Document B8dDgBxp2Kgr686BYqow2Ozdj

Apr-14-01 12:21pm Frorn- Acute m y e W leukemia (Ah&) is characrcJized by acquin=d. nonraadamclonal ~hromosorrreahmmalities, which have provedto be clinicaliy and biologicallyim- pomar sin& they provide diagrrostic. prognosck, e t b krgk and pahogen& infans;irau (1.2). soarr?experi- --'Imcatunsreadl isffceurdeinest indicate Qat different exposures m y types of clonal chmmomme abnomtali- rk(3-a Punbermom, AML followingd o orckm- 0cher;rPy differscytogenetically from de nova AML (6, 7).The ptrzms fCtrcIom1ChrWMPa b n m i i u e s ia agenu have been associared with total or partial losses of c h m ~ r r m e5s and 7 add ddcrionsaf the short arms of chmomnxs 3 and 12. WhmM topairomernse-lr inhibitMEhave been linked to srruciuralrewrangemtsof chrcrmosomebands 1lq23 and 21q22&9). In addition. id peripheral lymphocytes of healthy workers exposed to high coTlccntrariOnr of bcnscne, Qsedependenr griw (mainly trisomy)of ckom~somz8 (10)add deleubmof chromosomes 5 and 7 C11) havebeen found. Known risk factors for AML include radio- and chemorherapy. bcnzeneexposunk and smoking (12). In addition. exposure to o t k r organic solvznrs (13). ex- I Apr-18-01 12:21pm Fron- T-415 P.03/11 F-465 Afhher a1 mmdy low fiequoncy tlectrwlagnutic fields (ElMF) (14-18), hair dyes (1!+21), pesticides (22). petroleum products and exhusr gases (23). dmalbomt viruses (241, and fcmuy work (25) have beenindicated as risk factors,albeit with confiiainglesults(12,26). stlldies ofsu&ysted o c c u ~ n arilskfacms far spccific subtypes of AML, as defined by rnorpbbgy br karyotype, have aoo1been consistent. Exposure was not associami wirh any specific marphology in one study (271,urherw- others have indicated i m a s e d risks for acute myelomonocyticlcukemja &r benzene (28) and peaicide (29) exposum. i n d r j s k for acute promy- Czlocyticleukemia in elecuicians(30).and a possibleassocktion between exposure tosolvents.insecdcides,ot petroleumproducts and erythroleukemia(31). With regard IO c l m l chromosormalmormalirics, in some studies, AML.patients ~xpaPodu)sdwms 01 pemicides (31- 33)or 'chemicalu" (27.34) had a kighm proportion of clomal chqnc&ameabnonnalitie (cspacially cornpbte or p i a l lossdchnomosorae5 or 7. aod trisomy 8). but not in orhas (I d35.36).It has alsobeen ruggesredthat AML io ~ s o c i a rwi i~rh previous roxic occupational exposam hasa woise prognosis and qmsenti a disdnct clirlicd.as milas qtogenezic,entity (32). Limt is h o w n abaur rhc effccr modificarion of tx- posunby a&, genckr, and smoking in AML.However, sidlcrcl al(373ObscIvGd 86 exp6snrc-nspmstbehvcen SmQkmg andrisk for AML only fcx subjecrs above tbe age of 60years at &e ofdiagnosh. The pmwt study was unlnaJreato expkue prevaient apcwrcs. such BS organic sclvents, ELhdF,and la& dyes. suggcsrsdas risk hctonin preview studies wirh regardto o v d l risk for AML M m w , other objec- tives were IO study chararmisticclonal cimmosorneabnormalities@ markers of exposure, diffemtial risksfor mctrpldogicaisubtypes,and effecc moditicafi011 by age. $onflex,a d ~ ~ n ~ k i ~ g . cases Our study is based on a scsjes of 372 umse~udvecases d Ah&. d i a p o d h e m 1976 and 1993;the sub$cts were at least 20 years of age when cytogenetically dvestigaredat &e Dcpartmant of Clinical Generics,Ludd, which pelfcmls all cytegenctjcanalysesiaswcheanswedcn.AU referralsfor such analyses are ma& wirhh the pubiic Wdr system. "%e hatoIogy depar&m~81 he Lund Univemiry Huspital and at thc n&y b ~ p i t din Helsingbcug, thmughwt &e study paioti, included cytogCnetic Sfnalysesas