1 804 Occupatioal ad Evirometal Medicie 1994;51: Maligat mesothelioma: attributable risk of asbestos exposure Robert Spirtas, Elle F Heiema, Leslie Berstei, Gilbert W Beebe, Robert J Keeh, Alice Stark, Berard L Harlow, Jacques Beichou Epidemiology ad Biostatistics Program, Divisio of Cacer Etiology, Natioal Cacer Istitute, Bethesda, MD R Spirtas E F Heiema G W Beebe J Beichou Uiversity of Souther Califoria, School of Medicie, Los Ageles, CA L Berstei Medical Follow-up Agecy, Istitute of Medicie, Natioal Academy of Scieces, Washigto, DC R J Keeh (emeritus) New York State Departmet of Health, Albay, NY A Stark Westat Ic, Rockville, MD (curret address; Obstetric ad Gyecology Epidemiology Ceter, Brgham ad Wome's Hospital, Bosto, MA) B L Harlow Correspodece to: Dr Robert Spirtas, Ceter for Populatio Research, Natioal Istitute of Child Health ad Huma Developmet, Room 8B07, 6100 Executive Boulevard, Bethesda, MD 20892, USA. Accepted 18 July 1994 Abstract Objectives-To evaluate a case-cotrol study of maligat mesothelioma through patters of exposure to asbestos based upo iformatio from telephoe iterviews with ext of ki. Methods-Potetial cases, idetified from medical files ad death certificates, icluded all people diagosed with maligat mesothelioma ad registered durig by the Los Ageles Couty Cacer Surveillace Program, the New York State Cacer Registry (excludig New York City), ad 39 large Veteras Admiistratio hospitals. Cases whose diagosis was cofirmed i a special pathology review as defiite or probable mesothelioma ( = 208) were icluded i the aalysis. Cotrols ( = 533) had died of other causes, excludig cacer, respiratory disease, suicide, or violece. Direct exposure to asbestos was determied from resposes to three types of questios: specific queries as to ay exposure to asbestos; occupatioal or o-vocatioal participatio i ay of ie specific activities thought to etail exposure to asbestos; ad aalysis of lifetime work histories. Idirect exposures were assessed through residetial histories ad reported cotact with family members exposed to asbestos. Results-Amog me with pleural mesothelioma the attributable risk (AR) for exposure to asbestos was 88% (95% cofidece iterval (95% CI) 76-95%). For me, the AR ofperitoeal cacer was 58% (95% CI 20-89%/6). For wome (both sites combied), the AR was 23% (95% CI 3-72%). The large differeces i AR by sex are compatible with the explaatios: a lower backgroud icidece rate i wome, lower exposure to asbestos, ad greater misclassificatio amog wome. Coclusios-Most of the pleural ad peritoeal mesotheliomas i the me studied were attributable to exposure to asbestos. The situatio i wome was less defiitive. (Occup Eviro Med 1994;51: ) Keywords: asbestos, epidemiological factors, mesothelioma, occupatioal exposure, peritoeal, pleural The icidece of mesothelioma has bee icreasig throughout the idustrialised world.'-1" The overall upward tred i icidece of mesothelioma i the Uited States from is primarily due to icreased icidece amog me." Although asbestos exposure is geerally accepted as the primary cause of this tumour, other agets are suspected of causig or promotig mesothelioma i experimetal studies of aimals.'2-14 A review of the scietific literature o aimals ad humas idicated that a sigificat proportio of mesotheliomas may be due to factors other tha exposure to asbestos.'4 I this paper, we estimate the proportio of mesothelioma cases i the Uited States diagosed betwee 1975 ad 1980 that ca be attributed to asbestos, ad compare the proportios of mesotheliomas explaied by four differet measures of exposure. Materials ad methods STUDY SAMPLE Potetial cases were idetified from the New York State Health Departmet Cacer Registry, the Los Ageles Couty Cacer Surveillace Program, ad 39 large Veteras Admiistratio hospitals, ad were diagosed betwee 1 Jauary, 1975 ad 31 December, Those from Los Ageles Couty ad New York State (populatio based cacer registries) icluded all icidet cases whose registry files (icludig hospital, cliical, pathology, ad death certificate reports) metioed the word mesothelioma; ad from the Veteras Admiistratio hospitals all pleural ad peritoeal mesothelioma cases for whom pathology slides or tissues were available for study. For the Veteras Admiistratio, pathology services at idividual hospitals selected potetial cases i respose to a letter set from the pathology service i the Veteras Admiistratio Cetral Office. Telephoe iterviews were coducted with the ext of ki of eligible cases ad cotrols, betwee 1982 ad Of the 720 eligible cases, ext of ki of 536 (75%) were successfully iterviewed ad 184 respodets (25%) were ot iterviewed: 106 were ot located, 64 refused to be iterviewed, eight were ot approached due to refusal by the physicia to allow cotact, ad six had partially completed iterviews. Of these 536
