Document npqJgp1yL2dQk6vLG5veJwde2

Brithh Journal of Indutrial Medicine 1988;4533-38 Chronic lymphatic leukaemia and engine exhausts, fresh wood, and DDT: a case-referent study U FLODIN, M FREDRIKSSON, 6 PERSSON, 0 AXELSON From the Department of Occupational Medicine, University Hospital. LinkiTping. Sweden ABSTRACT The cffcct of potential risk factors for chronic lymphatic leukaemia was evaluated in a case-referent study encompassing 11 1 casesand 431 randomiscd referents, all alive. Information on exposure was obtained by questionnaires posted to the subjects. Crude rate ratioswen increased for occupational exposure to solvents, DDT,engine exhausts, fresh wood (lumberjacks, paper pulp workers, and sawmill workers, for example) and also in farming. Further analyrir of the material by means of the Miettinen confounder score technique reduced the number of rate ratiossignificantly exceeding unity to encompass only occupational exposure to engine exhaust, fresh wood, DDT,and contact with horses. Chronic lymphatic leukaemia has been epi- The aim of the present case-referent study was to demiologically d a t e d with farming' and determine whether or not an effect could be seen in cxposure to benzene is an established risk factor for relation to reponed risk factors and if some other development of myeloid leukaemia.' So far benzene relation could also bc obrcrvcd. Furthermore, it was has not been definitely linked with 0th- malig- importanv io see whether or not the relation with nancicr; it.is unclear whether or not benzene may background radiation found in our previous studies induce chronic lymphatic leukaemia but two studies for myeloid leukaemia would appear also for this give some indication that this may be the case,* as disorder" if so the relation found in these earlier discussed below. Some other agents, however, have studies would have to be looked on as likely to be due becn associated with chronic lymphatic leukaemia- to some sort of bias. namely, carbon tetrachlorideand carbon dirulphid~.~ Unspecified solvent exposure in the rub& industry M8ted.b .ndmethods has also been connected with lymphatic leukaemia, the crude rate ratio for high grade exposure amount- CASES ing to about reven.* In the Swedish Cancer- Cases of chronic lymphatic leukaemia (International Environment Registry (the linkage of census data Classification of Discara 1965, ICD 204.15) were with the Cancer Registq) shoemaken WM at excess obtained from the registers of the cytolo~cai risk for lymphatic leukaemia. They have probably departments at the hospitals of.Linkiiping, Non- been exposai to benzene and other soivents but no kiiping, and Jiinkiiping and from the medical clinics accurate information is given about cxposwc.' at the hospitals of Kalmar and 6rcbro. These hospi- Benzeneproduced from coal tar and xylcnc m a y be tals arc in the middle and south cast of Sweden in more leukacmogmic than petroleum baaed solvents provinces with a total population of about 1.5 mil- according to the rcaults of Arp eral.' In two register lion. The diagnoses of the cases had to k conArmcd studies, linking occupationsby dcath CcrtiSCata, car both by cytologists and clinical physicians. Most mechanics, gas station personnel, lumber and ply- cases were diagnosed betwan 197s and 1984 but wood millworken, school teachers, and health pro- some had b a n diagnosed as early as 1964, surviving resrionais had an increased risk from lymphatic into the period 1981-3when all casesfulfillingm a i n leukaemia' as had ~81penters.~ criteria w e n contacted. Hence, the age when By contrast with myeloid leukaemia no relation answering the questionnaire should not be above 80, has becn observed between ionising radiation and and they should be mentally capable of answering a chronic lymphatic leukaemia. questionnaire. They had to be Swedish born and live in the catchment a m of the particular hospitals at the time of the diagnosis. Eleven casa wcrc not ALXTP~C2~March 19x7 willing to participate but I 1 I cam?joined the study. 33 36 Hodin, Freakikaaon,P e r m , Axebon REFERENTS Exposum was considered in the tame way as in a Referentswere randomly drawn from the population previous study on acute myeloid leukaemia"; csti- registers corresponding to the catchment area of the mated expooute to background radiation from the particuiarhospitaL.Siaccwealrocondumdaparal- building material ia the houccr was categorid le1 study on multiple myeloma two nfcrants wem according to a-radietioa index as explained below. drawn for cach colt of either multipk myeloma or Only exposure that had taken place betwan five and chronic lymphatic leukaemia which resulted in 2S yean Wore diagnosis was taken into account as enrolling 484referents. Of theos; 17% (n = 83) were with tht cxporwo xray d n a t i o n . not able or willing to reply and wen mplaccd by The we of a timewindow d a t a tothe fact