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lhr. J. Cancer: 39, 162-169 (1987) 0 1987 Alan R. Liss, Inc. MEASUREMENTS OF PASSIVE SMOKING AND ESTIMATES OF LUNG CANCER RISK AMONG NON-SMOKING CHINESE FEMALES Linda C. Koot, John H-C. Ho2, Daisy SAw3 and Ching-yee Hot tDtpl: of CommuniFv Mtdicine„ Univrrsir) ojHong Kong. Hong 1Cong; 2Radiotherapy 1)tpt:, Baptisr Hospital, Kowloon, Hong Kong; and 3lnsriturr oJPanhology„Qurrn Eli;a6rth Hospital, Wylie Road: Kowloon.,Hong Kong. LNetime exposures to environmental tobacco smoke from the horne or workplace for ti "neversrnoked" female lung oncer patients and 137 "nevar-smoked" district cont.ois were estimated in Hong Kong to assess the possible causat ralation- ahip of passive smoking to lung uncer risk. Retative risks based on the husband's smoking habits, or lifetime estimates of total years, total hours, mean hours/day, or total ciKarettesJ day smoked by each househokd smoker did not show dose- response results. Similarly, when such categories as mean hours/day, or earlier a=e of initial eaposure, were combined with years of exposure, tl+ere were no apparent incnases In relative risk.. However, when the data were segregated by histological type and location of the primarx tumor, It was seen that peripheral tumors In the middle or lower lobes. or, loss strongly, squamous or small<ell tumors In ti+e middle or Ibwer lobes, had increasing relauve risks that might indicate some association with passive smoking exposure. Epidemiological data linking passive smoking with lung cancer among non-smokers have been controversial. Six stud- ies (Hirayama, 1981; Trichopoulos er a1., 19811. Correa et a1,, 1983; Knoth et al:, 1983; Miller, 1984; Garfinkel rt al., 1985)) found significantly elevated relative risks (RR) in the range of 2.0 to 3.5 based on the smoking habits of the spouse. Five other studies (Garfinkel, 1981; Kabat and Wynder, 1984; Chan and Fung, 1982; Koo er a1., 1984;, Wu er al:, 1985) two of which were conducted in Hong Kong. d'id not find significantly elevated RR from inhalation of sidestream tobacco smoke.. Four of these epidemiologieal studies (Hirayama. 1981; Tri- ehopoulos et al., 1981; Garfinkel; 1981; Chan and Fung, 1982) defined exposure solely by two questions: whether the spouse smoked (yes/no), and the number of'cigarettes smoked per day by the spouse. Five other studies (Correa et a!!, 1983; Miller, 1984; Garfinkel rt al., 1985; Kabat and Wynder, 1984; Wu er al., 1985) also included questions about whether invol- untary smoke exposure had occurred arwork (yes/no), and/or whether the parents has smoked (yes/no). Such data seem rather crude indices of exposure, providing only very indirect information on the degree and amount of exposure. Further- rnorc, although spouse(s), parents, or co-workers might have amoked, the actual' degree of contan of the non-smoker with these smokers could have been very low, or even nil (Fried- man et al., 1983). In our detailed studies (Koo et a1., 1983, 1984) of passive smoking exposures. srroking parents or spouses were sometimes raca)led as inflicting t'inle or no ex- posure on the sub~'Kt. In Base cases where, for example, the busband smoked but lived separated from the wife, then our tRUdy counted such wives as tutexposed wbjects. Among our mver-smoked subjectt, tttis was found to be true for 3 cases and 3 conu•ols. In order to assess the possible c{usal relationship of passive smoking to lung cancer tisk, data from detailed life-history exposures tfiat were elicited in intensive 1.5- to 2-hr tape- recorded interviews of never-smoked female lung cancer cases and district controls have been analyzee. Emphasis is placed on the eonsistency of the data, the strengths of the RR, and whether dose-response relati.onships were present. This study of the effects of passive smoking is particularly pertinent to Hong Kong beause it is one of the most crowded utban envirotur><nts in the worid. Its urban density averages 28,000 inhabitants/km2, with only 8 m2 of available living space per person. MATERIAL AND METHODS From 1981-3, 98 never-smoked female lung cancer patients and 137 never-smoked female district controls were inter- viewed as pan of a Vrger retrospective study of female lung cancer in Hong Kong covering 200 cases and 200 controls. in the original study, patients were matched with an equal number of healthy controls by age ( f S years), district of residence (N=34),, and housing type (public or private housing), the latter being an indication of sociotconomic status. Details of subject selection, lung cancer histological typing„and method of conducting the interviews have been discussed elsewhere (Koo et al., 1983, 19g4). Never-smoked subjects wlre definecd as those who had smoked less than 20 eigarenes ia the past. All data on passive smoking exposures were double-checked with other data elicited in the life-history interviews, espe- cially residential patterns since birth (i.e. where they lived, type of housing, number of rooms, number of co-habitants, etc.), occupations, and marital life to reduce errors in estimat- ing exposure levels. Among the never-smoked subjects, the mean age of the patients was 57.8 (sD 10:81):and that for tuhe controls was 59.3 (sD 9.94). This sample included 60 who were widows and 3 who had never married; none had married more than once. In the design of the interviews, separate data were collected to take into account that within the life-histories of the sub- jects, sidestream tobacco smoke could originate from: (a)' different people who smoked in the presence of the subject; (b) different places frequented by the subject; and (c) different types of tobacco. Persons who smoked included related and unrelated members of the household, and even co-habitants who shared an apartment unit (if their tobacco smoke was noticed byy the subject). It was difficult to quantify, exposure levels from places that could have varying daily amounts of envinonmental tobacco smoke andwere occasionally visited by the subject such as cinemas, while playing rnajong: or in transport vehicles. This anal)^sis will only take into account exposures that remained relatively regular during the lifetimes of the subjects i.e. from exposures at home and the work- place(s). Among our subjects. tobacco smoke mostly origi- ttated from cigarettes smoked by household members, and from pipes (water and regular) smoked by parents or in-laws. In addition to data based on the husband's stnoking habits, 4 other measurements of passive smoking were evaluated: (a) Iotal years of exposure. (b) total hours of exposure, (c) mean hours/day of exposure, and (d) total cigarettes per day smoked ~ by each household member weighed by their years of expo- sure. These measures should be a more accurate reflection of N past lifetime exposures than simple questions based on whether the spouse or parents smoked' (yes/no), or whether environ- W tnental tobacco smoke was encountered in the workplace (yesl CJ no). Receiwd: Junc 24, t986 and in revised fotm Seprmbbr 19, 1966.

