defense Fund, Inc. 1525 - 18th Street, N.W. Washington, D.C. 20036 * M a r g a r e t M. B r e i n h o l t J u d i t h A. W e n k e r T e r r e n c e G. J a c k s o n Room 2036, South Ag. Bldg. Office of the General Counsel U.S. Department of Agriculture Washington, D.C. 20250 * R o b e r t S. Kirk, Jr., Esq. Counsel for Vertac, Inc. 2414 Clark Tower 5100 Poplar Avenue Memphis, Tennessee 38137 Richard J. Wertheimer, Esq. Arnold & Porter Counsel for National Forest Products Association 1200 New Hampshire Avenue, N.W. Washington, D.C. 20036 Ste p h e n W. J a c o b s o n J o s e p h E. Stevens, Jr. William Ray Price, Jr. Lathrop, Koontz, Righter, Clagett, P a r k e r Sc N o r q u i s t 2600 Mutual Benefit Life Buildin Post Office Box 1200 2345 Grand Avenue Kansas City, Missouri 64108 Judy Kahle Northwest Coalition for Alternatives to Pesticides, P.O. Box 375 454 Willamette Street Eugene, Oregon 97401 Inc. *Sonia G . Anderson Hearing Clerk (A-110) U.S. Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 A l l e n A. L a u t e r b a c h J o h n J. R a d e m a c h e r American Farm Bureau Federation 425 - 13th Street, N.W. Washington, D.C. 20004 E l i z a b e t h M. Whelan, Sc.D., M.P.] Executive Director A m e r i c a n C o u n s e l on S c i e n c e Sc Health 1995 Broadway New York, New York 10023 September 15, 1980 U N ITED STATES ENVIRO NM ENTAL PR O TEC TIO N AGENCY BEFORE THE ADMINISTRATOR In re The Dow Chemical Company, et al ) FIFRA Docket Nos. 415, et al V DIRECT TESTIMONY OF DR. LENNART HARDELL Scheduled Date of Testimony: February 9, 1981 Dorothy E. P a tton Kevin M. Lee P a tricia A. Robe r t s Richard P. Bozof T i m o t h y D. B a c k s t r o m A n d r e w G. G o r d o n Karl 0. Bayer John W. O'Donnell Counsel for Respondent U.S. Environmental Protection 401 M Street, S.W. Washington, D.C. 20460 */ EPA Exhibit No. 956 U N IT ED S TA TES ENVIRO NM ENTAL PR O TEC TIO N AGENCY BEFORE THE ADMINISTRATOR In re: The Dow Chemical Company, et al. ) ) ) ) ) _____________________________________________ ) FIFRA Docket Nos. 415, et al. V DIRECT TESTIMONY OF DR. LENNART HARDELL M y name is Lennart Hardell. I r e c e i v e d m y m e d i c a l degree from the University of Uppsala in Sweden and have subsequently specialized in internal medicine and oncology. I am currently employed by the Department of Oncology at the Regional Hospital in U m e a , Sweden. My w o r k at the D e p a r t m e n t of O n c o l o g y includes diagnosis, treatment, and evaluation of possible causes of human cancer. , I have previously testified in this proceeding (Exhibit 762) concerning several case-control studies in which my colleagues and I found that exposure to phenoxy acids and/or to chlo r o p h e n o ls is associ a t e d w i t h a s i g n i f i c a n t l y e l e v a t e d relative risk for soft-tissue sarcoma and malignant lymphoma (Hardell and Sands t r o m 1979, Exhibit 594; Eriksson et al. 1980, E x h i b i t 763; Hardell et a l . 1980, E x h i b i t 764). In c a se-control studies, one important m e t h o d o l o g i c conc e r n is the possibility of systematic bias in the ascertainment of the exposure histories of the subjects. Indeed, in prior V EPA E x h i b i t No. "956 -2 - t e s t i m o n y in this p r o c e e d i n g (Reference 1), Dow wit n e s s Dr. Philip Cole suggested that the excess, risk for soft-tissue sarcoma and lymphoma associated with phenoxy acid exposure in our studies could be explained by bias in the recall and observation of exposure. In m y previous testimony, I described the techniques which we utilized to prevent observational bias from occurring and to evaluate our results for evidence of such bias. My colleagues and I have just recently completed a new epidemio logic study designed to provide further evidence concerning the likely magnitude of observational bias in our soft-tissue sarcoma and lymphoma studies (Hardell 1981, Exhibit 957). In this study, we e via l uated the r e l at,ion b e t(ween ;e x p o s u r e to / phenoxy acids or to chlorophenols and the risk for colon cancer, a disease not previously suspected of being associated with exposure to these substances We found no significant association between exposure to phenoxy acids or to chloro phenols and the risk for colon cancer. In my testimony today, I will describe the results of our colon cancer study. My testimony will also include further analysis of data from our previous studies of soft-tissue sarcoma and lymphoma and a discussion of new information concerning mortality among industrial workers exposed to 2,4,5-T. In each instance, the ne w d a t a r e i n f o r c e and -3- strengthen our previous conclusion that the positive associa tion between exposure to phenoxy acids and soft-tissue sarcoma and lymphoma cannot be reasonably attributed to mthodologie bias. I. B A C K G