2 Maligat mesothelioma: attributable risk of asbestos exposure completed iterviews, 208 pleural or peritoeal cacers were cofirmed by a expert pathology review (see ext sectio) as defiite or probable mesotheliomas. These 208 cofirmed cases form the case group for this study. Cotrols were selected from people who died of causes other tha cacer, respiratory disease, suicide, or violece. Cacer ad respiratory disease were excluded because several cacers ad respiratory diseases may be related to asbestos exposure.'5 Suicide ad violece were omitted because of cocer for the potetial trauma ivolved i iterviewig ext of ki of people who died from violet deaths. Cotrols from New York State ad Los Ageles Couty were selected from death certificate files. Cotrols from the Veteras Admiistratio-were selected from deaths i the beeficiary idetificatio ad records locatio subsystem (BIRLS), a computerised file of veteras who received medical ad fiacial beefits. The cotrols from the Veteras Admiistratio are represetative of all veteras who have sought beefits from the Veteras Admiistratio. Origially, pair matched cotrols (matched to cases o date of birth, race, sex, year of death, ad couty of residece (New York State, Los Ageles Couty) or hospital (Veteras Admiistratio) had bee selected for the 208 cofirmed cases who were used i the aalysis. A larger group of cotrols was available, however, the 678 eligible cotrols were matched to the origial 720 eligible cases (before review of histological slides). Of these 678, ext of ki of 533 (79%) were iterviewed, ad 145 respodets (21%) were ot iterviewed: 138 were ot located, four had partially completed iterviews, ad three refused. To take advatage of the iformatio available from the cotrols matched to ucofirmed cases, these 533 subjects were used i the aalysis as the cotrol group. Adjustmet for age, geographic area, ad smokig by stratificatio ad logistic regressio, rather tha with a matched aalysis, eabled us to cotrol cofoudig while maximisig precisio INTERVIEWS For each deceased case or cotrol, the ext of ki listed o the death certificate was cotacted by letter ad telephoe to idetify a appropriate respodet. The sequece of preferred respodets was spouse, child, siblig, other relative, or fried. Oe livig case self respoded. Four questioaires1821 were reviewed i developig the istrumet used for this study. The telephoe iterview solicited iformatio o lifetime exposures to chemical ad physical agets, disease history, smokig history, ad demographic backgroud. Potetial direct exposure to asbestos was defied i three ways based o iterview data: (a) ever or ever, accordig to the respose to the questio: "Was the study subject ever exposed to asbestos?"; (b) by ay oe or a combiatio of ie predetermied occupatioal or o-vocatioal activities i which asbestos exposure was thought likely (brake liig istallatio or repair, furace or boiler istallatio or repair, buildig demolitio, plumbig or heatig repair, isulatio work, shipbuildig, ship demolitio, or shipyard work, elevator istallatio or repair, textile productio, ad paper productio); ad (c) by job-exposure matrix, based o lifetime work histories. For the job-exposure matrix, each job held by a subject was classified as ivolvig oe, <10%, 10-19%, 20-49%, or > 50% likelihood of asbestos exposure, accordig to the results of the Natioal Istitute for Occupatioal Safety ad Health (NIOSH) Natioal Occupatioal Hazard Survey (NOHS)." The NOHS reported estimates of proportios of workers exposed to a variety of physical ad chemical agets, based o walk through surveys by idustrial hygieists of about 5000 o-agricultural busiesses i 67 metropolita areas coducted i NIOSH provided tables (Pederso, persoal commuicatio, 1982) which categorised likelihood of asbestos exposure for combiatios of four digit 1972 stadard idustrial classificatio (SIC) idustry codes23 ad three-digit 1970 cesus occupatio codes.'4 We coverted these categories to three-digit 1980 cesus idustry ad threedigit 1980 cesus