PASSIVE SMIOKING IN CHINESE FEMALES The total years of exposure were derived from adding the years during which tobacco exposure occurred in the home or workplace. Exposures of 6 or more months were rounded off to the next year. ln the home environment, household smokers were only, counted if the subject recalled that they had smoked in her presence. Where exposure was concurrent, as in the exse of both parents smoking, or exposure occurring at the home and workplace„then the years were not added. The total hours of exposure were calculated by multiplying the average hours/day of' exposure by the years of exposure from each household smoker„ or the amount of exposure at each workplace. Each of these sources of exposurc was then added together for each subject. The hours were not added for exposure to simultaneous smokers. For example, a husband and son smoking at the same tirre for 1 hr would only be counted as 1 hr. The mean houn/day of exposure were derivedby adding the hours/day of, home and workplace exposures and dividing this figure by the age of the subject. This figure approximates the average number of hours of exposure per day experienced by the subject, spread,over her lifetime. A weighted average of the total cigarettes per day smoke& by eachi household~ member was calculated from the summa- tion of the tuualinumber of cigarettes smoked, throughout the day by each household member multiplied by the years that each lived with the subject, divided' by the total years during which cigarette exposure had occurTed in the home. This figure ma?- give a better indication of: the intensity of cigarette exposure in the home than one simply based on the number of cigarettes smoked per day by the husband; because it accounts for: othec household smokers and the years that the subject was exposed to each smoker. This figure excluded exposure from pipe smoking and the cigarette consumption levels of co- workers because of difficulties in quantifying those amounts. Of, the 88' patients, 83 were typed: histologiully. Among the remaining 5 cases, biopsy or cytologic materials revealed'that malignant' cells were present, but they were too undtfferentia- ted orr unspecified for categorization by cell type. Chest radio- graphs,were examined for all cases, and the site of the primary lung turtwr.v.•as classified~ by its location in~the bronchial tree, and~whether it was centrally, or peripherally situated., In this analysis„the lingula was classified as equivalent to:the middle lobe, and peripheral tumors were de:fined' as those located beyond the segmental bronchus. Statistical analyses included the calculation of RR as the crude or adjusted odds ratio and tests for trend (Breslow and Day, 1980). Adjusted odds ratios were estimated' by the use of, a conditional logistic regression package. PECAN, (Lubin, 1981)' which was based on N:M~tTUtching by strau defined by district (N -34) and housing type (public or private).. To take into account the effects of potential confounders which af- fected the RR estimates, adjustments were made for age (< 50, 50-69, 70+), any formal,schooling (yesira); number of live births, and'years since exposure to cigarette smoke had' ceased iwthe home or workplace. The exact values were used for the last two variables. Because the resulting large numbers of tnatcliingttrata in the adjusted odds ratios may lead to unstable results, both crude and adjusted RR were presented for all risk analyses. The M,antel~Haenstel test for trend' was performed on all the enide odds ratios using the midpoint of~each interval, whereas the trend test of the logistic parameters was based on each variable as a continuous exposure factor. RSSllt.Ts To allow comparison of the results of this Study with tdwse done elsewhere, exposures based on the husband's cigarette smoking habits were analyzed for the ever-marricd~ women 163 (Table