a routine in the diagnmliccrtIrmtioxl of hemamlogical dgnancies, lodicading that the coverage of incidem cases is mclsf complete far rhese catchmcat areas (Lund-Helhgbmg). Intmkw mformah a was obtajntdfbr333 caas(9096) (table 1). The non- parcicipadng caseswcrc OW(median age 68years] and fLum cdknwamm 09%). The medical meo& for eachcase werereviewedby 1 Of3 Jmnadogisn(38)."hediagnosesw m based on tbc moiphoiogical hnd clinical findings present 81 the time 61the CyIPgeneric investigation. The m o ~ o g i ca1 subqpcs according to the French-Amerjcan-IBritkh FAB) cl;rsPiflcacianwe= as follows: miaimally M i x enrfawd (MO)1 case, myeloblastic without melmUim - Apr-18-Ol 12:22pw From- T-415 P.04/11 F 4 6 5 a Referents Statistics Swedcn seleaed 3 referents foreach case. -----Imatched wich e p e c t to gender, year ofbinh. and CyIun- ty of living fmnthesmdy popukion (souchemS w a n ) within the calends year in which each case was diag- * nosed. Ode referent in each matched set was randomly selected 10 be interviewed.Whcn referenrsor h k eext- I of kin could not k inrwizwud, orherreferems from rhe match& set were sekcced M t o g e t k 351referentswrra ineluded in the study (parriciphn rate 72%) (ubkI). The nonparticipatingrekrenrs wert alder (median age 68 years) and mmc o m women (60%). The s ~ b j e a sw r c r o t r o s w v d y cnrollcd in rhe study and conlacted with a letter describing the purpasc 484 Scand J work Envimn Hegllh 2o00,df26,no 6 dtht study and rhcmain question9 to be addmseddur- ing the inmiew. A life-hhg aecupati&nalbtrmy was &mined during chc Mod 1995-1997 in a rmuculred rekpbne 'mrview made by 1 of3 occupa- ticmadheal* nurSCS who were a w m of thecase-refemt st~hlli.The histmy inc!eW all jobs held far at h r 1 ycar. k l d i g w m h k ciepamm, d nameofcom- pany. No specific e s r p o s ~were asked fclr ia &e her- view, bur follow-up questions w e triggered iag cbzapp.iicacionufpesdeidesinwork as ilgardeRuor horricuhrisr, lumberjack, zdway w o r k (track main- renancc), f m m , oraamhmri;cype of WrgQ inwoslr,as a driver or un a m d m t ship;handlingofc y t o d c s in work as a rmmz; and working I a mea counter in work aa ashop Wpm oc shop assismm. Infbrrrmrionon extra jobti held f a at least 1 year wns collmtcd in tbe same way as for the regnlarjob. Tbe following hobby rriviries were explicitly in- quid abom:motor repair, mi& pluuing withoil. fur- nimm renovattoa,CcuJs~tionbfmOderkich%,animal h d i a g . hrmring, wd gardening. Follow-up questions were asked & h u rxrivity periodand average hours per week spcnr in ihbe aaivity. A follow-upquesrionOII reg- ular pcslicide use was triggered by gnrdsniag as a hob- by.Furthennore, qucsrions WCIS asked abouc awar hair dye UK.and smoking habits. Tlze medical histmy pre- ceding&a rim of the casediagnosis iacluded quesrianr &our radiotherapy. chtmtttewy,and ct- wim imp. lf rhz 3ubjjcct was deceasedMtaa ill to penicipe, a nexc-&kin was selsred in the fdhar;lg orda:spusc, parenr., siilmg. and cbild. Infomciw hadLDbe OMIiOcd fmrhtnext-&-kin more oftzn for cases rhan fm mfer- e m (tahle 1). The proporriOn of nexrsf-kin interviews increased as the age of thc subjtccs increased (eg. next- of kin imerviews were used & 933% of the cases and 23.5% ofthe refmnrs o mthan60y%Wsof agck S p - es and children were rbz most frrquently interviewed amng the next-&kin abath thecases (48% and 36%, respectively) and ehe r e f m r s (27% and 6396,rcspzc- tively). Exposure assessmerlt Exposure aSS2SSm2ntwas pesfwmcd by 1of 3 OCCUpational hygienists, CUI tho basis of the suuctured relep b inaetviewsmadeby the ocqat-malhedrhnurs- es. Tbe occuparional hygienists werc U M W ~of the casI?