occupatio codes25 to be compatible with the data files for the curret study. Each study subject was classified ito the highest achieved exposure category (without cosideratio of time weightig) based o the NOHS estimate for the etire work history. Idirect exposure was measured by questios about residece of study subject ad exposures of cohabitats. PATHOLOGY REVIEW 805 All available pathology material was iitially reviewed by pathologists, oe of whom was chose by each of the three participatig study cetres. No review was possible for 110 of the iterviewed cases, due to lack of pathology material. The stadard five category system was used for recordig the certaity of maligat mesothelioma (defiite, probable, possible, ulikely, ot mesothelioma).'6 As differeces were oted amog the three study cetres i the percetage of potetial cases judged to be true mesotheliomas, a more extesive pathological review of a sample of cases was coducted by a pael composed of five pathologists: the origial three pathologists from the three study cetres plus two referee pathologists recogised iteratioally as expert i the diagosis of mesothelioma. Based o the results of this pael review,27 ad to assure cosistecy of diagosis, it was decided to have all slides re-reviewed by the two referee pathologists. Oly the 208 cases deemed defiite or probable mesotheliomas i the fial expert review were icluded i this aalysis. STATISTICAL METHODS Crude ad stratified odds ratios (ORs) ad
3 806 Spirtas, Heiema, Berstei, Beebe, Keeh, Stark, Harlow, Beichou 95% cofidece itervals (95% CIs), cotrolled for age i four categories, geographic area, ad cigarette smokig (ever or ever), were calculated for the associatio of each idex of exposure ad mesothelioma. We cotrolled for smokig because it cofouded the associatio of mesothelioma ad asbestos exposure (cotrols were more likely tha cases to have bee cigarette smokers ad to have died of tobacco related causes). Six subjects without iformatio o smokig were excluded from the aalyses. The maximum likelihood method was used to estimate the OR ad the method of Corfield as modified by Gart2829 was used to estimate 95% CIs. Tests for tred over duratio of exposure were coducted with the method of Matel.0 For calculatios of ORs ad attributable risks, the uexposed group (ever exposed) was defied as those subjects with o reported exposure to asbestos, oe of the ie specified activities, o jobs with NOHS likelihood of exposure >0, o cohabitats with asbestos exposure, ad o residece withi two miles of a asbestos mie or mill. Blak resposes to questios o exposure were treated as if the subject was ot exposed, based o our judgmet that such a respose was closer to a egative aswer. Attributable risk (AR) was defied as the proportio of disease burde that ca be related to asbestos exposure. Adjusted overall ad partial ARs for asbestos ad correspodig 95% CIs were based o a computed ucoditioal logistic regressio.? 32 The models cotrolled for the mai effects ad iteractios of age (four levels), geographic area, ad sex, ad for the mai effect of smokig (ever or ever). Age, area, ad sex specific models, of course, omitted the respective covariate. The overall AR compared those ever exposed with the remaiig subjects, exposed by ay measure of exposure to asbestos. Partial ARs were calculated to evaluate the proportio of mesothelioma related to the idividual measures of asbestos. Partial AR is defied as the proportio of disease burde that ca be related to asbestos exposure captured by the particular measure. For the partial ARs, three categories of exposure had to be cosidered i the model; subjects exposed to the measure of iterest, those ever exposed, ad those either exposed to that measure or uexposed. Thus, each logistic model icluded two dummy variables (oe for the measure of iterest, ad aother for ay other exposure to asbestos) ad yielded a OR for the exposure of iterest adjusted for covariates ad the other measures of asbestos exposure. The prevalece for each AR was the proportio of cases exposed by the measure of iterest compared with the total umber of cases. For the NOHS classificatio, four categories, icludig two exposed levels (1-19% likelihood, ad 20-99% likelihood), ever exposed, ad those either exposed or ot exposed were cosidered i the computatio of partial ARs. Results Of the 208 cases that were cofirmed as defiite or probable mesothelioma, 183 (162 