I). In, response to the question of whether the husband had smoked cigarettes in the presence of the wife, the crude and adjusted RR were both a non-significant 1.6. RR for the usual number of cigarettes smoked per day by the husband did not indicate increasing risk with higher smoking levels, and the trend tests for the crude (p=0.10) ard adjusted (p- 0.43) RR were not significant. Likewise, when the data were analyzed in terms of cigarette amoke exposure during ehildhood7adultbood, or by the num- ber of smoking co-habitants, as in the study of Sandler~ a 01: (1985) (Table 11)„ no consistent pattern emerged. RR at the higher levels of exposure, i.e., both childhood1 and adultlwod; or 2+ smoking co-habitants, were found to be lower than those at lower levels of exposure. L'fitirru aposnn nuasuremenrs When the crude artd adjusted odds ratios were calculated for ete 4 lifetime exposure tneasurements, the RR for the inter- mediate exposure ievels of mean hours/day (1.94 ind ~ 4.10); and'ciguettes/day (1.57 and 2.56),were significant (Table III): Howeven, with the exception of total yean„all of the RR (0.9- 1.4) at, the high exposures were below those of low or inter- mediate levels. Even for totat', years, the Mantel-Haenszel linear trend tesu (p=0.55); for the crude RR, and the trend test for the logistic adjusted' parameters (p-0.23) indicated that the pattern was insignificant. When the crude and'adjusted RR are compared (Fig. 1), the adjusted RR for these measurements showed RR fluctuating between wider ranges of 11.0 to 4.1,,yet both, lacked evidence of a consistent dose-response pattern. /ntensiry . As a measure of intensity; RR were calculated to see whether there was a direct relationship between increasing years and mean hours/day of exposure in a 2x2 table (Table IV). Start- ing with the top lefi-hand square which was the group with the lowest exposure levels, one would expect, RR to be highen in all the other squares, especially the one at the lower right, because it had the highest years and mean hours/day of expo- sure. However, the crude RR at this highest intensit) level was only 1.07; and the category with the lowest intensityy values (top left) had the highest adjusted RR of any of the other groups. A similar panern etnerged~ if total hours or cigarettes/day were substituted for rtxan hours in this analysis. Age of inilial exposure We had previously found no difference in the age at which passive exposure had started (Koo era1., 1984). To seewhether earlier age of initial exposure combined with higher years of exposure were related with increasing risk, RR were calcu- lated for cigarette exposures ima 2 x 2 table (Table V). Again, we did not see any panern~suggesting a dose-rtxponse relation- ship. The top left square with the least years of exposure and older age at initial exposure had the highest crude and adjusted RR. Similar results were obtained if the years and age of exposure included allitypes of environmenul tobacco gmoke, i. e. from cigarettes and pipe. Hisrologicnl type The cases were divided into two groups, those with squa- mous or small-cell lung tumors, and those with adenocarci- noma or large-cell lung tumors. This division was made because the former group was previously found in Hong Kong to be more related to aetive smoking than the laner (Koo er a/., 1985). Five cases with mixed cell types and S with unspec- ified cell types were excluded from the analysis. Although nonc of the crude or adjusted FtR or trends by histology were found to be significant, it can be observed that a dose-response pattern seemed to be more apparent among

