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R' Cr T I C t Th'~S matertal rrtaw be proteste0' Cv cocYtlzrit le:, f(Ir'e 17 U'.$. CodeJ. t.uRt1rEAN uwRN.41. MruRLIc: HE!LLna tw ta,A4-t 7 Association of passive smoking with increased coronary heart disease risk is not explained by elevation of leucocyte count V, = GREE\, J SHAH.4S1. J GREEh, G HAR4RI. J. BER,HEI,1 ' The increased risk of coronary heart disease in cigarette smokers may be due at kasU partly to an elevation of the Ieucoryte count Chronic passive smoking has also been found to be associated with an increased risk of coronary heartAsease, but its effect~on the leucocyte count has nbt been reported! In this study 250 male factory employeess aged 20-64 years were interviewed on smoking behaviour and exposure to environmental tobacco smoke, and blood counts were determined. Urinary cotinine was measure by, radio-immunoassay and corrected for urinary creatinine concentrations. Mean leucocyte count was significantly higher among smokers compared with non- smoken (8,666 compared to 6,900; p<0.001). On the basis of smoking history, passive smokers had leucocyte counts similar to non-smokers. These findings were confirmed when leucocyte counts were compared4ith urine cotinine to creatinine ratios. The association of haematocritand haemoglobin with smoking was similar to thatof leucocyle count, These findings suggest tftatany association of passive smoking~with coronary heart disease is not through an elevation of leucocyte count. Ke. wor&:: srraking, passive smoking; urine cotinine. blbod count, kucoc.-tes, coronary heart disease Lruc.ycwc count ha, been shown to be tndependenth. a-.ctat e.i w rt h.un rncreased rtsk of ,coronars, hearudi sease (Friudm.tn er all 1974. Zalokar et al. 1981. Kostts et al. 191-4. Em« et al. 14~T ). ln addition. ct¢arette smokers ren,l tt) h,tvu hicher leucrrsie counts rhan nnn.smakers ( renn & l:ipr 19hG. Green et al. 199'_ l, and it has been su,_---estrdl thar rhis ma\ be one ot the mechantsms M which.mokrnh rncrea%esthe risk ofc nronarn heart drsease (K.):n ri aL 19,1:-i. Ernst et al. 195i1. E),Wsureto envi- nonmenral't,.haccosmoke lpassive smokmr1 hasalsn been :houn t,,ihr ass~xrated' with coronarc heart disease (Gar- lan.3 v.t a1. 1985. Glanr & Parml'ev 1991 ). although the mechanism ~,f this as.~utatrnn is not clear. Toxic a¢enu hasr been demonstrare,l in both maanstreamicrRarette sm.yke l smoke rnhaled' and exhaled Fv the smoker Yand stde-stream cJ>*amrtr smoke (emttted trom the bumrng :nncli(Hofiman & Hottman 1967. Enksoniet al! 148C): There ts ayme evidence that encme ssstems responsible fc.r the detoxification of smoke constituents are not rn- duced tn the same extent in passive smokers as in active smokers (Hoffman & Hoffman 1987. Enkson ct il. 1986). In a recent studN,, three h.wrs of heas\ exposure of 16 nnn-smokers to environmental tobacco smoke produced a mean increase of 33 per cent in leucocvte count (r°1n- derxtn et al. 1991). Howr%'er.to the besnof our knowledRe there are no reports on whether chronic passive exposure • M.s Gr.r.' °, 1 sMnrm'', 1 Green" G.urln'. 