me, 21 wome) were classified as pleural or pleural ad peritoeal, ad 25 (21 me, four wome) were classified as peritoeal oly. Table 1 shows the demographic characteristics of the cases ad cotrols. Most cases ad cotrols were white me (86% of cases, 76% of cotrols). Sixty five per cet of cases ad 75% of cotrols were past or curret cigarette smokers (ot show i table). Next of ki respodets were primarily spouses (55% of cases ad 47% of cotrols), sos or daughters (24% of cases ad 27% of cotrols), ad sibligs (7% of cases ad 12% of cotrols). The remaiig respodets were other relatives, frieds, ad oe self reportig case. All Veteras Admiistratio cases were me ad teded to be older at diagosis tha cases from New York State or Los Ageles Couty. Table 2 shows the umber ad percetage of cases ad cotrols exposed to asbestos. More ext of ki of cases tha of cotrols said Table 1 Demographic characteristics of cases ad cotrols, by geographic locatio New York State Los Ageles Couty Veteras Admiistratio Cases Cotrols Cases Cotrols Cases Cotrols (%) (%) (%) (%) (%) (%) 95 (100-0) 287 (100-0) 79 (100-0) 176 (100-0) 34 (100-0) 70 (100-0) Age at death: < 50 4 (4-2) 26 (9-1) 5 (6-3) 17 (9-7) 2 (2-9) (23-2) 51 (17-8) 15 (19-0) 30 (17-0) 8 (23-5) 18 (25-7) (36-8) 101 (35-2) 26 (32-9) 53 (30-1) 11 (32-4) 31 (44-3) (25-3) 67 (23-3) 20 (25-3) 39 (22-2) 7 (20-6) 6 (8-6) (2-1) 4 (1-4) 1 (1-3) Ukow 8 (8-4) 38 (13-2) 12 (15-2) 37 (21-0) 8 (23-5) 13 (18-6) Race ad sex groups* White M 78 (82-1) 203 (70-7) 69 (87-3) 139 (79-0) 32 (94-1) 64 (91-4) No-white M 2 (0-7) 1 (1-3) 7 (4-0) 2 (5-9) 4 (5-7) White F 17 (17-9) 78 (27-2) 8 (10-1) 27 (15-3) *Of the five o-white wome who were origially diagosed as havig mesothelioma, oly oe completed the questioaire. This case was ot cofirmed as havig mesothelioma ad was ot icluded i the aalysis. Not listed are oe case ad ie cotrols with ukow race.
4 Maligat mesothelioma: attributable risk of asbestos exposure Table 2 Frequecy ad percetages of cases ad cotrols with reported exposure to asbestos Cases Cotrols (%) (%ay) 208 (100 0) 533 (100-0) Ever exposed to asbestos 129 (62-0) 90 (16-9) Ever performed: Brake liig work or repair 33 (15-8) 72 (13-5) Furace or boiler istallatio or repair 51 (24-5) 39 (7.3) Buildig demolitio 11 (5 3) 29 (5 4) Plumbig or heatig 72 (34-6) 125 (23 5) Isulatio 83 (39 9) 83 (15-6) Shipbuildig or yard or repair 67 (32-2) 40 (7-5) Elevator istallatio or repair 5 (2.4) 5 (0.9) Productio of textiles 4 (19) 20 (3 8) Productio of paper products 7 (3 4) 21 (3 9) At least oe of these ie 150 (72-1) 238 (44 7) Highest likelihood of exposure by job history ad NOHS* (%): (52-9) 372 (69-8) (20 2) 99 (18-6) (1-0) 10 (1 9) (19-7) 40 (7 5) >50 13 (6 3) 12 (2-3) Cohabitat ever exposed 16 (7 7) 24 (4 5) Cohabitat ay of ie activities 37 (17-8) 93 (17-4) Lived withi two miles of asbestos mie or mill 0 (0 0) 8 (1-5) Overall reported exposure to asbestos: Potetial 186 (89-4) 335 (62 9) No kow exposure 22 (10-6) 198 (37-1) *For each study subject, highest likelihood of exposure was assiged based upo NOHS categorisatio of all jobs (see Methods sectio). tpotetial exposure = reports ever exposed to asbestos, ay of the ie specified activities, at least oe job with NOHS likelihood > 0, cohabitats with asbestos exposure, or residece withi two miles of asbestos mill. No kow exposure = reports ever exposed to asbestos, oe of the ie specified activities, o jobs with NOHS likelihood > 0, o cohabitats with asbestos exposure, ad o residece with two miles of asbestos mie or mill. 807 the study subject was ever exposed to asbestos, gave a positive respose to questios o occupatioal or o-vocatioal exposure to ay of the ie activities ivolvig suspected asbestos exposure, or were classified by the NOHS as beig employed i a job with >0% likelihood of asbestos exposure. Reports of ever livig withi two miles of a asbestos mie or mill were similar for cases ad cotrols. No kow source of asbestos exposure was reported for 22 cases (11%) ad 198 (37%) cotrols. Table 3 shows ORs ad 95% CIs for the risk of mesothelioma from exposure to asbestos by sex, age, ad tumour site (me oly). The ORs were early a order of magitude higher for me tha for wome for all measures of asbestos exposure. Noe of the ORs amog wome was sigificatly differet from uity, but female cases were few. Amog me, pleural mesothelioma was more strogly associated with asbestos exposure tha was