R O U N D In case-control studies, the calculation of relative risk is based on the c l a s s i f i c a t i o n of each case or c o n t r o l subject as exposed or unexposed for each type of exposure studied. Although occupational or historical records may occasionally be sufficient to enable such classification, exposure information in case-control studies is g e n e r a l l y o b t a i n e d by q u e s t i o n i n g or interviewing the subjects. In our soft-tissue sarcoma and lymphoma studies, exposure information was obtained initially by w r i t t e n q u e s t i o n n a i r e s (c o m p l e t e d by the s u b j e c t s or their next-of-kin and was supplemented subsequently by oral interviews. W h e n e x p o s u r e i n forma t i o n is o b t a i n e d fr o m s u b j e c t s or their next-of-kin, the investigator must be careful to use techniques which will prevent or minimize bias in the observa tion of exposure. As Dr. Cole has noted, o b s e r v a t i o n a l bias m i g h t arise if the cases, w h o are s u f f e r i n g fr o m a disease, are inclined to overstate past exposure as compared to healthy controls ("recall bias"), or if the m a n n e r in w h i c h an i n t e r v i e w e r elicits e x p o s u r e in f ormation is based on k n o w l e d g e of the case or control status of the subjects ("observer bias"). In our soft-tissue sarcoma and lymphoma studies, we employed -4- a number of measures to reduce bias in the ascertainment of the subjects' exposure histories, including many questions concerning extraneous variables, interviewers unaware of whether a subject was a case or control, verification of exposure by employers and acquaintances, and selection of deceased controls for deceased patients. Despite these precautions in the design of the softtissue sarcoma and lymphoma studies, we could not exclude all potential bias in the obs e r v a t i o n of exposure. (Indeed, it is not possible to design an epidemiologic study which is free of a l l p o t e n t i a l bias). I n p a r ticular, w e w e r e c o n c e r n e d about' the possibility that diseased subjects or their next-of-kin might be inclined to overstate exposure as compared to controls or their next-of-kin. Therefore, we also used a statistical technique developed by Dr. Axelson (Axelson 1980, Exhibit 597a) to evaluate the results of our studies for evidence of the presence of observational bias. Calculations utilizing this technique indicated that bias in the observation of exposure to phenoxy acids, if present in our studies, was not of sufficient magnitude to substantially influence the results (see Tables 2 and 3, E x hibit 762). One of the purposes of our new colon cancer study was to obtain further evidence concerning the validity of the observa tion of exposure in the previous studies. In our colon cancer study, we utilized the same basic questionnaire and the same interview procedure utilized in our prior .studies. Since colon -5- cancer is a disease w h i c h has not be e n p r e v i o u s l y linked to p h e n o x y acids (a so-ca l l e d "dummy disease"), d e t e c t i o n of an excess risk for colon cancer of the same magnitude as the relative risks previously observed for soft-tissue sarcoma and lymphoma would suggest that our prior findings could be explained by observational bias. (McMahon and Pugh 1970, Exhibit 767). However, no significant association between exposure to phenoxy acids or to chlorophenols and the risk for colon cancer was found, as discussed below. II. THE COLON C A N C E R STUDY A. Methodology The new case series utilized in our colon cancer study consisted of 92 living and 65 deceased male patients with I i; ; a d e n o c a r c i n o m a of the colon, ranging in age f r o m 25 to 85 years, who were residents of the admission area for the Department of Oncology in'Umea and who had been reported to the Swedish Cancer Registry in 1978-79. As in our previous studies of soft-tissue sarcoma and malignant lymphoma, all prospective subjects satisfying the selection criteria were included in the case series. Exposure was evaluated by the same basic questionnaire and the same interview procedure employed in our previous studies of soft-tissue sarcoma and lymphoma. However, unlike previous studies, the colon cancer study was conducted i m m e d i a t e l y before and during `the Swedish s p r a y i n g season, -6- when adverse publicity concerning phenoxy acids has generally been most pronounced. The completed questionnaires were supplemented as necessary by an interviewer who did not know V whether or not a particular subject was a colon cancer patient and who had been provided with no information concerning the special purpose of the study. Colon cancer cases were classi fied as exposed or unexposed for each category of substances, including phenoxy