164: TABI3r U - RR FOR.LUNGC/fNCER.FROM HOUSEHOLD E%POSURE TO CIGARETTE SMOKE EtP=R N.mber. d cues.' IM1etr of CtAlr014 CnOe RR.' (93E CI)~~ AdHw.O~.RR, ~r93% C11 By petiod in lik No exposure 27/49' 1.00 1.00 Children only~ 2/3 1.21 1(-) 2.07 (0.51. 95.17) Adulthood only' S7/77 1.34 (0 8A. 3.01) 1.68 (0:62_5,451 BotA childhood + adulcbood 2/8 0.45 (0;11, 3.32) 0.64 (0!57.,5.85) Bynumber of smoking oo-Aabisantss None 27/49 1.00 1.00: - 1 48/68 1.28 (0.82, 3.25Y 1.73 (0i7;,6:35) 2+ 13/20 1.18 (0.57. 3.65) ~ 1'1.35 (0.64. 5.03) 'Cruds odds raeio.?AdjusroQ for aRe. nnrnEerof IirepfrtM, rAodmS (*/-). and yeen eroee e:yowre to n~srene emoke cetud in tRe Aonr or awkplaee -)Frae ate or both ~ptmns. 'Froan epou.ee, w•Irrt. eRaldfeu.,or aAer co-A.Eiwes.-s' Fran .ppiu, p.eeKS.,.w~L~rc.. dtiWree,, or asAer oo-hebunu who trnokede¢-Roee iu dm paeKe of Nr wbjen. Expowrc C-W CGIKIDIf TAILE11I - MEASUREMENTS OF PASSIVE SMOIUNG AND RR FOR LUNG CANCER ToW yetrts RR' (9SS CI). RR' (43S CI) 0 22140 1.00 1.00 1-19 . 20/28 1.30 (0.63, 3.68) 1.95 (0.72, 5.31) 20-34 24/39 1.12 (0.59,3.06)~ 1.36 (0.55, 3.36) 35+ 22l30 1.33 (0.79,4.44), 2.26 (0:90„5.67) Exp- KOO ET AL. TAS1.E I - HUSBAND'SCfGARE7TE SMOKING NAatTS AND RR FOR LUNG CANCER.AMONGEVER-MARRIED WOMEN E+powre NwmAer of tarev ~nMtr o(cae.ols C1rOe RR (93t Cli Aejuwd:RR' (9SS n) Husband ever anoked?= No 35)70 1.00 1.00' Yes 51/66 1',.55 (0.94, 3.08) 1.64 (0.87, 3,09) CiBarenes/day, amoked Dy husband 0 32/67 1.00 11.00 1-10 17/15 2.37 (1.03. 5.91) 2.33(0.92. 5.92) 11-20 25/35 1.50 (0:87, 3.64) 1.74 (0.81. 3.75). 2 h+ 12/19 1.32 (0.45, 2.63): 1.19 (0.46. 3.03) 'Abywed' foe .Rt eo rber ,of Iwt lirtM. eNioalmS T+'/•-)j andd yun tince eapawre w nqreae vnde ceud to the Rome a.orkpiacc.-t11u:6nd ynoimd .r tlrc pa.erce of du -ik. 3 cara ..d 3 coee+ois .'at .a tspaed ro rMC c>tsreaes o(Iheu Wsb.nd. Casey toiecdi Taai ~~Aan. (r Iwdr.d.r RR'(93f Cq Ea~{M R CneV l.OnlfDlf NovNda) RRI (93s C71; RR'(95f CII, 0 22/40 1.00 1.00 < 1 15129 0.94 (0.41, 2.63) 1.03 (0.37; 2.94) <2' 33131 1.94(1.24„6.74) 4.10 (1.59. 10.61) 2+ 18/37 0.88 (0!42, 2.42) 1.00 (0.39, 2.58) Ct{eveawmy' E1P0Y1R taerait RRI (934 CI/ RR' (9SS Cll RR'(VS~CtfI 0 22/40 1.00 1.00 1-10 25138 1.20 (0:60.3.67) 1.68 (0.64,4.45)'. 101-200 23/27 1.55 (0:88.3.53) 2.28 (0.91. 5,72). 201 + 18/32 1.02 (0.54, 3.47) 1.42 (0.56, 3.62), 0 25/48 1.M 1.00 1-10 13/16 1.56 (0.74, 4.96), 1.83 (0.65. 5.11) 11-20 27/33 1.57 (:1.00, 4.99) 2.56 (f.06; 6.19) 21+ 23/401 1.10 (0.5L, 2.47) 1!.21 (0:51, 2.86) rCnde od6s ratio.-yAA)upedfa.Rt. annbero( Im biNr. a1~od'naS (4(-)..ad yran pner eapoewe a cipresu aro6e csW ia tAC bne a.vrarkplan.-"TAe .aeof wmEer of cisareneslday emokedpy ncA Inuuhdd manDtr .ei{Mtd by die yon o( eapowre from tlui.wurco M.me(•Hkm:d vend wly.n: Yean 0.SS: Roun: 0.75. 6owatdey: 0.70, c#ldey: 0.67. Lojirrc ed)wotd oad aee)yuc: Yetn: 0.23: Mwn 0.91: Raunrdey: 0:16: cyidey: 0.63. TAiLE IV -}iFECrS OF INCRFaSi NG YEARS AND MEAN IK TAiLl: V - EFFECYS~ OF INCRE IURSlDAY OF ASING YEARS AND E ARLIER AGE OF INRIAL 70iACCO E7CTOSURE EXPOSURE TO CIOARETy'E SM OKE Yrs a( tep.ne 1Wn af tap aun 1-24 I3* 1-24 dtean hours per day of expowre RRI RR2 ARe r first exposure RR' RR2 RR' RRy < 1.5 1.33y 2.2Y 1.47 2.13 ';il 25 1 L t'.954 1.50 1.67 (19/26)s (2Jl26) .. (20/25)S (8/10) s1.5 1.02 1.21 1.07 1.45 424 1.00 1.35 1.25 1.86 __ (9l16) j (17/29), (8/15), (28/42) rCnrSe oddt eetio-xAdjuerd fa.ye..umber of live birdu..elroolv4 (*(-). rCrude odds renn.-7Adjirsted for ye..umber of live birdu. ecAooluu (+ 4 atd yan sY1R eiPOY1R W c1a7RSe LRIOte OsisOd in IRC ROAY.Of YOIIpIKT.-193 Si Od. yfJn &IIIQ t;pOfYre b Ci[H!K NIIOke QifOd U1 IRe IleRle AwOfkpll4' -'"; a: 1.33 (0.6a. 4.00), . 1.47. (0.74. 4.30). 1.02 (019.. 3.Q5). 1.07 (0.57: , 3.39). Cl 1.50 (0.71. 3,99). 1.50 :(0.47. 4.64). 1.00 (0.41. 3..42); 1.25 (0.76. 3.60): -49SS Cl: 2.22 (0.79. 6.21T.:.U (0.t4. 5:43r 1:21 (0.37. 3,96), 1.45 (0.56. -*99s Clc 1.93 (0 .76. 4.9i). 1.67 (0.52. 5.33). 1.35 (0 30. 6 le,. 1.86 (0,7t., 3.7t).-sriwnEet of ertd.unEes of eetoeJs. 22 eesea atl 40 mmdt R.0 .o 6.A61:-lNYmEer doseM.nnber of' m.noli:. 24 oses tnd4S aosfob Wd to esOo.ure - RR 1.00; saFo.ure - RR 1.OD.

