DOD Letter to National Toxicity Panel on TCE

7/31/2019 DOD Letter to National Toxicity Panel on TCE

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DEPARTMENT OF THE AIR FORCEAIR FORCE INSTITUTE FOR ENVIRONMENT, SAFETY AND OCCUPATIONALHEALTH RISK ANALYSIS AFMCBROOKS AIR FORCE BASE TEXAS

1December 2000

MEMORANDUM I OR OR MARY S. WOLFEP.O. BOX 12233, A3-07RESEARCH TRIANGLE PARK NC 27709ATTENTION: EXECUTIVE SECRETARYFROM: AFIERA/RSRE2513 Kennedy CircleBrooks AFB TX 78235-5123SU BJECT: NTP Board of Scientific Counselors RoC Subcommittee Meeting, 13 15 Dec 00

I. In reference to the Federal RegisterNotice October 17,2000, Vol 65 Number 210: 65352-61354 , the U.S. AirForce would like to submit written comments regarding the proposed change in cancer classification fortrichloroethylene recommended by the National Toxicology Program NTP see Attachment . In addition, the U.S.Air Force requests time to speak on this topic at the up coming NTP Board ofScientific Counselors RoCSubcommittee, to take place 13 - December, 2000. The U.S. Air Force oral comments will cover and possiblyexpand on key issues discussed in the submitted written comments.2. Contact information for oml comments is as follows:

Elizabeth A. Maull. Ph.D.AF Institute For Environment. Safety and Occupational Health Risk Analysis AFIERA2513 Kennedy CircleBrooksAir Force Base TX 782355123210 536-6126210 [email protected]

3. J will your point of contact for b h the written and oral comments for the U.S. Air Force. Please address anyquestions or concerns to me at 210 536-6126 or e-mail [email protected]. The attached writtencomments have also been posted through the regular mail.

ttt JA A / . d ~ELIZABETH A. MAULL. Ph. D.Toxicologist

Attachment:SAF/MIO Memo. 29 Nov 00, w/l atchcc:SAF/MIQ


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2To rank a chemical as a known human cl1rcinopn is obviously a major decision with w i d e ~reac:hin; impact; once so rOlnkcd. it will bt extremely difficult to ccturn to it lower classificationrank. Consequently, it very impommt CtTittth;s bell welt-informed decision based 1 apreponderance of sc;jentific data. Without an) cItilt-cut evidence thuc TeE is c u s ily ASsociatedw;th cancer(s) in a significant manner, the Oepanmenl of Defense takes exception to theNational Toxicology Program s (NTP) proposal to elevate trichloroethylene to the status ofknown to be human carcinogen.Out point of contact is Dr. Elizabeth Maull. AFIERAJRSRE. (210) .5366126 or [email protected];

w MCCAI .JR.. ANi .nt SCCfelaq..-Air-fi1orce~ 1 . i i h m e l 1 f . Safety, amt O c c u ~ a t i o n a r e a I t h )

Attachment:T ~ h n i c - a J COiiiiuentscc:DUSD EstDASA (:SOH)DASN(E S)


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2 2 9 9 91 - ...... IL.> Department ofDefense1'4. ; 1N e m i , . _ Y ~ l e n e1. The Department ofDefensc (DoD) takes exception to the National Toxicolosy Program's(NIP)proposal to elevate lrichloroethylcne to the status of known to be human carcinogen.orTo..be.so..classified, N T f . ~ ~ l t h c = . i . s u f f i c i e n t evidence ofcarcinogenicity fiom studies in humanswhich indicate a causal relationship betWeenexpCl5Wl e to the agent, ln8 1 eM S IV ,f,h,spe C ~ The N Ii by,fei,lcd

demeBStHte that this criMliOllhM -.a1:Ut.2. Althoueb NTP gives consideration to all relevant information (to include but not limited todose response. route of exposure, chemical sa-acmrc:; ttlelabotism, pbarmlevkinerK:s,sensitive subpopulations, l.enetic e1fec1S. other data relating to mechanism of action) incategorizing chemicals u either rcuouably anucipatecl to be, or known to be, a humancarcinogen, there is a reqn;remem tot :tbe.latt.et.eatesp Y to apply that a causal relatioDShipbetween the cxposureto...the subs1JID ce ICE.lnJhis case) and cancer be established tbroup in humans.3. Hilrs criteria ofcausation (Hill, 1965,. as cited in Lavin et aI., 2000) are most frequently usedfor detenntmngcausatity. 8 r i e B y . ~ p o s t u i s include:

Temporality The exposure must precede the disease for a causal relationship to exist;Specificity. A causal relatiommp is m.orelikely to exist i f the exposure is lWOciatcawith a specific disease outcome than with amultitude ofpossible


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4. Based on the requirement that a ~ a w a l usociition be demollstrated in.humans, a review ofthe recont humau studies- was porfotmed.a. NTP included four each of cohort studies (Blair et aI., 1998;Moraan et aI 1998;Boice 111 1999; ancUtitz, 1999}'and cuc control studies (Vamvakaset 11., Fritschi and S i e m i a t y e l c i ~ 1996;Do eme&:1 et81.,1999; and Greenland etal., 1994) I

a.cd 3 reviews me human ~ o h o r t studies(Wcbs, 1996; McLau&h1in and Blot, 1997;and Wartenbera et aL.,2000) iD.tbcir ~ u t t e n l I C E b a U g r o u n d d o c u m a f o r ~ aocJ O ~ not cov d in backirotmd paper.b. Withinall ofthcsc studies there are methodological problems and discrepancieswhk:h -do not 5UJ'PC'tf'ltoabSaI' lII IOCiatfoa betwccu to1ltE allek.Net.,..Wat1Cnbcrg et al. 5\Di1DIIlized 1hese timitatimJs DiOSl-mecinctly:

1) All of the expCWJaillfhnnatioD is cmde and itdoa.not isolate TCEexposuresfrom otbctt possible solvent exposures.2) Few ofthc traditional confounders have been assc:s.sed in any study.3) Limited dose respo.asc information exists, limitina the ability to make inferences.4) Diseases of interest are relatively rate thus limiting the sensitivity oftbe studiesf8view.d.) Specifically for the Wartenbc:rg study. lhe fashion In wbich the ditl'erent studieswere c : a t e g o r W d . . w u s ) J ~ v e a Gould influence the Sl1m mm::l.tcla.tive risks.

c. Reviews of'the LiteratureThe three review papers covered a total of 8 occupational cohort studies ofTeE exposedworb:rs.-Fct1hc WlltC11beii et-ai.-work, we a:re1mly comidcriDg-b:is-bcst-chatacMizedexposure poup, the Ttet r StUdies:; Dr. Weig, being the earliest paper, consideaedon:ly4of the eieht commonpapers;McLaupwn anct:8lot included 6 ofei ~ t studies; anaWartenberg et aI., covered 70f eight oripw studies. Results for these papers werereported as either Standardized Incidence htics.or Standardized MonalityRatios. Theonly obvi