1. tirnr,enn`~ ~ D[CMWSC~N~ M~~Rn ~n{~RYItRYNM ~ SatklNf"URy o1~MpaM. TN Ainr Vm..lrt~Ty. ' Dfplr*"nt ol ~L/eDnrpCqy: Ml...Np{p.11~ I klaN earrnpon6.nctMrnJreO SGl~. Duuwlonai tieaRn rftenwte. El • DSo. I ruann& 43'tpp. Kr.N to environmental tobacco smoke rsreflecte,3 in an eles•a- tJon of the leucoctu count. Self-reported exposure to environmental tobaece smoke mac onh be a crude estimate ot actual e.T.o~ure Since nicotine in the blood has a short hali-liie -it ahiut rwo hours (Curvall et al. 19901 u is not suitable as a measure oi chronic exl+osure On t}ie other han.f. e rtrnme. the ma)or metahohte ofnrcottne, ts sFecrfic to rnhac:.n and ts, concentrated and~excreted'm the urine and sali%a lCur- \all et al'. 199,11. It has a half-life of aMout 19 hours m the blood and it has been shown that the urrnarn conrnne level ts a sensitive measure of darv exposure to tobacco smoke (Wald et al. 1'9h4,',X''all!cral 19Sc.,CumminFs et al 199'L')', The aim of thts studvwas to compare the leuc,x\ae count tn crgarette smokers wrth that of non-smokers e.rx-,sed to varying eoncentntoons of enrrronmental tobacco smoke. Urtnan cottntne concentratJons were used I to determine the extent of exposure to environmental tobacco smoke. Whtle the emphasis in this studi• was to e%allJare the association of exposure to tobacco smoke and leucoevtr count, haematocrit per cent and haemoglohtn concentra- tion are also analyzed for the sake ofcomparison tgTtlODS Sub)eces Three hundred ses•entv-frve men aced :C%4,4 and~ em- ployed in a single industrial worksne (93>''. - ere Hue-col- lar workers); undenvent routine health scrrrninc carried out by sratt ttom our tnstrtute. Part icrpat urn w a:< \ nluntan and the examtnattons were ottered~tree oi charge The response rate for participation tn thc stu,fv ua alm,-~st 1cIL 2023512304

Passisti smrJ fng mrd corona*. hrcn, diseate rer cenn A random sample of '_Si were included tn a special studx- of Fasslx,e smoking The sublects were all mten•rewed b,, the same trained uttera-iewer. ustnF a quesrtonnatre on current smoklng hablts, exposure to tobacco tnzhe workplace and exl+osure to tobacco smoke at home. A n-ptcal questton was structured a.< foliows: Do vour co-worken smoke in vour work area' 11iNa at all, 2) lntreaueni 31 Frequentlt; 4) Most ot the ttme. Answers 2. 3 and 4' correspond to the classification of mild; moderate and extenstve exposure to tobaccosmoke. Four gruur- were dettned a) Active smokers (categorLed bc <10. 1:-:C and >.O ctearertes pen dav); bi non- smokers reportanF mtntmal' exposure to tobacco smoke both in the workplace and ar home; c) non-smokers reporttn^ moderate exposure to tobacco smoke ofiothers m tnc workplace orar home: and d) ncm-smokers repor- tmc extensive exposure to tobacco smoke of others in the wwrk`lacz Or at home Sublects were askedo to provide urine sami durrnc a reeular wtirkdat, between 1.'.CL'` p.m. and :.th r.m Altauots of 1'.5 ml were kept in serum storage tubes tscrew top) at -7C`'C until tested. L:nna-_% cnnrune ar.-' creannme measurements Unnan cottntnr c.rncentrarnons were deterTrtsned in the nephrolomi research laKxaton- at Metr GenerallHosprcal. ustnCradw-tmmunoassa% (R1A)'(Double Axtttbodti-Nico- nne htetai+oltre. Dtarnostic Products Corporatton; Los AnceleO1 Qualtn• control was monitored by means of controllstandard's which were included with the test kit anSaOnrrnl urtnes which werestored an-2C'C. Since it was not l.oAsthle to obtain 24-hour urine samples. unnar., creannme wa~ determined using standard method's on,an auromanc anah:er in