-rcfemntstatus, The ssesfllocncs For all cases,and for rb ccurespondingrefeenu, were rtsrrictcdUI erposure periodsof at least 1 year duringthe 20 years before [he diagnwis of the case. All ccdings w p e supervised by double-checks petformed by one of the hygienists (m. Apr-14-01 12:23pm From- Albin QIai Exposure assessments were performed for estab- judged from coinparisonswith rhe medical recordsavail- lished, and suggcsred.cccupaficnaland leisure-timerisk ableforthe cases (&le I ). ThusThe effect cstimareswcrc lacton for AMI.(listed in table 2). Quantitative defini- likely to be biased and therefore have not been presai- tions of the diffaenr exposurr intensity catcpories were 4. uscdfor organic solvents, benzene. and U F ."W. `modeme",and "high"exposure 10 organic solvenrscor- Statisisticalanalfies responded to t--5%, 5-1546, and >15%, of the present When Only -& mMCMg ~CCOISsuch Bs @md gCn- Swr?dishaccupational exposure limits;,reipmvely. For der are uscd, confounding can narmslly be rno* c,E- knzene. rhc comspondingcargwics WEE 0.05-02, ciently controlled in a suarified analysis rhan in a 0 2 4 . 5 , and ;.OS rngld. Exposure to ELMFwas c b - matched mnalyUu(45). In om smdy, all effat estimates rified m x m i i i g u)S-hour arithmetic averages reported were therefore obtainedby uneandiritmllogis& rcgresl for differem occuparions (441,with the fallowing cate- sion (36),sfzttified[or age into 3 b a d eaiipbrics (G4, gories: 0.2%0.30.0.3043.50. and rO.50 pT. For #I 55-69,md 270 yean) md gender. Comprpison with -. Mher occupational exposures. thedifferentexposurein- estimates from a conditional logistic regression model tensity caregcnies ryere &heated by examplesofw u - (46)showed hah e stratification sufficiemlyaccounted patioas or rasls. Pot txposurc to aromacic organic sol- for the cfftct of the matching vaiablcs. Year of diagno- vents (exchdiq borneat), ChloridptedO I p i c solvents. L and county ofresidence did not influence the e f k t and cytostatic drug. only dichoramous assessmznc (ex- cstimces and were therefore noT included. When rhe posedhnexposed)was pdble. Expowretocattle7po~& [rends were tested,the m&icienr from a logistic mods1 rry mB fnesh mew was consideredtogether due to the hy- with h e exposureintensity (L=bobby-low, kmderate. potherisofaannmon causal factor (animalhe v i m - 3=bigh)add dumian (as a continuous variabk). respec- IS)-The main occuparion in this exposure catego- was tively, was IS^ as Ihr wt mrixic, ppovided drar tbtdata fkllner. were furly cmsisun! v,+krih such a model (47). Thzpop Fm rtgular hair dye use and smoking. classificatiou ulrruon atrribucabh risk, with 95% cadfidence ialrarals was dincrly bawdM the specificquestionsin he inrer- obtained witb tbc ManuA-Hacnszel qpmach, was esti- view. Cases add refmatswere classified3s smokers if mated whcn appropriate (48,49). rbeyhadmoLEdrwarlensr1 yearduringtheMyears Tn wdcr to miucc cxponse midasdACadon, only before &e dugnosisofthe case. Mure-time expornma expos^ assesswnts wilh bigh cbniideoctfaroccupa- were asses& for9 tbe agmars,excepr EIUIIF.ionizing tional exposive~were used indK:a o a l y s ~ as l l b j a were &ion and cb-puric drugs. classifiedas uncxpd fora particulara g a only if they For &e occuparional expawms, rhc ~mfidzncein he were unexposed with bigk confidenceduring rbt tntirr: mpmureoodinps was assessed (high CDafidonCc or not) &szssmeni period. subjects were clarified a i exposed on the basis af the quality of informadm on worktasks 