acids such as 2,4,5-T, in the same manner as in previous studies. Information concerning exposure among the colon cancer patients was then evaluated in two ways, as described below. B . Colon Cancer Patients as Controls As one means of testing whether the previously observed, association of soft-tissue sarcoma and lymphoma with phenoxy acids was due to disease-based differences in observation of exposure', we employed the colon c a n c e r ** pja t i e n t s as an additional reference entity (or set of controls) for the cancer patients *_/ The colon c ancer q u e s t i o n n a i r e s were m i x e d w i t h a set of identical questionnaires for a study of nasopharyngeal cancer being conducted at the same time. **/ During my previous appearance in this proceeding, I was asked why our previous studies did not utilize other patients at the Regional Hospital in Umea as controls ("hospital controls"). In general, n o n - d i s e a s e d c ontrols d r a w n from the same population as the cases are preferable to hospital controls. W h e n hospital controls are used, the b asic p u r p o s e is to control for potential bias in the selection of a treatment facility. Thus, conventional hospital controls have little utility in countries with centralized health care systems like that in Sweden, sinc the non-diseased controls would, if they had the disease in question, be admitted to the same treatment facility as the cases. -7- wh o were previously included in our studies of soft-tissue sarcoma (Hardell and Sandstrom 1979, Exhibit 594) and lymphoma (Hardell et al. 1980, Exhibit 764) in the same geographic region in northern Sweden. Since referents had not been individually matched to cases, we stratified all subjects according to the possible confounding factors of age and place of residence (urban vs. rural) and used the standard Mantel-Haenszel statistical techniques to calculate relative risks and p - v a l u e s (Mantel and Hae n s z e l 1959, R e f erence 2). When we used the colon cancer patients as controls and stratified the material to control for differences in age and place of residence, the relative risk for soft-tissue sarcoma associated with exposure to phenoxy acids was 4.5 (95% confidence interval 2.0-10.0, p . <0.001). The correspond ing relative risk for malignant lymphoma associated with exposure to p h e n o x y acids was 3.5 (95% confidence interval 1.9-6.5, p<0.001). The similarity of these findings to our previously observed values indicates that our findings in the original soft-tissue sarcoma and lymphoma studies cannot be reasonably attributed solely to observational bias. C. E v a l u a t i o n of Risk Factors for Colon C a ncer We also evaluated the risk for colon cancer associated with exposure to phenoxy acids and to chlorophenols by using all 541 controls included in our previous studies of soft- fi -8 - tissue sarcoma and lymphoma in the same region in Northern V Sweden. All cases and controls were again stratified according to age and p l a c e of residence to. cont r o l confounding. Relative risks and p-values were calculated utilizing the Mantel-Haenszel statistical techniques. When we compared the colon cancer cases to previously studied controls drawn from the same geographic region and stratified the material to control for differences in age and place of residence, we found no significant association between phenoxy acid e x p* *o sju r e or chloro p h e n o l e x p o s u r e and the risk for colon cancer. The relative risk for colon cancer associated with exposure to phenoxy acids was 1.7 (95% confidence interval 0.4-6.6). Eleven of the 154 colon cancer patients (7.1%) and 43 of the 541 controls (7.9i) reported exposure to phenoxy jV Selection of new individually matched controls for each colon cancer patient was judged impractical because of the additional expenditure of time and resources which would have been involved. **/ In the colon cancer study, we also analyzed the influence oif a n u m b e r of o t h e r p o s s i b l e e t i o l o g i c factors, including exposure to organic solvents, antihypertensive drugs, asbestos, glass fiber, motor saws, DDT, and mercury seed dressings (see Table 6, E x h i b i t ). Exposure to m o s t of these factors was essentially comparable between cases and controls. One notable exception was exposure to asbestos, which was reported by 10.4% of the colon cancer cases, but only by 5.7% of the controls. After stratification by age and place of residence, the relative risk for colon cancer associated with exposure to asbestos was 1.9 (95% confidence interval 1.0-3.6), which is in a g r e e m e n t with the risk ratios for colon c a n c e r of 2.1 and 2.9 pre v i o u s l y reported in cohorts of asbestos workers (Selikoff and Hammond 1975, Re f e r e n c e 3). 