order to correct for, the cotutme concentratrons tn randbm urine spectmens. The cottntne resultc (tn ng/ml) were expressed relati+e to the unnan creattrrtne concentrations (mgJdl); a method tued suc- eesstullc hr other investigators (Wall et al. 1956, Cum- mtmR et al. 1090). St.uzsn:al mtal:ses The mean cortntne concentrattons.cortnmr to creatintnr ratios and blood counts tor, each uf the suhgroups tdenn - tied br the quesnonnatre were compared ht one-Ka, anahats of.artance and Duncan's multlple ranee test. Tne mean blood counts were compared graphicalll tor dtrtcr• ent tntervalsof cottntne:aeattntne rattosand tested tor trend bN Itteans of lrnear reg•resston. In addtnon., the association between blood counts and the cotrntne crea- nntne ratios were examined using non,ltnear regressWn. RESULTS Some degree of passrve exposure to tobacco smoke at work was reponed by$5,6 per cent, wwhereas onh- 27.3 per cent reported aml such exposure at home. Unnam cotinine concentrations and conntne to creatrntne ratios are shown bv smoking status in tnbie 1 The cottntne erea- trnme ratios disnnguish, betweem four distinct Rroup~ based on self-reported exposure to tobacco smoke: mtni- mal or moderate passive exposure. hearv passive exposure orsmoktnglessthan 1Cclgarertesperdat.smoking, l~ ctgarettes per dav: and smoking more than .C'ctgarettes per dac.lveverzheless, there was overlapping of the range~ of cotrnane to creattntnerataos betweenrthe self-reported categones„suggesttng either tn-aii of self-reportane. or variation in nicotine absorpuon or metaboltsm. or; both. Results for the comparison of the blood parameters rrnthe different sub-groups classtfred br• reported smoking or exposure to tobacco smoke are shown in tabie 2. Those smoking more than 10 cigarettes pen dar had a stgnttr- cantly higher mean leucocyTe counn than the ltghr smokers ornon-smokers regardless of the degree of passrvt exposure to tobacco smoke. Haematocnt and haemc- glbbrn showed a stmilar pattern. The mean blood counts bp, different tnterti•aL< of the cottntne to creatmtne ratio are shown in the figure While the linear trends were stgntftcann tn all three„the counts were clearh elevated onh• at levels of the cottrnne to creattntne ratioconsistent with heasj•,smokersan.3 rnuchi higher than those seen in non-smokers exposed to envi- Table I Iaran t- uandard'drs'taton l unnarc connme and cotwne:creannrne raatoi , amoksrsQ status (minimum and maximum,Rwen in pareneii Uritsary rtrrken i;,omnme concentntton (rsp,/ml) CottmnacTratramne nno Smoi'm¢ status n Mean SD Range Mean SD Range Pion-smokers iv,me rsr minimal rass+ve exrosure 6C 36'.3' 36.2 11i5 0.3` C:k (ti-1.2 Mn,ierate Fassrve exrosure 64 1'i4.3' 4i3._ Q2.644 Q.9' (L14.: Heasv passive expaure 22 1.D 2.i45':i D-I0.593 10 41, t 25.6 (L93.i Smoken < 10n¢arertes per da, . :aoC'6, '. 3: 7.6 4 5-8. 5:2 1: 91' 11.6 C 4--4: : 11-:CnRarettes rn da+ 4: i.24: 3' 456-:'.'_99 38 1` 20:1' 2:0 'nparrttes per di 35, 7.9533' 3.B(•r { 65-==.036 44 6° 169 .'rr: e Fe:.~ (oi analvsu ot variance) 65 7 85-9 1 r <:.Yl'I <CATI 'e'~'IrrLca~~iuc.and~d~nnemp~.F~D~can~ttnultrE+/eraneatesist dmitr+ceni, level.ni.gritrffioncc

