Document 15ppk9ejXYvjzBYavXdnXoK15

:A ., N 0 (L. c;; ~ 0 z0 (]'I N 1.0 ~ 1.0 (]'I 1....0. .... u 0 N N 0 ..,1'- N N - 0. z _I w 1- B ieo>liogJlcaJllliruf\G>JTm2J.Lbl(Q)lDl lillpp({J)rrtfunlg 21 TILV for JBeffilZ<eiDle J?Jres;entted11t<Q} ACGIDHI Oc1t<D100Jr 149 R99>5 JP>atridk W" IDeatUy IP>lhlJDJO~ D"AJBJr." Crev[<OJIDl R~e2Drch & ToclhnokDgy CompMy BP-00018008 I') 0 a.. 0 ~ 0 z0 0'1. "' 1...0.. ... <> Jimplic8t~ioiDl of JRecernrc Adv~IDJ.ces fum ttlhle u. 0 1Undlers1t2lmldb1II1g (())f JB3e1DlZeillle=llimd1illcedl JLel1111kemogenesiis "N' ,0..._ ~I <'< _z0, w I- . 'il '" BP-00018009 .. > I-------- --- q ~ "- .0.... - m0 JRe101Zene Epidemiology Q1illes1i({]}lffi~ ~clbl z0 -(1l "..' Mec1hl2lmli~Ji~ DIBllli me Uefuli - lO Ln ...0:0 <) <> ~a~ fcypes(s) of lieilllktemlia <dloes lbemeiDle tea:tlJJlse fum +' u 0 llmmm,eJIDl1 <> W1hall: i t1he sh~pe (O)f fdble dlose-res~illlse ZJ.lt N 0"' ""q"' oc<euptal1blonru expo1\ll1Te <e(Q)mt<CtelTh1br211tii<D>rms1 "' z0 w...1 1- BP-00018010 l/) 0 Q._ 0.... ~ z0 II> "~'I ~I I I I ~I ~0 I N""' .; j ::z: -w 1- ' ' .. .~ ~==== == IS!rFU!J~ ====t>8=t>@ ==l> ==~i> BP-00018011 . \J) 0 a.. .0.... 0 :0z 0> (\1 .l.t..l Lf) m ".........'.. 0 "'(\1 0 . ".".",' N z" _J ,_LLJ - 0 Ate1illtt~ MyelitDlgelllo1Ul~ Lellllkemita! (AJMIIL) orrigillm<6l~zeg ilDl fdble myelioizdl progemfc@Jl" c~lili c())JY li<at1tceit o OlmrtO>mc MyelitO>geiiTLous 1Leilll1ke1IIDlliat (CMJL) origfum8!.1te~ fum tiline 1Phrriipo1teilll1t fcem Celill (JP>SC)a <> JEe1DlZeJme mefc~bolillsm lt(Q) roxie qullimome metmbo>Rflll:es Keqpunbres myeloper(Q)ruldlffie (JMIPO)o <> JMJPO ii IOlrot f(Q)t!lllDl<dl iin \the JPSCCa <> Colll.cTil!llsioilll = JE.emelill.e <CZliDliDl.Ofc c~un~e CMIJL.. BP-00018012 .. - - - - - - - o - - - - -II') "" "'..-< o Bemerme emibiltB sforollllg sfurmuilmlties lto econdlaury ~etmJk~rnt(DgJrnS ogo? dlnemoilierrapeuntoic agelDltSo - Hema1ttoltoxic att lliliglbl COIIJlCIOlfcn:atiolillso ~ Similarr effects Olll cyfcolk:fume respoli1lseo ('.1 ('.1 0 1'('.1 o JKJmowrn sectDJndaury liellJllkemJ>geiDlS lffiJI'e cam1saillly """' 0 z: ffi<G>Cimte<dl omJly wittJh AMILo .....J. 1- I o CC<eJITLcclitnsieo>n = Beilllzerue cStusruliy associSJ.tte<dl oruy wiilt1bl AMILc . BP-00018013 . co 0 0... 