peritoeal mesothelioma. Amog the measures of asbestos exposure, the questio, "Was the study subject ever exposed to asbestos?", geerally yielded higher ORs tha the other measures, followed by the subgroup of jobs for which the likelihood of exposure to asbestos was at least 20%. Whe ORs for age at death <65 ad > 65 were compared, there were o importat differeces. May subjects had multiple activities ivolvig asbestos exposure. For example, amog subjects with brake liig istallatio or repair history, 33% also had shipbuildig or shipyard work ad 55% had performed isulatio work. For this Table 3 Odds ratios (95% CIs) for the associatio ofasbestos exposure with maligat mesothelioma, by sex, age, ad by tumour site for me* Met Womet Age <65t Age > 65* Mepkuralt ( =179) ( = 25) ( = 86) ( = 118) ( = 159) Me peritoealt ( = 20) Overall exposure reporteds ( ) ( ) ( ) ( ) ( ) ( ) Ever exposed to asbestos ( ) ( ) ( ) ( ) ( ) ( ) Ever ay of ie activities ( ) ( ) ( ) ( ) ( ) ( ) Highest likelihood of exposure with job history ad NOHS 1-19% ( ) 20-99% ( ) ( ) ( ) ( ) Cohabitat ever exposed to asbestos ( ) ( ) ( ) Cohabitat ay of ie activities No kow exposure ( ) (47-360) ( ) ( ) ( ) ( ) ( ) (39-797) ( ) ( ) ( ) ( ) ( ) ( ) *AU comparisos are made with people with o reported exposure to asbestos, oe of ie specified activities, o jobs with NOHS likelihood of asbestos exposure > 0, o cohabitats with asbestos exposure, ad o residece withi two miles of asbestos mie or mill. Blak respose treated as if ot exposed. Cases ad cotrols with missig data o smokig have bee excluded from aalysis. Subjects may have aswered yes to more tha oe questio; measures of asbestos exposure are ot cotrolled for each other. tadjusted for age i four levels, geographic locatio, smokig. *Adjusted for sex, geographic locatio, smokig. Reports ever exposed to asbestos, ay of ie specified activities, at least oe job with NOHS likelihood > 1 %, cohabitats with asbestos exposure, or residece withi two miles of asbestos mie or mill. Job histories classified with the results of the NOHS survey of workplaces coducted by NIOSH i (Pederse, persoal commuicatios, 1982). Each subject was classified ito the highest attaied exposure category.
5 808 Spirtas, Heiema, Berstei, Beebe, Keeh, Stark, Harlow, Beichou Table 4 Adjusted odds ratios (95% CI) for the associatio of asbestos exposure with pleural maligat mesothelioma amog me, by duratio, latecy, age at first exposure, decade offirst exposure, ad decade of last exposure* NOHS likelihood of asbestos exposure Ever exposed to asbestos Duratio of exposure (y): < ( ) ( ) ( ) Tred P value 0-07 Latecy (first exposure to diagosis) (y): < ( ) ( ), ( ) Age at first exposure: < >35 Exposed ( ) ( ) ( ) 21 Decade of first exposure: ( ) ( ) ( ) 20 Decade of last exposure: ( ) ( ) ( ) 67 Ever ay of 9 activities 15-6 ( ) 16 1 ( ) 14 2 ( ) 043 Exposed ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) (32-690) (53-590) ( ) % 4-3 ( ) 16-6 ( ) 10-9 ( ) 0 13 Exposed ( ) 6 6-6( ) ( ) ( ) (24-340) ( ) 7 85 (26-286) 12 70( ) (18-226) ( ) ( ) 6 92 ( ) 23 >20% 21-2 ( ) 15-2 ( ) 42-1 ( ) 0 05 Exposed (06-930) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) (38-706) ( ) 36 *All comparisos are made with people with o reported exposure to asbestos, oe of ie specified activities, o jobs with NOHS likelihood of asbestos exposure > 0, o cohabitats with asbestos exposure, ad o residece withi two miles of asbestos mie or mill. Odds ratios adjusted for age ad smokig. Cases ad cotrols with missig data o smokig were excluded. P value based o Matel tred test.29 tfor each study subject, highest likelihood of exposure was assiged based upo NOHS categorisatio of all jobs. (Pederso D, persoal commuicatio 1982). reaso, results are ot preseted idividually for each of the ie activities. For the three methods of classifyig asbestos exposure, table 4 shows patters of risk of pleural mesothelioma amog me by duratio, latecy, age at first exposure, ad decade of first ad last exposure. Dates whe first ad last exposed for each measure were obtaied from reported start ad stop dates for jobs held by the subject, or from dates durig which the subject lived with a cohabitat who was reportedly exposed. Reported asbestos exposure that was related to either job or cohabitat lacked dates ad thus could ot be cosidered i these aalyses. The measures of exposure i table 4 are ot cotrolled for each