1•ASSIVE SM/OKtNG IN CHINE.SE FEMALES ,.~ ..... ,«., .., 4 .n r..w FIatneE 1- Measuremems for passive smoking and RR for lung an- cer. 'Adjusied'for age, number of live birt)u, schooling (+l-) and years since exposure to cigarette smoke ceased in the home or work- pLce. y C 0.05. 165 the squarnous or small-cell lung tumors than among the ade- nocarcinoma or large-cell types (Table VI). This was espe- cially true for the adjusted RR in the former group, as 3 of the 4 measurements consistently indicated increasing risk with increasing exposure. Loaarion by lobe Eighty of the cases had'the nnin tumor residing in one of Ihe lobes. The remaining 8 cases, with primary tumors in the right or left main bronchus, or in the right inttrmedius region, were too few for analysis. Calculations of the RR sAowed that none of the crude or adjusted values were signifscun for upper-Uobe tumors (Table VII). For the middle or lower lobes, all of the ad,'usted RR were in the comparatively higher range of 1.9-3.5 for those with some passive exposure.~ Moreover, for 3 of the exposure measuretrxnts, total yeus, liours/day, and eigarenes/day, the confidettce intervals for the entde and idjusted RR indicated some borderline significant values. However, none of the vend analyses for the lobe data came out significant. TAaI.E VI.- MEASIJREMENTS OF PASSIVE SMOlUNG AND RR.FOR LUNG CANCERRY,N1STOl:OGICAL TYPE iqrunww.aamdltcN Adenow,n.onra k*}easlli .. Nrmtisr ~of ufebI rmr0er of camrott RR' (9S1i. C1)', RR= f1Sf CIl N.nttr of cne.r ..nber d. eanvds RR' 19ST CI) RR7IfSf Ct) Tau) ynrs 0 7/40, 1.00 1.00 12/40 1.00 1.00 1-26 10/46 1.24 (0.37, 5.40) 1.5&(0.37. 6.77) 17/46 2.11 (0.54. 3.74) 2:07 (0.64. 6.71) 27+ 15151, 1.68 (0.47; 5.79) 1.82 (0.49, 6.80) 17151 1.90 (0.5), 3.27) 1.43 (0.51, 4.02) Total hours (in hundreds) 0 7/40 1.00, 1.00 1'2)40 1.00 1.00 1-150 12/56 1.22 (0.34, 4.71) 1.40 (0.34. 5.77) 18/56 1.07 (0;46,3.05) 1.70 (0.55. 5.20) 151 + 13141' 1.81 (0.52. 6:54) 2.04 (0.53, 7.85) 16/41 1.30 (0.59, 4.02) 1.57 (0.55,4.49) Hours/day 0 7J40 1.00 1.00 12/40 1.00 1.00 <1.3 8/44 1.04I(0.31. 4.70) 1.34 (0.31, 5.84), 17/44 1.29 (0.56, 3.61) 2.19 (0.71, 6.77) ;t 1.3 , 17/53 1.83 (0.52. 6.69) 2.01 (0.52. 7.72) 17/53 1.07 (0.49, 3.23Y 1.34 (0.47, 3.82) Cigattneslds) 0 9/48 1.00 1.00 13J48 1.00 1.00 149 9/26 1.85 (0:57;7.20), 2.02 (0.53, 7.68) 12/26 1.70 (0.77, 5:72) 2.05 (0.63„6.72) 20+ 14/62 1.20 (0.36. 3,31) 1.19 (0.36, 3.93) 19/62 1.13 (0.59, 3.57) 1.88 (0:68, 5.17) 'Cndeaddx ruia -7Adjuaed for a~. smrber of Nve bnb..cfiooiiry Md ~ynn smes t>vpowrt ro eipmu awtr nwrd u tIe (wnr a.brtpt.ee. TAEI.E VII- MEASUREMEriTS OF PASSIVE SMOKING AND RR FOR LUNG CANCER EY. LOBAR LOCATION . (lOpn M6es MdONr a.lewer MM Nw"Eer or cue+r RR. 195! Cr RR! i1Sf C1 NmnM. d m" .ymAer d arwd. ) I wnnha d.toMrd. RR' r9S[ OI RR* tris C11 Taal years 0 10140 1.00 1.00 11/40 1.00 1.00 1-26 11'l46 0.96 (0:43, 3.82) 0.98 (0•27; 3.64) 17/46 1.34 (0.86, 8.72) 3.08 (0.83,11.38) 27+ 1615) 1.25 (0.40, 2.87) 1.42 (0.46, 4.42) 15151 1.07 (0.62, 6.15) 2.13 (0.62, 7.24). Total hours (ia hundreds) 0 10/40 1.00 1.00 11140 1.00 1.00 1-a50 15/56 1.07 (0.30, 2.38) 1.30 (0.38. 4.50) 18/56 1.17 (0.76. 7.26) 2.37 (0.67. 8.35). 151+ 12i41 1.17 (0.38, 3.01) 1.23 (0.39. 3.91) 14141 1.24 (0.68, 7.17) 2.51 (0.72, 8.84) Hours/day 0 10/40 1.00 1.00 11140 1.00 1.00 < 1.3 7/44 0s64 (0.13„ 1.58) 0.69 (0.18, 2:61), 17/44 1.40 (0.95. 9.51) 3.24 (0:90; 11.66) ~ 1.3 Ci areust/da 20/53 1.51 (0.51, 3.70) 1.64 (0.54. 5.01) 15153 1.03 (0.55. 5.55) 1.97 (0:57„6.82) s y 0 10148 1.00 1.00 12/48 1.00 1.00 1-19 10/26 1.95 (0.57, 5.39)2'.32 (0.62. 8.76) 12/26 1.85 (1.08, 1i0:39) 3.49 (0.98,12.50) 20+ 17162 1.32 (0.48, 3.32) 1.79 (0.59, 5.45) 17/62 1.10 (0.61. 4.61) 1.93 (0.63, 5.95) . 'Grde aldr nuo.?Adrm.d far .Re, r.nEex d li.e lrtla, sloWuK (+/-), a.d y..n wiwes esperwrs tlo eipnac .wke ard i. Me Wns a.akpl-