5&cy were e x p e d 4 t h bigb confidence for at bast 1 and erpoams in Ehe iareiviev data and the confidence y e w duing rhc assessmeni period. Subjects that could of possibleexposure for differentworkrafks. not bc classlftd as txpased Munexposedwith highcon- kmte~rcbbiliy was assessed a f m the exposure frdcncc were excluded fromrheanalyses. A kss restric- assessments were finabed for all the interview forms. tiveappwachdidMI change tbe results subsranrially. and Tht main occupatiamlbygienisr (HW) reaq$essed198 they herefon have nor been presuftcd However, the randomly sd~cltdirh\riew fomts. unawareof the arig- appmch implies that the psesented exposumdurations inal exposure -KS. h rbe ctrigiaal Lusessmenr47 and intentities are minimumvalues. of these subjerns were dasSi3ed as ha- certainoccu- pational OT Icim-t* exposue IO organic solvents, 70%of tbem were ctwrifid in same way in the itassesmen&The 193 iPerViews were alsor o s ~ ~ a bcyd Retvllr aZndaecapMidhy~.Tbeconcardaawbetwcm the 2 r c a p ~ e s s mw~as~s~iightly benn (8wL;shpn bc- tweenrbenew and old assesuncnts;thisdifference indi- caw Lt SIighS sbift ia asasmml with riw. However, lb#wxenot&fkmws io &ecoac-bttween he wssaodrribartf. OntytbeoldassesrmentEw c n mcd in the anai]nar of wpi%ufceffects. Wecbwetoincludeinfmmrion on jwevjous chemo- arm- h m beU~h e ir#crvicw d tht medical d s (casesd y l in cbe chsihuian. sincetbe inter- view was insensitive i m detecting such trcaunenls as .. ...I :' -_ t . Apr-18-01 12:23pm From- .# T-415 P.06/11 F-465 -. 5 63 237 33 28 -25 10 65 288 7 a73 0.23-2.4 67 252 92 1.0 0.66-13 35 1196 0.56-1.7 28 1.1 6.8&+1 -IS 69 262 Ll82 0.35-1.9 0.98 0.64-15 indicatedan i-mg risk with increasing intensity of exposure [ m e 3, wsr fervend (hobby-low, maderape, high),Pd).Ql]. Trpicrla t m p t.m s in rhc modcmc-high intenshy caregory WCR painters and a b b e industry workas. slrd in rbeIow-intensitycalcgory carpentersand mtor mechanicsprevailed. S u p d asvaciations were observed for eqosure to kozene. bur not fcrr chlorinatedhyhnsbons. No in- creasing Lislr by intensity of benzene txpowc WBS ob- w e d . E f f e fFomexposum to organic sthcnts and to benzene were separated by rzsmcrionof rhe analyses rn mbjccrs c q w d 10 sokenrs othzr than benzene. The odds ratio was 1.2 (95% CI 0.69-2.6) Tor the hobby- low category and 27(%% CI 1.0-7.3) for them d x - *high categoty;this m u I t indicates that the observed cffcct was not due to be~llencexposwe aloae. Separa- tion of the &acts from exposum IOall organic solvents from rh3z of sromatic solvenu orher rhaa W n c was not gossiblcbdeauhthey w e too closely associated. Analyses by dunrion of only occupationalexposure (ic,excluding kisure-rimzexposures) to all organic sol- vents &Q indicated 2 positive assmiation with risk far AML [1-7 0 2 case^, I5 rr4-u): OR 0.!38,45% CT 0.44-2.2: 8-14 ye- (IS cases, 15 refmenu): OR 1.2. 95% CI -2.5; 215 y a ' ( 3 0 C- 17 nfet- 486 &and J Wwk Engiron NmNn 2#0, w26,cIa6 Albin er d 0355-3141 Apr-19-01 12:Zlpm FroM- ~ b mz t prevalmt qusure wag white spirit. For this agenk thcokd-wouldconespolsd madcffccrlcv- el of<lS rnghd, which is remarlrabiy LOW. In addition, an effectfrom leisure-timc exposurr only [OR1.8,95% cIO.92-33. WC in WBS indirMed, E- txposurc, which is Bn established risk as- rnfar AML, did not fully explain &? e m s risk for ex- pururc:to organic wlvents. +IkobservedleveIs of ben- zene e x @ m were low(72% ofthe exposedcases were e x p d to iarensities belnw 0.07 ppmj. uul our modest- ly elevatedO R estimates fw benzene exposrule are thus rlw ia conflictwith