other. Patters of risk with latecy, age at first exposure, ad decades of first ad last exposure were similar amog differet duratios of exposure categories (ot show). Although risk of mesothelioma is icreased i all categories for every measure, patters differ betwee measures. Risk decreases with legth of reported exposure to asbestos for the ever exposed to asbestos category, is uchaged with time egaged i the ie suspect activities, ad is icosistet with time i jobs judged to have 1-19% or >,20% likelihood of exposure to asbestos. Oly the icrease with duratio of exposure i the >20% likelihood category is sigificat. Resposes to the ever or ever exposed to asbestos questio yielded the highest risk (OR = 234-7, 95% CI 17' ) amog subjects most recetly exposed, ad lower risks with loger latet periods. I cotrast, risks were similar for all itervals sice first exposure to ay of the ie activities, ad higher for loger latecy periods for the two likelihood categories. The ORs based o the ie suspected activities gave icosistet results for age at first exposure. Accordig to the ever or ever questio, the risk was higher with youger age at first exposure. For both categories of likelihood of asbestos exposure, subjects had lower risks if they were exposed after the age of 35, but the patter was ot cosistet i youger age groups. Results by decade of first exposure were complemetary to those for latecy, with the two likelihood measures showig higher risks for subjects exposed earlier, ad the ever or ever questios showig highest risk amog subjects begiig exposure most recetly. Risks were ot relatively higher for first exposure durig the 1940s, except for those subjects who were ivolved i at least oe of the ie suspect activities. Of the me with pleural mesothelioma 70-80% were judged to have bee still exposed i the 1950s ad later by each of the measures of asbestos exposure. Risk patters were icosistet across categories of decade of last exposure by the differet measures. Table 5 shows the overall AR of mesothelioma that ca be related to asbestos ad partial ARs for each idividual measure of exposure. Amog me, pleural mesothelioma was associated with higher ARs tha was peritoeal mesothelioma. A substatially smaller percetage of the cases amog wome were attributable to asbestos, both overall (AR = 22-5) ad for idividual measures of exposure. Except for the ever or ever questio, ARs for wome were ot detectably differet from zero. Overall ad partial ARs were higher amog the all male Veteras Admiistratio populatio tha amog the New York State or Los Ageles Couty total
6 Maligat mesothelioma: attributable risk of asbestos exposure 809 Table S Percetage ofoverall ad partial attributable risk (95% CIs) of maligat mesothelioma due to asbestos exposure by geographic locatio, site, sex, ad age* New Los York Ageles Veteras Me Me Statet Coutyt Admiistratiot Me* Womet <65 > 65S pleuralt peritoealt ( = 94) ( = 76) ( = 34) ( = 179) ( = 25) ( = 86) ( = 118) ( = 159) ( = 20) Attributable risk risk for asbestos: Overall exposure reportedly ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Partial attributable risks: Ever exposed to tt asbestos ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Ever ay of ie activities ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Highest likelihood of exposure from job history ad NOHS:II 1-19% ** ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 20-99% ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Cohabitat ever if exposed ( ) ( ) ( ) (3 4-11i1) ( ) ( ) ( ) ( ) Cohabitat ay of ie activities ( ) -( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) *Attributable risk % calculated with a approach based o logistic regressio (see Methods sectio). All comparisos are made with people with o reported exposure to asbestos, oe of ie specified activities, o jobs with NOHS likelihood of asbestos exposure >0, o cohabitats with asbestos exposure, ad o residece withi two miles of asbestos mie or mill. Cases ad cotrols with missig data o smokig have bee excluded from aalysis. Partial attributable risks may add to >100 because subjects may be classified as exposed by more tha oe measure. tadjusted for age, sex (except Veteras Admiistratio where all subjects were me) ad smokig status. 