166 KOO ET AL. Prozirrol/ptriplitrnl lotarion Among the 95 determinable cases, 46 had peripheral tu- mors, and 39 proximal rumors. Although only the crude R'RR of 2.00 and adjusted RR of 3.52 for 1-19 cigarettes/day were slightly significant for the proximal tumon, in general, all of the crude and adjusted RR for the peripheral ttunon were greater than 1.00 (Table VIII). M'irrologicof typt and location In order to see whether any particular combination of histo- logical type, l'obe, or proximal+peripheral location of the tu- mor would result in stronger dose-response patterns by the 4 lifetime measurements of passive smoking. RR were analyzed for the 12 possible 1:1 combinations. We were unable to segregate the cases into any finer categories than 2 of the 3 groups because of the small' resulting number of cases for analysis. Space does not allow us to present all, the tables, but the best combination was that of peripheral tumors in the middle or lower lobes (Table IX), Among the RR, significant or nearly significant figures were found for the crude or adjusted RR relating to at least one of the exposure categories for each type of ineasurement. Moreover, the adjusted RR tended'to range between the relatively high values of 6.5 to 18.7 for those with some exposure (Fig. 2), and most of these were significant or nearly significant. None of the trend tests came out significant, but this and the tendency for the higher levels of exposure to have lower RR than the low, levels of exposure may have been due to the small number of cases (N=24). Although not as apparent, squamous and small-cell lung cancers in the middle or lower lobes (Fig. 3) also seemed to show some positive association with passive smoking. There were only 18 cases with this type for analysis and none ofthe RR or tests for trend were found to be statistically significant (Table X). Yet it was promising to see that all l the RR with some exposure were greater than 1.0. Among the highest exposure levels for the adjusted RR, values as high as 7.0 were found for total hours, and 6.2 for hours/day. DLSCUSSION' For comparative purposes, the more commonly used mea- surernents of passive smoking based on yes/no questions of whether household co-habitants (husband, childhood/adult- hood, or others), had smoked, or on the number of cigarettes the husband smoked per day, were presented. Only the crude RR of 2:37 (9S9E Cli:1.03-5.91) for husbands smoking 1-10 eigarenes/day was of borderline significance and none of the adjusted odds ratios were significant at the <S% probability level. There was little indication tltat iacreasing kvels of such exposure led to increased RR. On the basis of our extensive Iife-history data, we were able to calculate tbe total years, hours, mean hours/day, and ciga- rettes/day to which the subjects had been exposed to tobacco smoke at home or at work. Our estimates were based on the understanding that the household' composition of each subject would ciiange as she progressed through the life-cycle of birth, childhood, adulthood, marriage, motlierhood and, for 27%, widowhood. We also included exposures from each workplace at which the subject hadworked for at least 3 months. In our adjusted RR, the effect of cessation of exposure to passive smoking was accounted for by putting in the years that expo- sure had ceased at home and/or workplace as a continuous regressor variable. Despite such detailed accounting, we were unable to find a significant trend in the crude or adjusted RR for these 4 lifetime measurements of passive taraking. Although the RR for the intermediate level exposures of hours/day and eiga- Y a i : ~ 6.00 2.00 1.00 0 -~ None Low Exposure Levels --I High Fieuae 2- Mrssurements of passive smoking and RR for peripFieral lung cancers in the middle or lower lobes. Adjusted odds rauo. 7.00 6.00 5.00 Y w or . > : It 4.00 3.00 2.00 1.00 0 ,, . Norie i /W 'Totab ysrs LDw Exposure Levels ~'~ Ciy/tley }, Ey W W ~ High Fiouae 3- Measunements of passive snwking ud RR for squamous and small-cell 'lung cancer in the middle or lower lobes. Adjuaed odds ratio. rettes/day were significant, the RR at the highest levels of exposure for these two variables fell to a non-significant 1_0- 1.2. In fact, the RR for the highest exposure levels for 3 out of the 4 rrxasursments were below all, of those with lower exposures, and ranged from a very weak 1.0 to 1.4. On the other hand; most of the crude and adjusted RR were greater than 1.00.