rRuseof formcr srudies. We did not observean increased risk in association with oven11c x p m topesticides.Thc fquent ust of Uhxssion prpxy mpdnJcals fw thecases didDOE p e d a classlfi- catitioa of tbc type of peticicle. Our frnd-5 of no in- ?he salientfeature of the ~ 6 s e a ustudy was thz ccmsist- creaved risk with regard to the u ~ oef hair d y u am in a t &ahan bemeenexp- m organic salvcslrs and acrordaaEewith rheresults of 2 f m m r studies {51,52), 1 risk for AML,c~pecidlyia cases wirh rrisamy a as rhe while 3 other mdjes[l9-21) have b mmo&stly sup sole abwarion.Cmrrary to our hypochis, che a s s ~ c i a - portive of such a risk. Revibus studies of &e risk far uoas were essentially Rondiffemwial with regard to the A M L associared c k h cxpogurc to ELMF are conflicting O V pres~ence dclond ch.romosolllt!&mrmaliticr, as well as co LOWur paltiidlosses ofchmrnosows5 and7, The hypothesis of an associarimh w e m suchexposure andtrLomy 8 was less sadng, having been Wed only and indicate a modmrdy incmacdri* if any (26). C~IK resulrs ate compatib[c with thistinding. We may, IO somr?extent.have underestimated the in- Ensity and duration oexposure among the subjars by oll a&w earlierpublicarioay (10,31,331. Inou1study, 7 out of 13 wirh 4 3 as a sole anomaly hada history of exposuretoorganic sdvmts (table4). a pnvakncesimilar to that rcporced by Dwico et a1 (33). It Is. in his contrxf. mtew0Ifby rbat a mriew of mament-nhtcd AML ody wing m p s m jgsessmeftts with high confidwcc. Bias resmiting fronsuch miscldfication may be in eid m direction when mre than 2 exposmo categoriesare used in the analysis (53). However, for hoch fht cases and referenu classified as expossd to organic sohrer~s. did not reveal a s @ ~ t I y higherincidenceof uisomy 8 in such AML.w h camparedwirh de novoAML {7]. The possibility rbat expwure TO o r p i c solvents thus comulrsin difmntkaryotypic patterns thandoes exporn to radio- or chcrnotkapy is fuitber suppond by rhe the average number of years assessedwirh high c M - dencewm I8 (out of20 possible); this fiading indicares that this is a minor problem. In addrim. we chose. rn the basis of pnviws&s of treaaneat-rehd AMlL (13)and AMLrelatedtohighbenzew exposum(S),to present lwk of an associaion bwbea exposure to solv c m and itbwmalitieS of ~ h r o ~ s a m5d asnd 7, aber- rations that are commod id mstmc?nt-dated AML (7). focus exposure assessmaton the 20 years before d q nosis. If kss inwnse, aad kss toxic, exposure is associacd wirh P longer lsrznCy t h e rhno 20 p&So,ur assess- It remains to he sezn v t h e h other myeloid malignan- men&would u n k r r s ~ m w&vam cxpomwdurations cies with trisomy 8 as a soh anomaly, especially myelo- An i m p m r spcct of rhc vaIidiry af the study ist&e dysphdc Syndtomcs and chronic myclopdiferaiivc dis- diffcrrndalUSE of proxy~ e q w d c mfsor cases amirefa- orders [1). are also associated with exposure to organic enrs; rbis us(! violacesthe camparable accuwy principle.. . solvents. for;rhcselection ofrdcmns (55) and may lead TO negir- The suggested higher risk for eryrhmhukmia rhaa rive damation bias. However, when there is no indica- for other subtypes of AML in relation to exposunsto all rimb asubstantial difference ia in far ma ti^^qnality.the organic solventsis inmesting,but it bas previously only dominsrlr usz:of pmxy ".pbAdentp for Lht:caacsand selfbeen repxd in relatian to a similar small number of r q x m EMxcfc=nts is justified (W.Thenfemts in our cases frona pooled study (3I>and a case-seriesof kn- study rewned tht s ~ m icnediaanumher ofjobs held as