that the other, rimiiariy drawn, subjects. In the anal- the inadenceof(mye1oid)leukaarmaamong the Japanese age span for the referents was restricted to 40-80, A-bomb survivon camr to have increated at about since the cam were in that age range, thereby rcduc- five ycan aRer expcmur~.F~u~rtherexposure consid- ing the primarily tligibk referents by 53 so that the erations w m b a d on an earlier Swedish material finally consists of 431 randomly drawn investigation rhowing that the gamma radiation in rtferents. wooden houses is similar in magnitude to outdoor background radiatiod* (the average absorbed dose ASSESSMENT OF EXPOSURE being about 1mGy or 0.1 rad/ycar9cosmic radiation information about various type, of exposure among included), whereas concrete houses lccm to provide thecasa and Feferenuwas obtained by means of a about double that exposure; plastered h o w and nine pagequestionnaire,proadodby an introductory brick houses have exposure ltwls in between these letter and ported to the subject%The qwrtionnain two e x t m u . contained 17 main quatiom, of which IO concrrmd These various aspects wen accounted for by a occupotid some of which w c r ~further gamma radiationindex that was created to make the subrpscifiedwitbngsrrdtocertaindetoilr.Fivequa- Study (U ti^ as pOrrible with to back- tionsweradevotad tomedicalcarc, particularly thc ground radiation exposure. Hence, for every year of use of drug#,x ray treatment, and x my e X O m i ~ t i 0 ~ .residencein a concrete house a penon got two thirds Aminimmexporuntofomyarwmrcquircci of a point in terms of thh index, whems working in and in gcnmi a live year latency time requirement a c o w building gave one M d of a point a year; was appIiai4mt is, the last fivs yean of exposure tbb exposure was t h e weighted over the day. Fur- wcm dhgwdcd both for cases and d k m t s . Since thermore, om ''concrete point"could beobtained for thecffccr of low dorsradiation was OW oftheconsid- evory ycar and be cumulated from a minium of zero erations in our series of studies of haematologiCal up to a mnimum of 20 within the time window. nulignancia'oL' (U FIodin. unpublished o b - Thra catqorim of the index were than chosen for wtions), dorsutimatufor the rcdbone m ~ o with analyra, a Ant category of -99 points, a second re& to xray examinations wcrc considered and category of 7-13-99 points, and a third category of band on available cstimata of radiation doses to 14-20 points. The detailed gamma radiation paticnt~.'~ Ths exporura wcrc divided into three d a u i h t i o n was g..Il.lyJ blindly for the subjects catcgoria, light, d i u m , and heavy. In that part of with regard to their status as casu or referents. the refmat series that was directly tied to chronic Information about solvent exposure in qualitative lymphatic ieukaemia only those examinations that terms was directly obtained from the questionnaires t o o k p b betwan aod 25 Y C S W~ OChCd @ - whereas the quantitativedawihtion was referred to n d s were accounted for in view of latency consid- fivecategoriuor intensity on ajudgmental basis, sim- erationswhicb have bendiscwed in o w of our pre- ilarly to a cJassi8cation used by Ranrkov erul.ls vious studies' on myeloid I ~ U k a m 3 i a ' ~For the Information about exposure to engine exhaust was refnentsoriginally chosen for the multiple myeloma obtained f m the questionnaire as was information study the corresponding "time window**was 10-30 about smoking habits and various environmental years before d i a g n d a slight inconrirteacy had to aspects and leisure time. be acccpwd for cort related tecirnical m o n s , since the ~ ~ p ~ o~f uther iaetter nlhmts primarily STATISTICAL METHODS codal as optimal for multiple myeloma The statistical analyau of the data wcrc based on x Ray treatment for joint pain. skin disordm, and stratification and application of the Mantel-Haenszcl tumours, for exampie,alto r d t s in a dose to the red The Mhtinen confounder technique" bone manow. Such treatmentswm considered with- involving multiple linear regression was also used as out any quantification, however,because the few sub- an alternative or an additional method in the anal- jects affated did not pmnit a useful subclassification yses. The method applied for calculatingayproximatc into different exposure categories. confidence intervals of the raw ratios has bccn out- 41 41 4 59 17 4 58 200 lined by Miettinen.lDMultiple linear rrgnsrion was indicate significant risk factors(or preventive factors) aim applied and bawd on the SPSS-X package.'