0 0 :z0: 0'1 "' .l..f..l. ...,_ u 0 N N 0 1'N <:1 N :0z: w...J f- GellJletic Meclhtoonsms f(())r !Bell':ilZene Le_1lJJJkemogelDlesils 0 JlliJlDJZ~ITilce lki ITil~mlfrnwce ll@IT' [p)nrmtt I11Jil1Jll~atlcmrrno 0 IffiIIDLZffil liD~~ IID(Q)lt IID~rrn llil<IDWIID111ill IIDfumcdl11 IlJ)NAo 0 lBSliD~TIIl ~~~ <ellmrCIDIITffi<IDDITIJllm cill~DiiDCdl~~o o wnnnnIffiIffi7kITD niiDrh~uffrr~ cr;lffilr<IDITIID<IDmm~rr li'[p)llii~fcfi(0)]]10 - o CIIDrnmmm<GJ@JIDD2cli ~~rre~SJltTIITilo 0 1r(Q)lJ~@I!I!J)~lJ'~~ 1IrmllilnilDnfilli!DliDo CoiDlcRusi(Q)Iffi ~ GeiDleuic effects of beilllZeime <dl\0> IITLO~ fit 1tihle oillle=mt paur2tdligmL BP-00018014 ~ 00"1 o._ 0 ~ 0 0 z. 0"1 "" .t.r..l .... u 0 N N 0 1'- q"" "" z0 .w.J t- -. N'@JIDoGceiiDceltfite liMI<e~lhl~IIDDJTIIi) if({))IT Illiilil~rmce ILceTilllkmm~IID~D <> IFIT;rllir<IMIJ.unfillil!Jll n!Jllttrriflf~ wmtlhllTilliTlliDmll If~llfalftfi<IDITfl \UlfJ llll<eIII:WJltr(Q)IfWI'R~fl. = Ctdlm~ C@M=<CIFlU <OOil~ rl<lll llil Ihlytp)If=l!~J:Pl1~nw fc@ Iill(J])IrmiD:IDll ~ytr<IDlkniiD<e IF~TI$lllllUilo = .ITil1lltrru~IT'~ wnttllil IfrmttwU~wlkfum=Jl ~yiiD11llix~~ll.~o = lli>nJID~ D<ID JL'JTID)=4} !l<e~<e[!D11<!Dir <!Dill! ([rroCCJFUJo <> IHiycd!If(!)JtqlUllfum<IDIID<e lliiDLcrrffrr wllulln mrul11ID~ll eilTI allcetdll1Iln ((ID[p)[p)~@~ll~)o. CCDrnK~lll!JJD([))IID "' IID~rrnLZffilce llncru~ IIDn@::lli:t~IriTlln~ll ~ff'ff'eoo trtCE~ce]p)ft~cdl lt<ID ftrmllllw IID@ITllllliJID~IT' lkniiD~11licr;o BP-00018015 .......... CL~ 0 ~ 0 z0 (]) N ."..'. "'(]) .l..O.... <> C1JJlmU1ll21.1tiive ExpJ)sme is CQJ\illiDl~erimnruilitoiveo u 0 o 1ExposUJJ.re roooy i as importslml1t ldl XJP([DSUJlre 4A]) yea1rn agoo im]plliic~olTh - effoctts m\Ulst be ~rreverniilbleo o !_ppm expos1Unre folf-45 ye3l.lr' is 2:\S risky as 45 ppm lfolr li N yeu. Jimplikafdtorm - Dose-rrespolillse musft re line&1ro N 0 ."",".' o Ommwlllltbive ExposMe is nolt 1bioliog].ca1illy pli~:tlxsil1ble N :0z: wiili ilie obseJIVedl effecw of \hernzelffieo ,w._.J o Effectts rure lrll~Bt iiT~rvJrsilblie. o Effecl[s dlo lTilOJIC foliliow linecaur lkirmetics. BP-00018016 I ' .1' .0... "- 0..... 0 z0 0> <..'I .I.n.. .In <7> "....'. +' u CJ "N" CJ. 1'N "Of N z0 ,w._J o The germeti.c effects off 100mIDle memoolliilte do IOl((]~ mef<Q)lllow 1tlble (!;(!;one~m1t)l)l mooel celiiltraill ~<n> Ilme<aur)l li<D:lw cdl(())s<e extrapO>latioiDl m<DJdlel o The IDlO>illl=geiDletic effeccfc of ooruzelDle OIDl reguli&doiDl of llllile hem~fc({))poieti.c system foll(Q)W s1tmdlm'cdl m(Q)cdlteRs of 1biocllilemicru plh~lDl.romeiOl~ whlcch mcorportd11t IDl<G>1Dl]binewr Jkil.JmeU:ic~ 0 BP-00018017 -- -- - - - - - - - . - - N 0.. 0 ~ 0 z0 I~ CONCLUSRONS l..