0 -9 - acids. If there is no t i o l o g i e r e l a t i o n s h i p b e t w e e n exposure to phenoxy acids and colon cancer, the relative risk for colon cancer associated with exposure to phenoxy acids should be one. The observed value of 1.7 may be the result of random statistical variation. It could also indicate that phenoxy acid e x p osure is a s s o c i a t e d with a small increase in the risk for colon cancer. Alternatively, it may indicate the presence of some m t h o d o l o g i e bias. In any event, these da t a indicate tha't the s u b s t a n t i a l l y h i g h e r r e lative risks a s s o c i a t e d with exposure to phenoxy acids in each of our previous case-control studies of soft-tissue sarcoma and lymphoma cannot be reasonably attributed solely to mthodologie bias. III. ADDITIONAL ANALYSIS OF PREVIOUS DATA ' ! -------------------- :----------------------- i In p r i o r t e s t i m o n y in this p r o c e e d i n g (Reference 1), Dir. Cole cited a n u m b e r of all e g e d pro b l e m s o r d e f i c i e n c i e s Vin the d e sign and c o nduct of our soft-tissue s a r c o m a and lymphoma studies. Despite their hypothetical character, in other testimony, Dow witness Dr. Michel Ibrahim implied that recent negative case-control studies of reserpine and breast cancer demonstrate that three initial studies which reported a positive association between reserpine use and breast cancer w e r e biased (Reference 4, at 25-7). I have not a t t e m p t e d to evaluate the adequacy of the methodology employed in any of the s t udies in question. Nevertheless, it is i n t e r e s t i n g to note that a recent National Cancer Institute bioassay of reserpine (Reference 5) reports a s i g n i f i c a n t excess of tumors in treated male rats and in treated mice of both sexes, including an increased incidence of mammary cancer in treated female mice. I  -10 - two concerns emphasized by Dr. Cole can be tested objectively and therefore warrant further analysis of the previous data. In each of our studies, the interviewer who supplemented the written questionnaire responses was initially unaware of the case or control status of the subjects. However, Dr. Cole suggested that the disease status of some subjects might nevertheless have been subsequently disclosed to or discerned by the interviewer, thereby providing a basis for introduction of bias by the i n t e r v i e w e r (Reference 1, at 13). To test this hypothesis, we evaluated the relative risks associated with exposure to phenoxy acids based solely on the written questionnaires as returned by the subjects, w i t h o u t c o n s i d e r i n g the more det a i l e d iijvformation pbt a i n e d during subsequent oral interviews. After allowing for a minimum latency period of five years and excluding exposure of less than one day, the resultant relative risks for the first soft-tissue sarcoma, second soft-tissue sarcoma, and lymphoma studies were 4.2, 5.6, and 4.1 respectively (see Table 1, Exhibit ), demon s t r a t i n g that the e x cess c a ncer risk associated with phenoxy acid exposure cannot reasonably be imputed to bias introduced by the interviewer. In his testimony, Dr. Cole also discussed some of the assumptions underlying the application of Dr. Axelson's o b s e r v a t i o n al bias technique. In general, the data indicate i & -11- that these assumptions were valid and reasonable in the context of our studies. As Dr. Cole noted, the most important a s s u m p t i o n underl y i n g a p p l i c a t i o n of the A x e l s o n technique is that cases and controls will accurately report the occupations in which they have been employed. Dr. Cole then suggested that, if cases are more likely to recall exposure than controls, cases who were employed in a related occupation for a short duration many years ago might be more likely to recall such e m p l o y m e n t than comparable con t r o l s (Reference 1, at 17; Tr. 16491-2). In my view, it is implausible that such an effect would significantly bias the classification of subjects by occupational category. Nevertheless, in order to test Dr. Cole's hypothesis, subjects who had reported work in a g r i c u l t u r e or f o r estry weire s u b d i v i d e d into thosd whd reported employment in agriculture or forestry during the entire period since 1950 (approximately when phenoxy acid preparations were first introduced in Sweden) and those who reported employment in agriculture or forestry for shorter durations. Relative risks were then calculated for exposed and unexposed workers in each group, as compared to unexposed workers employed exclusively in other occupations (see Tables 2 and 3, E x h i b i t ). Utilizing this special a p p l i c a t i o n of the Axelson technique, no evidence of bias in the classification of subjects by occupational category could be detected. I