ELR,-FE~~ 1Oti_RtiAl OF FLBLIC H'cfiLTH \'OL 3 1~ ~~R I Tabir: t'ranlruc.x.•tecoun- haemat.tiniand'naemn.rlnFmFvsmcrkineuatu1954,contrdencptnrrr,alrnrarn;o;.e. Smnhmt sraru Lel corarnnlxL.c?Cl t Blood parameters' Haemurcnt Haem4,plr,rm , _ 1 V rr, li:on•smoker• Nnne or mrmmal rassrve expmsurr 6 690 (65:'._31? 43.6 14.9.443)' 14r !ii 1+= M,1.ieratC tVSSl CXPDSIDe ba 7.03 16 frl. i 411j 43 1 14_ 6-43 51' ) 4 4 t'14 : . 14 5 Hpa.~ passrsr exroaure 6.76 16.15-i.3(iii 434 t4:.3•44 51' 147 l'14 '"-14 01' .Zm,+ier, < I"Cr¢arette>r•er,1a' i.13 (6 bf+- i.66.1' 434 l 4: >-44. : ' 14 5. 1'» I 1'-:.' ct¢arecte,pil 4. fi:~C ('.34•6.631t' 44 5 14 3 i-a5._1 14 G Cs e. ? :, crrarnres t,rn,9a, 35 6,6E (R 0 1 9.?41h 44,E (43 6.45 ct' 15 : 1. Fe:-~~'(Jnp~Y'a1anal\'slf p t'arlaneel 7.8 3.2 3 4 F MEAN HEMOGLOBIN (q/dl) 15.5 -- - - p-0 001 (TREND) '' InJrcarp >usnncansl..lmaens s+.vtR !~s An: ms. multrrk nnRr ten .r the 5 rel k-l or ssRnrnioncr MEAN LEUKOCYTE COUNT 10000 p-0.001 (TREND)l il•1 1-10 11-20 l 2T-30 31-40 140 URINE COTININE/CREATINE 15.2 14.9 ~ atrl ctl ' x5 r40 URINE COTININE/CREATINE •-t 1-10 tr20 21-30 31-40 11~4_.63 a _ 14 - 46MEAN HEMATOCRIT (ti,) - _ p-0.001 (TREND) •1 1-10 11-20 21-30 31T40 -40 URINE COTININE/CREATINE 4S• 44• 3._i_i- - 42 Fiessrp Mean ltukonre count. hemasoan ratro and hemoRiobsn by ~ mren+als oi the urrnary coesmne to creatarnne rano ronmental smoke. Non-ltnear regression ot the bload ' counts on the cottntne to creattntne ratto>,•lelded a ht¢hls stgntficant second degree F+ollromral term. conttrmtng thts obsen•atton (deta+ledlanaivses not shouTt). DlSCUSSIOI; These findings d'emonstrare that leucocne count is not stgntficantly, elevated in non-smokers exposed to different levels of environmental tobacco smoke. ln ad,ittton• among light smokers there was no increase in leucocyte count.,Thtssuggests that if tn fact elevation of the leuco- cyte count contributes to the risk of coronan heart disease in smokers, this is not ltkel!t• to be the mechanism for passlve smokers or indeed for ltght smokers. in general the mechantsm for the mcreased risk of coronarv heart disease in passive smokers is non well understood' lt has been, postulated that it mar be due to effects on bloodlractors such as platelet aggregation or through a role ofl the damaging and mutagenic eftecu of agents such as the pokcvcttc aromatic ht•drocarbons ( PAH) on the endo• thelial and'smooth muscle cells (Glant: & Parinlev 1991). in addttton, extensive exposure to environmental tobacco smoke may,result in reduced'ox}gen supph to the mva cardtum (Glant: & Parrnley 1991). It has been suggested that the elevation of the white cell count in smokers results ftom a chronic tntlammaton response in thebroncht~ofregularstnokers (Pettrtt & Kipp 1966); Toxic products in cigarette smoke such as tar and cadmium may be responsible for this effect (LeM•ts et al. 1972). Despite the fact that cigarette smoking has an acute effect on, the kucocyte count (Fned'man, et al. 1973), this effect persists for some time after q}irttang (Penttilet al. 198ts): This may brdue at least in l+an too changes in hormonal levels resulting from smokine x•htch tn turn might affect the leucocyte count (Pentu &}apF 1986);. The findings in this study , suggest that ar the populatton level, at leasn among adult men., chronic exposure to en•tronmental tobacco smoke has ltrtle or no effect on Icucocyte cotutn The relkuvely narroK contidence tnter• vals for the kucocvTe counts suggest that even tf the study,