4Adjusted for age, smokig status, ad geographic area. SAdjusted for age, sex, smokig status, ad geographic area. IReports ever exposed to asbestos, ay of ie specified activities, at least oe job with NOHS likelihood > 1%, cohabitats with asbestos exposure, or residece withi two miles of asbestos mie or mill. IlFor each study subject, highest likelihood of exposure was assiged based o NOHS categorizatio of all jobs (see Methods sectio). **Attributable risks ot preseted; ureliable because oly oe exposed case. ttattributable risks ot preseted; o exposed cases. #Partial attributable risk is greater tha overall attributable risk because the odds ratio i itermediate category i logistic model, either ever exposed by this measure or ever exposed, was < 1. populatios, but are comparable with those for all me i the study. For cases <65 years old ARs are cosistetly higher tha for cases > 65, but there is cosiderable overlap i 95% CIs. Discussio Previous estimates of the percetage of cases of mesothelioma that had had asbestos exposure have varied from % Amog these studies the paper by McDoald et al 45 provided a formal measure of risk attributable to type of asbestos fibre. No other study gave ay measure of attributable risk. The results of our study foud the overall AR to be highest amog male pleural cases, which is also the group with greatest frequecy of asbestos exposure. Previous aalyses of icidece ad of mortality from mesothelioma foud the highest rates ad icreasig treds for older me with pleural mesothelioma Eterlie ad Hederso studied Uited States death rates for maligat eoplasms of the pleura (the disease classificatio closest to mesothelioma of the pleura) durig the years They foud a icrease i death rates for me aged >65, but ot for youger me or for wome. We foud slightly, but geerally higher partial ARs amog the youger male cases. There may have bee better reportig by respodets for youger cases. Also, very high exposures, which were likely to have occurred i the 1930s ad 1940s, may have resulted i lug cacer or asbestosis before mesothelioma could develop. Studies that showed a high percetage of cases exposed to asbestos (>80%) have teded to come from geographic areas ear shipyards or crocidolite asbestos mies.4656 I our study, 20%, 46%, ad 35% of the respodets for cases from New York State, Los Ageles Couty ad the Veteras Admiistratio reported exposure i shipyards, shipbuildig, or ship repair. The relatively high percetage of cases from Los Ageles Couty with shipyard exposure is cosistet with the large shipyard idustry i that area. Studies that reported a low percetage (<30%) of mesothelioma cases exposed to asbestos have teded to come from geographic areas remote from a mai source of asbestos exposure.4950 The ARs calculated from the two populatio based registries are likely to be represetative of their geographic areas. Data from the Veteras Admiistratio (all me), which were icluded for compariso, provided results that were similar to results for me from the two populatio based cacer registries. They are ot represetative, however, of a easily defied populatio ad the BIRLS cotrols are likely to be more similar to all veteras tha are the Veteras Admiistratio cases, who may have lacked access to other medical care. Mesothelioma was ot sigificatly associated with asbestos exposure amog wome i our study, although the OR for ever exposed wome was 2-7. Although over 50% of the female cases reported some exposure to asbestos, the umber of female cases was small, ad wome were less likely tha me to be employed i jobs expected to have the
7 810 Spirtas, Heiema, Berstei, Beebe, Keeh, Stark, Harlow, Beichou highest exposure to asbestos, such as shipbuildig ad isulatio work. It is geerally accepted that < 10% of the workforce exposed to asbestos is female.6' Viaa ad Pola, i a study restricted to wome, reported a sigificat associatio with idirect exposure to asbestos (husbad or father had occupatioal exposure; OR = 10 for pleural ad peritoeal cases combied).54 Our results are cosistet with previous studies i suggestig that differeces i icidece rates of mesothelioma by sex ad geographic site may be due to differeces i exposure to asbestos. I a previous study of a cohort of asbestos isulatio workers the icidece of mesothelioma icreased with time sice first exposure, but ot age at first exposure.20 For most measures we foud ORs were higher for youger ages at first exposure. The wide CIs aroud the ORs for age at first exposure, idicate that our study has limited power to assess this issue. The