•ASSIVE SMOXING JN CHINESE FEMALES TAlLE Vltl - MEASUREMENTSOF PASSIVE SMOi(!NG AND RR FOR,LUNG{ANCER BY LOCATIONOFTIIMOR. 167, hnpmenl Apymrl NumEer ef tasts' tmenEtr of ronaoll RR' f957i CI/ RR= 1957 Cll Numlcr of .caw.( mum!`e. nf tedrdi RJt' f4S4 CI) RR, (9SS.C1). T o~ 10/40 1.00 1.00 11/40 1.00 1.00 1-26 18/46 1.57 (0.59, 4.e4) 1.52 (0.44. 5.17). 14)46 1.11 ro.5fl, 4.14) 2.15 (0:64, 7a9) 27+ 18/51 1.41 (0.64. 4.78) 1.84 (0.62. 5.45) . 14/SI 1,00 (0.43, 3.51) 1.58 (0:51, 4.92) Taul hours (in hundtnds) 0 10/40 1.00 1.00 11140 1.00 1.00 1-130 20/b6 1.43 (0.63, 4.97) 1.82 (0;57, 5.85) 16/56 1.04 (0.46, 3.53) 1.86 (0.58, 5.97). 151+ 16/41 1.56 (0.60,4.71) 1.66 (0.54, 5.06) 12/41 1.06 (0.47, 4.19) 1.72 (034. 5.51). Hours/day, 0 10/40 1.00 1.00 11140 1.00 1.00 <1.3 14/44 1.27 (0.56, 4.62) 1.66 (0.52, 5.33) 13144 1.07 (0.48, 3.94) 2.21 (0:63„7:75) '01.3 22/53 1.66 (0.66. 4.98) 1.77 (0.59, 5.32) 15/53 0.89 (0.44, 3.69) 1.59 (0.51, 4.93) e~r~n«la.y 12/48 1.00 1.00 12/48 1.00 1.00, 1-19 . 11/26 1.69 (0.73. 6.14) 1.91 (0.57, 6.35) 13/26, 2.00 (0.98, 9.17) 3t52 (1.01, 12.27) 20+ 23162' 1.48 (0,70, 4.34) 1.79 (0j64, 5.03) 12162 0.77(0.34, 2.45) 1.23 (0.42, 3.62) tCYttOe o0tls rauo -TAdfusted fa aSe..umEer of' IWC Mnln. scAoolug t+J-1. wd ynn sinte e>,powee so eqnrcne nnate esud'm drc Aarc or workpiace TAiIE IX'.- MEASUREMEwTS OF. PASSIVE SMOKING,AyD RR FOR. rER1M1ERAL LUNG CANCERS IN THE MIDDLE OR,LOM'ER LABES EiPO{YR NumAer dtue.• •YnY~ef Uf tCnlrUl1. RR' f9Sf.C1'l RR=~~f9S{.CII Tonl years 0 4/40 1.00 1.00 1-26 10146, 2.17 (0;98. 84.95) 10.44(0;91. 119.53) 27+ 10151 1.96 (0.98, 66 91) 8.61 (0:84,88.21) Total hours (in hundreds) 0 4/40 1.00 1.00 1-150 12/56 2.14 (1s24, 1)0.17) 13.51(1.16, 157.74) 151 + 8141 IL95 (0.69, 5635) 7.02 (0.64, 76.93) Hours[day. 0 4/40 1.00 1.00 < 1.3 11144 2.50 (1.71, 160.18) 18.70 (1.53, 228.03) ;e 1.3 9/53 1.70 (0:62. 49.89) 6.49 (0.60; 70:37) Ci ~srcna/my 0 6148 1.00 1.00 1-19 6f26 1.85 (0.95. 24.36), 5.53 (0;79: 38.86) 20+ 12/62 1.53(0~74, )3.14) 4.16(0.77;22.55) 'Cnde oddsrnu.-`Adjuswd for aEe. tmm+bet of IaeA+Mse scMnlimg (-1- 1..nd ynrm una espaaurt toelprene.smoke.w eemd in tAe Mnw or wrkptact. Msmel.Hsenutl rrend anrly.l.. Yean0. FS: IAaun. 0.16. houn/day- 0.14, crF/di5 0.?V LoSiuicad)usud tnand.us4ysis: Ynrn:0.15. Raun 066'. 1wwNd:i) : 0.d?.,ciF'day 0.22. TAf1Z X- MEASUREMENTS OF PASSIVE SMOKING AND RR,FOR SpUAMOUS AND SMALLtF1:L LUNG CANCERS IN THE. MIDDLE OR LONER LOBF.S 6tpaure Nndet ~~d crnr .mMn dsarml.. RR'.'tMT 01 RR, f9SI CII~. Taul years 0 3/40 1.00 1.00 1-26 7/46 2.03 (0:52, 44.44) S.29 (0:5C, 54.71) 27+ 1151 2.09 (0.42, 33.01) 3.97 (0.41', 38.22) Toul hours (in hundrods) 0 3/40 1.00, 1.00. 1-150 6/56 1.43(0.35, 29.32) 3.44 (0.35,34,17) 151+ 9141 2.93 (0.59, 46.98) 7.01 (0.64, 76.60) Hours/day 0 3/40 1.00 1.00 < 1.3 4/44 1.21 (0.30; 29.64) 3.05 (0.28„33.14) > 1'.3 11/53 2.77 (0:37,44.05) 6.16 (0:59,64.48) CieRreneslday, 0 4148 1.00 1.00 1-19 5126 2.31 (0.58, 23.25): 3.97 (0.54, 29.20) 20+ 9162 1.74 (0.44, 11.87); 2.58 (0.42, 15.93) tCruec oeds eaio.?Adj...d Rs aSe. rntber d Ii.e [trws. scAcduK t a-) rd y..rs wa esyawre a e~.eaer .rotr tssed in, tAt Aome tM.vkpisce. Mamel•H.enaei nnd andysu: Y.an: 0.23, Aours 0.20: AwnNfsy: 0.26: cyldsy 0.20. LoSiiaic s,djoa.0 nad rdyus: Yen: 0:71: Rsarr. 0.76; ,bun0dsy: 0.70. cqrp.y: 0.7t.