A Patslt c smok-inR mtd corona- hean duease was E+enOrmed on a lateer, sample., the results would be largelc unchanged. DesFtte this flndmc, an etiect in somr }ieavIh exFvsed Indivldualstannotbe excluded. It should' he mentioned that most' ot the sub)ecrs were blue•collar workers, alEhough there is no obvious reason to predlctt dtnerent tlndln¢c tor w•hlte>collar workers. The F+ossiMiltt.• thar passive smoking mar have some etiect on subtrac• tlons ot leucoct•tes cannot be excluded SAnderson et al. 19991. !',evertheless. the results ot the present stud% mdl- cate thar the mechanism underll•tnR the tnereased risk of coronart• heart disease in passlve smokers is not through elevation of leuCOctTe count. REFERENCES Anderson R, Theron Al; Richards GA et al! (1991): Passive smokmg by humans sensrti:evaircuHtmg neutrophds. Am ~Rev, r(esprr Drs 144 5704 Cummrngs KM. Markello S1. Mtnoney Met.al. (1990) M'easurementOf.c~urrentliposure to envrronmental tobacco smoke Arcn EnvrronheaItn 45 74-9Curvau M vale EK, Enren CR et al (1990)', Stimulation and evaluatron of nrcotrne mtace ourmg passive smoking cotrnrne measurement.rnboor flurdslof nonsmok'ers.gwen intravenous rnfusion of nicotine Uin Pnarmacol Tner47-42-9 Errkson MP, Le Maistre CA:.Newell GR (1988) . health hazard of passwe smoarngAnn Rev Pubhc Mealth 947-70ErnstF', Ma * menrnmrat DE. Bagge U et al (1997) Leukocytes and the risk of rschemK dlseaSeS. 1AMIA257:231'8-24 Fnedman GD. Sregelaub AS. Seltzer CC et aL (1973). Smoking habrls.an0 the.leukocyte count,.Arcfi Environ Mealtn. 26 137-43: Frredrnan GD: Klttsky AL Srege(auo-A8:09741 Tnee kueocyte Count as a preoiClOr of myoCardUl mfarHron N'Eng! 1 Mec 290 1275-8' Garland C.,Barrett-Connor E, Suare: L et al (1985) Eftecu of passive smok ing on ,scnemicneael Orsease mort alrty of nonsmokers, A proypectlve study Am 1 Ebioerniol 121'6J5-SO GlantZ 5A. Pa.mLey WW (1991) Passive smoking and rsear;, disease Eprdemiolog.y, physrology.,andbiocnemrstry Clrculat on 83'1-12 Green MS.,PCIed I.,Na7enson.T (1992)Gender drfferences rnplitekt count and its association wrtn cigarette smot ng in a large cohon in Krael. 1.Clin Eprdemrol45 77-S.A Mo+tman D. rlo+tman I (1987). Significance of eaposure to srdesrream tobacco smoke In. Dne,lle 1K:.Brunnerrnann KD.. Dooei B ei a('..,eds En.nronmental care nogenesn metnoos of analysusand ecposure measurement. International Agenty.forResearcn on Cancer pp.3-t0 (IARC suenu/w pubbrrtrons $.91) ~ Kostis 1B. Turkevrch D. Sharp 1(t984). Assocla on txtween leukocyee count and the presence and emtent of coronary /t herosclerosls as determined by, coronary arier rography Am 1 CardaolS3:997RV . LewIs.GP, lusko W1;.CoughLn LLet al':.(1972). Cadmium accumulation rn_rtVn. /nfiuence of,Nnok'rng, ocpupatron alcohol habit and drsease. l Chron Dis 2S 717.26 Petrtt, D8, Krpp M(1986)' The./eukpCYte counlt assocratron wrih Intensrtyof'smokingrnd persistence of effert after purninS. Am 1 Epioemrol 123.89-95 WalO NJ, Boreham 1, Badey,A et al (1984)', UnnarycoUnrne as a marter of'breathrngOther people's tobacco Smole Lan(et, r:230-1 Wall MA. Johnson 1, Jacob P etal. (1988) Cotrnrne in the serur„ salrvaa and urine of.nonsrnok'ers:,passive smocers ano active smokers Am 1 Pub c heatth 78 600-701 Zalokar7B.AichartiJL C(auoe 1R (1981). Leukocyte count, smoking and myocardial mfarnlon, N'Engl 1 Med 304 465-8 m