z e n e - e x w wcarbrr (91- rht casts (table 1). In additian, no d&rcncc in the Our dbsrrvations of censirtontty increased risb,.even n u m k of yzars assessedwih high mfidenct WSxecn Awn low-kveicltposlsrr [not exceeding5% ofthe Swe+ ish accuparional cxpc~urclimits) to organic solvents are a s o u t f e ofworry. The results also indicate rhat expo- beween &C E B S ~ S&r&mntr f& expsuro ta OTgsolvents. Thus no substantialMerencz in infannation quality ws indicmd, b u ~tke ~ ~ S U X EaSre crude. W e WIZ to osganic solvents m y concribwe IOan impomnr refrained fmm addingrrsponden~S f a N S US acovdate in ~ o p t i o dof &e A M L cases in&e generalpopulatiw. tht togietic r e p s i o n model becaosc such adjustments 488 scan6J Work ~nvimnHeal* MM. VOI2s. o 8 . Apr-lfl-01 12:Zlpm From- Atbin dl ar F-46 5 1 do not secewidy nedpce tbe net bias (57). An effect e+ data entry. Asra Pcrsson and Gunnel Nilsson rzuicved timate fororganic svIvencs lestricfad io self-ftspondenls the mcdical records. did not indjcrte any subsranrialbias. SrilI, rhe dear dif- The pmjm was sapponed by grants fromtbr Swcd- ference in rhe pmpcmiun d ~ ~ ~ - d -i nk ~ivni c w ms ay ish C m c i l for Work Lift &search, rhe Swedish Can- have Hecred the affect csricnares. Thjs possibility espe- cer Society, the Medical Fxulry of h a d Uoiverrity, cially app1iesto cases diagnowd for DMrs people. Lunds URivessity Hospital, Crunnar.Arvid and Elisakth Although Iheassess men^ of exposure was made wirh- Nilsfoms Rt$earc.h Foundation, and PRBEM Resmch out b l c d g o~f c a s c d m r st~m5h, r ethical m o n sI Founddon. The pmjcct w e a p p ~ v e dby the Ethics' the nurseswho c m t d but tbc inmiews hadh i s bowl- Cbmmirlccof Lund University. edge. This situcion may have inrroduced a ipositive) bias, bot, in OUT opinion, it i s likely io have becd m a l l since the interviews were nrherArmly svucNIzd References All refmals far cytogeneticinresrigsrionsare made wilhin h e Swedish public bed&spun, and there is dwcforc no reason to suspect any socioecmxnically bared sekicm biasamong tbe cms, althoughcases di- agnosed at older ages, whhl mrarive i d d therapy is kss frequent,me likely u)be urrdtmprr+lented.A lower pUr;cipar;oll RAILamong the mfuents rkan amoqs the cases may, however. h8VC introdtlceddifferentialseis- daa into che uudy with rcgud ta,for example, socio- ocmmmicfaam, aad &erefox resulred in biased e f f a esfixwcs. Sucha seltction w d d be likely to invMJuce a bias in the same directioa for bropd carzgaritsofex- posure. We foundno iabicatimsof such a gencnl shift inthtefFendmawsforindasajstl-utban(g~esnd diesel fir4 and exhausr gases add ELf+=Golr s@cultUr- f-m(pesticides, frefh-m~t-mimalcontact, fresh wood) exposmw (table 2). bar u CBMOI btmlcd out- The resulrs of a nasmafof expsrs\ae to organic solvtms agreedwofl with rhcnsuhs aftbe initial il~ses5- m e a Them wcre rn difftxeruxs in the rtpeement be- cwen rhe c&sSandreferen&. The medim durationof occupationatexposurewith- in dose categaks was dightly higherforcases di-d at olderages(261 yws),and the propdon of oexr-of- kin inrerpiewswas higharhpdmIhe younge~age p u p , but it is ques~0a;lblewhether or nor thio differme LX- plains the sugge!md effM mabrfica~mby age. Oned- temarjveintaprera*wn Lrh;rrAhfLinddQccgohganic solvcn~occprsa ~ a molder agefhim AML withothered- o~.~possibiliyisan~g~cffectfros,slr- p u r e in that it h a beEI snggatd thttse effect a f a k-stagecarcimgm would b~ m4e prmpouacedat an ddor age (58). - Apr-14-01 1Z:ZGpm From- 1 -4 I t - Apr-18-01 12:27n Fron- T-415 P.11/11 &Oh e! at F465 U i ?