168 Koo ET AL.. Measurements based on increasing intensity of exposure, defined~ as increasing years (or hours, or cigarettes/day) by mean hours/day of exposure, also did not indicate a dose- response relationship. Likewise, the analysis of total years of exposure with, age of ezposure did not suggest that earlier age of initial~ exposure and increasing years of exposure led to higher RR. It was troubling to find that in both types of analysis, the RR for the lowest amounts of exposure were among the highest values. Dalhamn rt al. (1958),noted from their study ofithe retention of cigarette smoke components in human lung, that water- insoluble volatile compounds and particulate matter from cig- arettes tended to be deposited primarily in the deeper. parts of the respiratory tree. Since adenocarcinoma is predominant among non-smoker lung cancer cases (595Yo- of our typed cases) and it is generally a peripheral tumor, we wanted to see whether the passive smoking measurements would exhibit a more consistent pattern among the adenocarcinoma and large- eell'types, andYor among the peripheral tumors. In general, the peripherali tumors as a group showed stronger dose-re- sponse results than the adenocarcinomas. • The RR for totaliyears, hours, and hours/day measurements of squamous and small-cell lung tumors indicated consistently elevated risks with increasing exposure. This pattern was not found for any of the adjusted RR for adenocarcittoma or large- cell lung cancers. This association of histology with passive smoking is also suggested from previous studies by Trichopou- los rr a!: (1981) and Correa rt al. (11983). Analysis of the cases by the lobe location of the tumor was done to see whether the primary tumor resided more fre- quently in the upper lobes than in the lower lobes. This is because it is known that when dust is inhaled, it firsti enters the upper lobes where much of it is deposited, and then travels down to the lower, lobes (Time, 1980): Furthermore, it has been observed (J.H-C. Ho+ personal observation) that up to half of the Hong Kong adult population have radiologically evident scars on the upper lobes of their lungs. Most of these scars are due to previous tuberculosis infection. Since "lungj cancer is more common in the scarred and chronically diseased lung" (Stone et al., 1978), we were interested to see whether the lobe data would substantiate any of these possibilities. In fact, 37 of the lung cancers were found in the upper, lobes, and 43 in the middle or lower lobes. The results from the RR estimates from the 4 types of measurements did na show the upper lobes to be more sensitive to environmenta& tobacco smoke. Wynder and Goodman (1983), suggested that lung cancer in non-smokerslvas more likely to occur in the periphery of the lung. This was found in our siudy, as 5496 of the determinable cases had peripheral tumors vs. 46% with proximal tumors.. Moreover, the pattern of RR with the various measurements of passive smoking indiuted thar peripheral tumors seemed to exhibit better dose-response R3t than proximal tumors. -'-Mhea the RR.were ealculated for the 12 poasibk 1:1 eottr binatiotn nesutting from histologieat type, bcation by lobe, or proxittta!' Iperipheral tttmms, the highest RR wese foend for peripheral tatrnors in the tniddk or lower lobes. Significant adjusted RR as high as 18.7 were fouod for sotne of rhese ateasuretrterrcs. Ah]tottgh RR at the lower doses tended to be ltigher than that for the higher doses, the data were oonsistent io dtat all the RR for tlwse with soroe exposure were much Fr than 1.0„ and the adjusted; RR for at least one of the RR fsateror eachrype of >neasurenw= was atatistically si);nif,cant or ttearly sigru'ficant. The RR analysis for squamous and small-cell lung cancers in the middle or lower lobes also appearsd somewhu better dsan the others, with total hours and hours/day measurements showing some dose-rssponse pattern. With the above two combined analyses showing some promise, perhaps the best RR would have been obtained if analysis had been done with squamous or small+cell peripheral tumors in the middle or lower lobes. We were unable to do these calculations because only 8 cases fined into this category. Aetually, the finding of a possible risk of squamous and' small-cell tumors in the middle or lower lobes was somewhat unexpected, given that dust particles tend to adhere to the upper lobes, and tuberculosis usually affects the upper lobes. To see whether calcified foci or fibrosis in the upper lobes could account for the higher RR in the middle or lower lobes because the previous presence of such lesions might disturb the expected distribution of inhaled particulate ot, gaseous matter, most of the chest radiographs of cases with squamous and small-cell lung tumors were retxamined. No significant difference was found in the proportion of positive cases with upper lobe vs. lower lobe tumors. In our analysis of all never-smoked cases, the lack of a dose- response panern, and an almost consistent drop in the RR at the highest doses of exposure would' seem to lend linle, or only weak suppon for the passive smoking linkage with lung cancer for women in Hong Kong. This might be due to the fact that it has been estimated (RylYnder et af:, 1983) that the non-smoker exposed to environmental tobacco smoke receives about I 96 of the active smoker s dose of tobacco smoke based on cotinine levels in the body; and this is rough4y equivalent to the tobacco smoke of 0.1-1.0 cigarette inhaled by an active smoker in a day. Moreover, a 15- to 17-year longitudinal study of 97 non-smoking females in Holland did not find an associ- ation between passive smoking exposure and pulmonary func- tion decline (Brunekreef et al., 1985). Thus the effects of passive smoking might be so weak that they art easily over- shadowed by other environmental i factors such as diet: or ex- posure to inhaled gaseous/particulate matter from other sources in the home or the workplace. W hen the lung tumors were scgregated' by histological i type and location, the resulting analyses showed that pcripherali tumors in the middle or lower lobes, and squamous or small- cellitumors in the same lobes, exhibited better RR patterns for passive smoking in terms of consistency, strength, and dose- response. We are not sure whether this proclivity for passive- smoking-related lung tumors to reside inithe middle or lower lobes might be due to the fact t)iat the lower lobes have more bronchial cellk at risk than the upper lobes, or whether the size, weight, or composition of gaseous or particulate matter from passive smoking may favor its adherence to the periph- eral areas and the lower lobes. Nevertheless, the overall prsr poruon of lung tumors in the middle or lower lobes among our 88 cases ranged from 27 96 for the peripheral i tumors to 20% for the squamous or small-cell tumors. Thus, the majority of lung cancers among our non-smoking population were proba- bly due to some factor(s) which yet remain to be identified. The results from this study, showing a weak effect of passive smoking on the risk of lung cancer among never-smoked Hong Kong Chinese women, must be interpreted autiously; since it was based on only 88 cases and 137 controls. With this sample size, RR less than approximately 1.4 would' be difficult to detect with 95% power and at the 5% level of significance. This problem was even greater when the cases were stntified by histological type and location of the primary tumor. How- ~ ever, these data seem consistent with the findings from other ~ epidemiological, biochemical, and physiologicali studies in ~ showing higher risks for squamous-cell tumors in the periph- eral areas of the lung. Confirmation of these findings from Cc other stuidies is therefore needed. CJ ACKNOWLEDGEMENTS We t3unk the Hong Kong Anti-Cancer Society and'the Gni-K versity of Hong Kong for financial assistance in the carryingzi N

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