(..l. .., MDECJHIANJISTIC DATA SUJP>IPORT 1HlE au CONCILTUliONS 1TIHIA1r: o JEENZIENE JIS CAUAJULY JLKNlKJED ONJLY TO N N 0 AMDLo.,.1'- N N z0 o 1rHE JLJEUKJEJMIJIA JDOSIE lRJESPONSJE SJHIOUIUD w..J t- BlE NON=lLJINEARO o CU-i'~ATJIVJE EIDPOSWRE JI NOT AN APJPIROPRliATJE ID>OSE=METRJICC BP-00018018 I~-- ..... ----- N N 0 "N"" ~ N z0 : - ~--' '. .. :IIJMDPJL}[CATIONS JFOJR JrJHIE . JEJENZJENE 1rJLV <> A JRliOC ASIESMITENT OF JRJENZJENE JEASEID U1PON AN AJLJL JLJEUKEMKAS~ USmG A LIIl\JEAJR JDOSE=JRJESIPONSJE MOJDEL AND EXIPOSUJRJE JEXJPJRJESED A CUJMNJJLATIVJE PPM=YEAJRS JI mACC1IJRA1rE AND WJTILJL JREUJLT IrNr AN OVJERJES1I1ITWA11E OF IRJISKo <> 1IJBDE CURIRENT EIROPOSED TLV OJF ((J)o3 PPM KS \IJNNJECJES~Y S1rlRJIN"GENro BP-00018019 .,G ! O.r. =-------- 0.... 0 0 z. 0\ "" .l.f..). .... v Meclh!BillJl~iic Datta- S1!llppomtmg EpicdlemntioliJ)gy (.J 0. Condmu~ion ~ A 1rLV of ((l3 lis IOJVerrliy slbrimlgenrc mtdlnon: coiDli1tenfrwirch itlhle lbliol((J)gy of OOJillrelille-furudmtcoo llillkemi~o . <> Re=Amlaliysis (Q>}f ~Ible JE>lifl(Q)fllilm C~D>IhtrDJrt ColDlcl1lllsion~ Worlkern never exp(])SOO 1al.OOVe 20-50 ppm Jlnave IDlO furucreZtSedl ri5Jk ~f A.JiMLIL" <> Mefca=Aml21.liysJl (Qlf JP>etr([]llellllm W <Dnrkers Cromtclutsiion - AMDL risk-its IillO~ mcreaJSoo mpetroleum WOK'Jkf5o BP-00018020 II A. R. Schnatter Exxon Biomedical Sciences, Inc. BP-00018021 Reanalysis of JP-Hoillm Data Si.llbjec~s: AH (l7! 7) White Male (Non-BRack9 Noli1l=fema[e) Workers. Akron and! t Marys P~a1t1ts. foHowup: tart of StUid!y l'hrmnglbt 1987 for We~sidte Worlkers9 Thrmnglht 1981 for Other Workers. Comparisoli1l U.S. MortaBiey for Toital Leukemia (1950=1987). lPopll.!la.tion: U.S. Mortallity for Ac\Ulte Mydocy~ic and Monocy~ic Le\l.llkemi:m (1950=1987). StatisHcafi AII1lalysis:. Observed! Deaths Using Updated! FoUoW1l.llp Data. Expected Deaths Using U.S. Lelllkemia MortaJHy. SMR9s (0/E) Caficll.lliatedl Using St:mndlan.ll LifetabieProgrrun. BP-00018022 Reanalysis ofJPHofilm Data (coilllt~ dl) Strategy: Defined. Maximum Eight Hour Time Weighted! Average Estimate Over Each Worker's C2ll!'eer. Examined Sub=Popu!aUons Always ExposedllB\eXow x ppm. Advantages: No Modd Necessary. No Rdialrl.ce om Cumulative Exposme (ppm=years). Resullts Show Actl!.lai Beru2:ene Concelrl.tratlions Whnch linillluumce Leukemia Risk. BP-00018023 o Benzene Exposures Calculated Using Midpoint of Crump and Allen 0 984)~ Rinsky 0 981 ), and Paustenlbach (1992) Estimates ... Called "Median~~ Exposure o Results Also Presented for Riinslky (1981) Estllm.ates o PHofnlm Worlk:ers Always Exposed: Under 1 ppm Under 5 ppm Under 20 ppm Under 40 ppm Under 60 ppm AU Workers N (Medlnam) 175 300 650 U77 1438 1710 N (Rinslky) 677 736 993 1487 nno 1710 BP-00018024 Reanaliysis of PHofHm Data (conf dl) Medlfian Exposllllre Estfimsttes Always Exposed Under: (ppm) I 5 20 40 60 ll40 (ARll Wmkers) Total Leukemnm IObsellVed IExpecl!edl 0 0.9li 0 ll.66 5 3.ll7 g 4.32 lltlJ SAS AMML I Obserrvoo ) E"ljlectedl ([)l 0.29 ([)l 0.55 ll l([)l5 4 llAll g l75. BP-00018025 Reana~ysis ofJPHofHm Data (cont~dl) Riltllsky Exposl!llJre Estima~es Always Exposed Under: (ppm) I 5 20 40 60 R40 (Alill Workers) Total Leukemia lObserved Expected! ft V9~ 3 2.55 10 4.5~ 14 5.45 14 5.45 AMML I Obsell"Ved . Expected 0 0.64 0 0.85 5 L-416 8 R.75 8 1.75 BP-00018026 Leukemia Risk by Maximum Expowre 4 3 ~2 i i 1i 0~~0~~0~~0==~~~~~~~~~~~~~~ 10 20 30 40 50 60 Maximum Exposure (ppm) Nllllm\blell"S rpre;seffilft xmmlbe;r of observed! cases BP-00018027 8Z08TOOO-dH ~~ftOM~it@ @[Mi][Ri [Q)@l~@ @UO [Mi]&mOffiQJJLFLFU ~@~11!JO" ~~o'tl'mm [Q)~~~~ lfiktaJil IL[!J]~motaJ tallnl~ ~MM[b,g ~ ~~M!r ~~OM@1~!3 5- 88 e Rlnsky, AMI\Ill 8 8 8 88 8 8 8 . Q- - - - - 9- - - - - 9- .. - - - t- - - - - Q- - - - - +J- - - - - _!] 4 oc w~ s "'0 ~ 0~ 2 wtl H.. .. ... 4 'f. '' 5 4 .:-. 5 Median, AMIViL a' 0 ,s ~~-1,'m 14 14 r:4l u4 - ', ,:rJ ~~..c;..____~ ~1~2 "o .~ . -~---' o_ 10 0 ' o11 .-. 1 "" .03 ;; 7 - !l. ,J Iw-_ 8- - ' '"5---4'( -- -"o----=--- ,. "M ....,..,. Tobol r_r5 - - M 11 -,f', 1 . R" ' " " ' Tota-l M __.....___..o " ----- 1 1 o,._,.., .......... .-.]:..::...~. -2--.. - . : ,..,1.. - - - ', u- _ 1 ' i 1 :: 0- - ) ~"""I " l,0: ,ri, , 9 , ,ri, 1! , , 1 ''1 .----.----.--,- 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 Max~mum Expo~ure: (ppm) - --- --""- -"'-.,_ UCI- ---~----o ,.,h.,...,...,_,Q .,.........._..,. 10110/95 ConcliusiolDls o Reannuatlysns Useful in DetermmiJrug_ Benzene Concentratnm11s Whklhl Resuh nlt'l1 lLeulkemna Rllsk Wn~holl.llt Modleli ()lr 0Lmr1IllllllRatnve ExposUlre Assump~iolffi o lLeukemia Risk 0lt'l1liy AppareJ[]nt for: [> 20=25 ppm Usfurug Rmslky Exposmes [> 50=55 ppm Usnng Median Approach o ARllaRysns Supports BiioRogic Evndlence for NonolLfrllle:aur Res]pHt))Jiile alt'l1d lProbalblle Tllrresholid Mechanisms o A li ppm U v-wo11dd Offer20o.SO-JFoRd MMgm tOlf Safety ftOlr lLelLlllkemm Rislk BP-00018029