* and were therefore not further considered. Sina the study is a combinationof an incidence den- Cruderate ratioswere significantlyraised for those sity and a p r m h c e t y p e , theartimaterarc rcferrai exposed to roivmu in higher exposure categories, t0 M h a w rat8 ratios rather thoD OddS ratios 2-5, as compared with thom with low grade or no dthough num#ically the mnc.20zLFisher's exact exposure. Occupational contacts with horses, DDT, tat was applied in crude anrlyrer when the numkn frrrh wood (lumberjacks, paper pulp workers, sawo~neernedwcn unratirfaaorily small for the Mantel- mill workers) wem found to k associated with Haenael chi-square tat. chronic lymphatic ieukaaniaas were the occupations of farmen and paintem. Proferrional exposure to engine exbrurt alro appeorcdasa determinant of the Results disease (table I). Dwelling in a concrete buiiding (gamma radiation Of thr 11I cu=. 71 WCIC men, w h e w of the 431 category 111) was not found to k a determinant for refmts, only 200 were men, which milacts tha well chmnic lymphntk Ieukamh nar was radiologicai known rclativoCXCFU of women in higher agogroups. work or radiologicllltmtmcnt or heavy xray exam- Thir dvoa a m d a m i ratio for mria gandur of 2-0s ination orrodatod with any QXCQU drk. Working in (93% confidence intmal, 1*34-3.14). the plastic8 or rubber industria or welding did not Scvcral analyses were undertaken with reg~rdto appear to krisk factors, nor were the occupationsof various cxposuru for orientation and identification electrician or chemical worker associated with any of confounding factors. This was done by calculating sipificantly raised risk (cf discussion in nfmnce to crude rate ratios as a first step. Slightlydeviating risk findingsfor myeloid leukaemia). Long tcrm drug con- ratios would not, maficr more sensitive analyses, sumption was not seen more often among the cases Siam w exponm 36 Flodln. Fretjrikssm. Person, Axehan than among the n f m a t r and then was no associ- could perhaps be that the responsible compounds in ation with smoking (table 2). fresh wood may change their character whcn thc Sixm CIUcb wiyais mifit k afbted by con- wood is stored. founding effku macb as the facl that the cases wen In this context it is interesting that an effect of son older than the rekrents,and the rex distribution was wood bedding o r t h e liver enzymes of rodcnts is unequal bet- ams and rcfstonts, and bocam known from laboratory expcrimen~Z,s~T~his cffkct various ex- might confound t h d~fact of ercb is strongest Cor md cedar but other typu of soft other, further analyses were ~lfft#~cTyhe. needs for woods also incream the activity of liver enzymesmore an d u a t i o a with regardto confounding in the data than hard wood balding.'* zs Furthermore, in some between the different risk facton waa b a d on judg- susceptible strains of mice the use of red cedar bed- ments a h the alcuirtions of the crude rate ratio as ding significantlyi n d the incidenceof spontane shown in table 1. Thesubsequent use ofevaluation by ous tumoun of the liver and mammary glands.26 multiple linear mgmsion indicated age >60, engine Hcncc, animal studies a h seem to suggest somecar- exhaWt, DDT, working in contact with fresh wood cinogenic activity from soft wood; further studies in (paper pulp industry, lumbejackr, aarmill worken) this respect a n certainly warranted before any more to be pertinent risk factors(p 09s). Application of definite conclusions can be drawn. the Micttinen confounder (core technique, b a d on As could be expcted from the experiences of the the iiaat multiple regcrdoafunction to account for atomic bomb survivors and other existing informa- the stronger detmnina~tsof risk in this matcrial tion no relation was found between chronic lymphatic (thosefacton with a lower than95% confidanw limit leukaemia and xray therapy or heavy xray cxam- for d rate ratios d g unity (exporum to ination or dwelling in concrete buildings for a long fresh wood, age over 60, engine exhausts, DDT, sol- period (gamma radiation category 3)." To our VCI&frerh WOO& h o r n fma -&)) ~ V dO - knowkdgc chronic lymphatic leukaemia has never matesof the M a n ( c l - H a u ~ drate ratlor with a lower beendescribed asking induced by ionising radiation. limit of the 95% confidence interval uccaiing unity The negative findingin this respect scems to validate only for age over 60, engineexhaurtr,DUT, and con- the observation of a relation between background tactswith horses. For freshwood the 90% but not the radiation and myeloid leukaemia in our previous 95% confidence intervat exoccdcd unity (tabie 5). studies as the methodology in those studies was simi- lar or identical to that of the present study. Dhcodoa Exhaust both from diad and gasoline engines and from two stroke cycle engines appeared to be associ- The incidence for chronic lymphatic leukaemia rises ated with an cxccu risk from chronic lymphatic leu- with increasing age, presumably due to someinherent kaemia. Lumberjacks with exposun to two stroke factor in aging itself rather than to any particular enginesarc oncn fanners and therefore often cxposcd exposurc. to thc exhausts from tractors. so that some indistin- Wood workm in contact with fresh wood as in guishablc confounding might be involved in this sawmills and paper pulp factories and lumbcrjacks respect.