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cancer and TeE . d a t a failed to. mect Hill's t:.Iiteria of.s1rength o,f as ociat jon (in. the:...form of relatively small relariv.e.rislis) a D d . ~ f . a d a r expOSLUr.-JCSptmse pattern.The last review cons.eel by the-NtP w a s ~ m p J e t e d in 2000 by WarkMerS e t ~ Thisstudy was mislabclccMtrthemP:re ' baellroumtck1earuent Ii. mera-aI2l1i'ysis. lt r the BUthOrs have recommended that a mcta-anaIysisbc done on the extant d a t a : ~ eWartenber et aI. study is a complicated analysis where studies are ranked accordiiig tothe best characterized cxpnsurc: CIi&tJ)t (Tier 1I),.dIy c1canerslDd....laundry workers (Tier Ill). Althou,Jh it i.a lib[y thai all of these aremixed exposures,only .the. Tier III is labclc:d . . .M.i. . . e x p o s e a ~ .Yarietyof solvents. SolJle..Q( t1J .COI11z:ovcrsial Oetmaa .Qlld, bl e been includrA in the.I1er I stud,es despite the ftct thatthey are considered to-ee-......JI8Wth of. cercluster investiaatiQn. Basee c.theTier l-studies, Wartmbcl etat-tra'Ye ideutified 11 ~ r s with relative risks > 1.2 (orthe incidence ofcancer(cexvicatcmcer, smrcmm'; liver cancer, kidney cancer,l bItcaneer, non-Hodp'slymphoma, lIodp 1sdisease, multiple myc[oma.,lymphohematopoietic cancer. larynx cancer, and prostate cancer). For four ofthese sites(cervix, l8.I ) DX, rectum and skin), tbarelative risk is baed on only one study. Six ofthese sites were: included in more than one study with the null value included in theassociated confidence iDterval( Uiag jOOiyjdually_m.fu.lfi.ll the criteria for a s s o c i a t i o ~The onlyW w i t h Q i A c r e u e 4 ~ v c a g e r e l a t i v e risk fbat iaclI Ided in.multipleiBvestiaations aod exce tywithin ~ i n t e r v a l sugpstingstati..significance, was il t kidueyQSlCCf. ~ IOcs.furtMt and loob t iBdividualstuc1ics, however, the iDuea:sed nmBge teta1i'e rist-wa driven 'by lteJac lfez et arm.t:r.Tbis rcview fails to demoasttate cUlISUtcJlcy Krass studies.d. Cue Control StudiesFQur..addirionaJ c a u ~ stud_were SACllidcrcd fo r the lQ111 edition of R9'rI otL.CArcino8IJDS.: Dngemectet.IIL ( ~ F r i w b j Ind Siem,iltFki (1996). c....n[aM.et.aJ (994) and Vamvalll& In . e studiea_ eX' . r ' .

~ u p o w o c r f u 1 a ..-AlJ ~ e flaM thet...wlimit lhnuppon they piCl,fde 1ft efasif5rfDlr1C l 1s' a - ~ hWJiIll eadllO CiZl'IIe-study ofDosemeci et 11. wa:s J. P 1 1 a t i O J 1 ~ case -cmftrol StUdy t'Dnc ucJteel inMinnesota lookinl at tfie impact exposures to a variety of chlorinated anp&aticbydrocarbons.on the risk ofdevelr9Dlpel ccItcarcinoma Altho . ~ v e r a n U Q O s u mto Te resulted in an iDcreased risk for RAC, this increase was only consideredsipiliicant in women,.epd .... cgp#Wep'VC iR1KYM iDcludld the oulLvaluL.'Ib& .nllKa ipeJiealc tbet there i .an d c a r ~ v i d C l C e t o . ] ; 0 Abe . . . , . . difer.r.D lad t h a t theseresults could be e x p ~ a l O M t ~ . catbersma11 numberofc 'JhW;..studywas limitedtJytBe 'the,;,. by- eYeI OHxpostll '( CO iMiicIuAl501VCl115. madditiou'lbe aafkr,s Oldy had1tmitt'occ:opatiwal histories': .Oree damt ctat.(1994)were restrictecho looking at1 CE npondvsUDeXpC.JSeCiforlhrirnudyiD. a

M u s ~ u s e t t s transfOrmer manu1iCturing pram. TfIis study cannot providcmy datarCIIItdin. dose tespoDIc. They were unable to dcmODlU'llC any statistically significantelevatiOllS in odds ratios for the C ~ examined Limitations ofthis StUdy intludeselection bias, exposure misclassificatio1'1, 105 to follow up aDd uncontrolledconfoWKiing.


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c. OccupationalCohort StudiesThe NTP backaround document includes an additional 4 occupational cobort studiesbeyond those covered in 1ht previous R a C : ' ~ O f cohort studies, Btairet al. andMorgan et at are follow-ups orprevious cohort groups. These cohorts inclUded thefoUowing numbers ofworken (TeE exposed andtotal workers): 1)U4'ancrf4,4$i(Btltretai., 1 9 9 ~ 2,267 awi:11 965 Wcaiu et u..1999)..4,733 and 20,508 ( M o r ~ , e l . .J.998), and 3,814 a n d . J . 8 1 ~ 1 9 9 9 ) .For the Blair ct a1. paper, all ofthc confidence in1e1'Vab surroundinS the point estimates,with the exception o f 1 4 ilier. . . _ ~ S g l s t i n g non. . . . .f i TOit