* The observed eff't from engine cxhaust wcm at a r a i d risk for chronic lymphatic lcukacmia misht well be biologically valid. however, since both in this study. a finding corresponding to multr garoline and diesel exhaust contain mutagcnic reported by other Milham has reported a agents." No information about the possibie non-significantexcess of lymphatic leukaemia among mutagenicity of two stroke cngine exhausts sccms to paper pulp workm." have been published so far. Earlier studies dealing Son wood is handkd to a considerable extent in with the effkct of engine exiraurt has focused on lung Sweden. Naturally occumngcompounds in the wood cancerfs:no study on chroniclymphatic leukaemia as may exert a cytotoxiceffect on man. and it is known related to engine exhaust has k e n found. that different typa of tcrpcnes may cause irritation of Measurements of bmzcne concentrations within the mucous membranesaccordingto studieson work- car cabinsin city traffichave shown lcvelsof40pg/m3 en in sawmill^.^' Nothing seems to havc been of bcnzcnc in d i d can whcn driving, and whcn described so far about the mutagenic cffcclr from qucueing, benzene concentrationsarc cvcn highcr, up pure wood. however, and it should be cmphasid in to IIOligjm'. Duringforestry work with a motor saw. this context that according to the analyses made, thc bcnzcnc concentrations seem to be much higher, lev- cffmof creosote or wood preservatives do not con- CIS up lo 700pg/m' (Swedish TLV = 16000pg/m3) found thc CXCQI risk sccn after contact with frcsh have bccn Benzene concentrations of wood. Working with wood that had k e n stored for around I ppm(3200pg/m3)may bc Icukacmogcnic,.'O drying was not associatcd with any significantly but no cchain cflccts havc bccn sccn from bcnme at raiscd risk in carpenten. for cxamplc. Thc mson lowcr Icvclr. so that othcr ugcnts should @ thought of 1 as responsible for the kukaemogcnicekecuof engine exhaurt. solvenu of diffennt typa have ban dircurrcd as risk factonfor chroniclymphaticleukaemia. Benzene is establishedas a risk factor for myeloid leukacmir and them arc come reportr ctlto indicatingan associ- -to explain the excess seen in farmers. This is also re&ctsd in the regmion equation (table 3) where fannm were a negative codWcnt. In 1\u11111~cy,tbisrtudy has&own a rathercomplex picture with regard to various exposures which may be potcntiaily important for the aetiology of chronic ation with lymphatic leukrem'u.4 s In our study two lymphtic Exposure to engine exhausts CIUCI and two d k n t r wendcariy exposed to bcn- andcontact with f a wood appear to beconvincing zus, resulting in a crude rate ratio of 3.3, but the risk facton in view of the datively large number of numben are obviously too small to pennit any individudsnportingthaecxporuraandthenis~ coociutiOllS. arclrtivelygood idoiogicoiarpiraatioaforthemcana In the cohort studia mcntioncd in the by whicb thwecxposuruQ#1thcireffcct,cwn if the introduction4" positive correlations are dacribai specific agents involved remain unidcntikd. betwcer,dilf-t tvpa Of ~ l ~ nant drchronic 1 ~ - phatic kukada, but no analysts have ken under- Thisstudy wusupported by the SwedishWork Envi- trrLen to elucidate thc effect of confounding from ronment Fund.We thank DrCarl436ranOluonand other possible risk factorr. The lack of an eiaborate M n Muita NyrUam, Dqmrtmmt of Occupational analysis in that studia may t h d o r e explain the Medicine, Medical Center, C)rrbro, for support and hdingr of mlvmts in general as associated with help. Chmnic lymphaticlcukacda. DIYI' is kuluanogmicinmice,31and oral admin- Requcst for reprints to: Dr Ulf Flcrdin, Department istration has been reportedto cause lymphomas and of Occupational Medicine, University Hospital, lung neoplaun&'' Among people there is alto an S-581 85 LinkBping, Sweden. observation of an association ktwcen DDT and mrli-t iym~-.33 Analyses regardbg associations between different t y p of domaticanimaisand chmnic lymphatic leu- kamia were UnderULen but resulted in a positive findingwith respectonly to the horse. Galloet al have described a viral aetiologyfor leukoemiasamongwild mice, domaticcats, cattle,and gibbon So far there is no definite infortnation about the viral aetiology of leukaemia in man, bowem. Exposures to chemicals should not k forgotten in thiscontext. as they occw in the maintenance of harness for honer. Fannm have ken rrported to be at an excess risk from chronic lymphatic leukaemia.' In our study contact with horses, engineexhausts, and DDT seems lkrtrratioaofInMwcri* From I July 198s articla submitted for publication wiU not be returned. Authon whom papm 8n rejected will be advid of the decision and tho manuscripts will be kept under security for thrre monthstodeal with any inquiriesand thendertmyad.