' ~ U l ' e S - a s a possible mwepsetBlion.-In a t h I ~ R B & - - a m o n g ~other chemicals, but DO[ h2 ofttiu bad tUG a-f:irge-U'workcrs exposed., ~ r.. --mair et aI . the authors star.ethatG:leir data fait to suppon1lill's C r l t e t i a t t e a u s e ~ i sinsufficient evidence for strenp-ofassoc:iation, dOSe-response, or consistency.Morgan ct al. (199e).havc...simi1ar CQIlClusicn.s; their data offer little Sl PPort for UU'UIOci.a1ioa betWeen IC5 I de ri from Inkcwia. C'Mes QitKhemaWpoietic tissyos, . l t i v . e ~ v e r re_tory .sancers. AIrbmllb 'ydid Dnd

a l 1 i g h t ~ s o f ~ . . . I t ; b I ,andovari_CI2I1.;- IUu.-.wtie not sipiticmt aud dtus caeaaiityII sappetteel, In additierl.;S2 Il lM i s.lack: of infonnation 011 COIlf&undiJ g factoi 5 sue lIS' smolin and lack-ofqaantibI t' c:exposure infonn8tion11mit 'the fui inp oflJlorpn et a .Boice et 1 (1999) examined IC:VCra1 chemica. e x p ~ S W ' C s (TeE, perch1oroethylcnc.asbestos, and ehrouwe) commonlY found in aerospace mauufacturing processes. As withthe abo emenuoned.5Pvt i.... t I I A ~ , m d Jim evid.=cc that exposures to TCE.in.aerospaceiDdUJtty reluJII'd D e Sutable increases in amy_cancer.. In fact, B o i c e ~ U Jwas unable to confi.lm tho liS lOlDt n obselved il l citbel' BI.;ael aL.QIt:Mmp a -et a1. lmtdeoe ' lOt d C l l l O t L f t r . ~ , : i e D C r in fi.adin s botweea sbKies,4Dimpottant criterion fO causclity:--The analysis ofRia (1999) shows the strongest association between biliary and livercancer and TeE exposures 0lR 12..ct- 1.03 to 144). However, this is based on theincidence ofOt1C caoeer. It is also to note the extremely wide confidenceintervals. In tbiI stUd)l, besWII paw.iq of. tumars...some C J1ccg:.l needed mbegrouped. Therd'ore iUajmpo.lible to t M.4Ut the Jhu:rulW J'sJmm biliary. A CIITS.TheR were treads for U l ma o t h e . - c U ~ i a t e d With TeE, butkidlllpcancer was notODe1lle iBere.a4 caacers..'BIis-eehort-tsawbolehad MIl; JipiMaatiJlcreues in mortality-forQiiXetS ofthc'csopha,CLS, sto:m8Ch,liver, pliiC1eas, pres... .brain. and lymphopoietic cancer IUld HodJ)in'sdisease. l'bialJtUdy nnlt oddI Withotbcr 3 lIdctitiowcohort studies consideNCIsince the ~ 9 edition. HoWever, 1I1is is adifficult study to n ~ No wbaa is then;ac1eaLc:q1anationofthe comph'isol1group. It is also unclear as to how many individuals were po5ed tu TeE alOllc,altlwuah there are comment' to- tba- ,ff.,.,. that ' 305taftbe-TCE expo_ individuals .W8m..J Xposnrelo other SOlvents,


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One final concern with all ofthese .studies .is that althoush exposure reconstruction isattempted, there are _MULLan _for expMurc. In ailljlceJjhood, exposure did not acearby itIelf; -5ewralWldieslu8sest that exposwes to.ad.ditioaaJ.solvents results in incRacd callCei irlcidenoea similar to-TeE or that the MIt cbemicallyexposcc:1 had similar riSk ratios as l h c ~ E exposed (for cumple see 80icz et.lnmlc 8and. Blair et at, Table 3, Jdtiy cancers). 1lie collective trend demonstrated in alI 1hcse cohorts is that TCE exp,osma i.s...not ~ v o c a l y causally associated Withincreased risk of CImCeI1.f. Additional StudiesWartenbetg et aI. SUiiests e\'iden(:e support.iD& a hypothesis ofan association betweenTCE exposme and. tam:e1' is a-strcmgor SUODlef fer the kidDe)' as for any other . . . . .There i some eoncem,however. 1batmostof the -data SapPOl ting this h,pothesis-babeen generated by a sereet group ofScientiSts in Germany md has not been replica.elsewhere. It is not oW' intentiollto find fault with either these scientists or their work.There is abundant discu.uion in the literature addressing the controversial nature ofthesestudies, beJimrlns with th e gjt i r isms of tbc.nrimn,I dudy (HenschlcI ct al...J 9 9 S ) ~ Tha ..Ocan.ua. stIadies have heeD (4Qsjdercd 10 be fJ.awed...However, 1hey..may be useful..iDeMimatiD(t- the TeE I . 01_ Wi I.'*- 5F IDly b e . s o e i a t e d . . w i t l : l . . ~ c c l l L _C&Icmoma. V I I D V l r i c l l d . ~ (1991), flazetller--.a1. {-i99S}, R r u u i B I . ~ . { l 9 9 7 f . iBrauch er-ai. (1999) an mapl 'PilarahtwillBflnoqallt i tee expos\lftll__ .asts their cohons, it is likely1hat1hese iDdividaals-were exposed to ememet, mpdevds OfTeE in d1e workplace OUeerOD rccoIrections Orpn-DllrCOUC effects.The exact role ofTCE qpOSlllCS in the development ofrenal cell carcinomas CRee) huyct.tn bacanc1usivcb.dn Bnd. . . a.aL.(J.9a7) andBrauM c:t II. (199i}.provide a . h ~ b e s i s 'bat ' R: i t o b;,b tMMntmiQDs ofTCE. or...po1aQgecl.J'Criodsof.m.el'ORllt in m,1( ~ . , . JIll l . I ] 2 b im bamor sll1J1FIIJi-lIiScali 1.1III1I ;1I:cBnmis2,--aI. U iut a'IR;a _ is . hot.,of' for T e c _ 1 f 1 ~ lIlI'atetJonSThis is supported bym'aueIt erlf. __sanes15 ~ d : 454-efttJ, WIl. is ispecific1arpt for1hcx ftUffltitJllS.11u wev6i.1hac li e s= e inccDSisltJ1Cies betwCCAthese two sttJdies. Iii Shmiq et at,~ o f t h : t T'C'. ' exposed RCe pa1ients wacobserved to have mnJanons in tbc-YHL uP'; ~ . O f . t h o s e mutatioDSOCCUned. in ex:oD2In the s e c o D d ~ 7.5 .Qfthe TCE eosed bad mutations in the Vtn.e=c. but il l thiscue S2% ofthc m tas'=& 7EP OD 1 ~ A t 1 U I I i p I F S c h r a m 1 eta1.,.lj9.9).examinedRCC &om the Balin 'M found p o dUfcamr-cs betwaD t h e _ p o p n J a r i O J l . Q f J 1 Q J l ~ t C EexpQ&ed aad the TeE . . , 0 - ia ofltism1aeicaJ t1lmot type or iA tbG.perwa aLVliL mutalioDS. Sdnml s - &y trOUP WIS land it ia hard. to draw firm ~ 1 u a i o a sfrom it. The autborsl1lO ~ u a c s t _ the-.,.aeaes in their study may have bee mlfMSI.to lower dose5 ofTCE tbanill the Braudnn.L' IIld BI tmiDi-et aI. papexli. The ~ s u l t s 1 ) fthe three c r o U P ~ thar mON :reseach is required before definitive conclusions canbe drawn regarc:ltngVHL mldatiou ariQTCE exposures.


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It is possible, under the conditions cited by the numerous German investigaton. that amaximum tolerated doseP WD'Kkic;; to ,...gfdl.se-workplaces during tJa.timinvestigations. Under tbeR high-spos8 e waditions,. the oxidative patftweys TeEmetabolism were saturatedll:l4more l'CE wa meb6JftZlld through the 6fJH-eoqioi l fhe ..pathway leadina to renal damag:-C>ther evidence, both animal and human. 5 U 1 1 ~ncbc a humaa eueiawawz

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DOD Letter to National Toxicity Panel on TCE

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