relatio betwee ORs ad latecy (time sice first exposure) differed for the various measures of exposure. Results for the NOHS likelihood measures were cosistet with previous fidigs, whereas those of the other two measures were ot. McDoald ad McDoald described larger relative risks with selected occupatios that have bee associated with mesothelioma tha by assigig probability of exposure to all jobs listed.'8 Their cotrols cosisted of people matched to give cases o age, sex, ad year of death, ad were restricted to people dyig of pulmoary metastases from a o-pulmoary maligat tumour. They icluded a small group of jobs that had possible asbestos exposure as o-exposed i their aalysis. I our study, the largest ORs come from the ever exposed questio, the from the NOHS ratig of the likelihood of asbestos exposure, which assiged probabilities of exposure to each job, for jobs where the probability of exposure to asbestos was >20%. I our study, the defiitio of o-exposed was made as restrictive as possible ad excluded ay study subject ever exposed who had ay of ie specified activities, ay job with NOHS likelihood of exposure >0, ever cohabited with someoe exposed to asbestos, or ever residet withi two miles of a asbestos mie or mill. Because of the well kow associatio betwee asbestos exposure ad mesothelioma, there may have bee reportig bias by ext of ki of cases i respodig to the questio: "Was (study subject) ever exposed to asbestos?" Such a bias would result i artificially high estimates of OR ad AR. All measures of asbestos exposure show the expected gradiets i ORs for tumour site ad sex. The NOHS, used to estimate likelihood of asbestos exposure i tables 2-5, was based o surveys coducted i ad seemed ot to have captured all exposures i the 1940s to the 1960s, the aetiologically meaigful period for our study, as oted by previous researchers."' Also, it omitted subjects who performed some activities-for example, isulatio work-outside work ad lacked ay measure of itesity. O the other had, both the NOHS evaluatio ad ivolvemet i the ie specified activities would be expected to iclude subjects with little or o exposure to asbestos. Such misclassificatio would ted to bias the estimates of risk toward the ull. Noe of these measures is ideal, as the ext of ki could ot be expected to recall all jobs ad exposures for the study subject.6566 I particular, it is possible that exposures ad jobs i the more distat past may have bee missed. As oe of the measures of asbestos exposure used i our study ca be cosidered as the gold stadard, it is impossible to measure sesitivity or specificity. Because of the presece of a large shipyard idustry i the Los Ageles Couty area ad the uiqueess of the Veteras Admiistratio cases ad cotrols, we do ot cosider these ARs to be directly represetative of the whole populatio of the Uited States. Coclusios I our study early 90% of icideces of pleural mesothelioma amog me were directly attributable to past exposures to asbestos. Although there were oly a small umber of peritoeal mesothelioma cases amog me available for study, it seems that a substatial percetage of these cases, perhaps 60%, also could be attributed to asbestos exposure. Amog wome, however, oly about 20% of the cases were attributable to asbestos exposure. As the icidece of mesothelioma amog wome (about three cases per millio wome per year for all primary sites combied) is much lower tha amog me ad has remaied reasoably costat over time, it is possible that the icidece i wome may be close to the backgroud level. Alteratively, exposure to asbestos is lower ad misclassificatio of exposure may be greater amog wome, which would also reduce their AR. Use of ext of ki iterviews may have resulted i biased resposes. If time dulled the memories of ext of ki of cotrols more tha cases, the resultig ORs ad ARs would be artificially iflated. The large percetage of cases first exposed i 1950 or later, argues for cotiued surveillace of future mesothelioma cases. We thak Drs J C Wager ad L Hochholzer for review of histopathology slides. 1 Adersso M, Olse JH. Tred ad distributio of mesothelioma i Demark. Br Y Cacer 1985;51: Bruckma L, Rubio RS, Christie B. Asbestos ad mesothelioma icidece i Coecticut. Joural of the Air Pollutio Cotrol Associatio 1977;27: Churg A. Maligat mesothelioma i British Columbia i Cacer 1985;55: Maker H, Weier JA, McLaughli JK. Register epidemiology studies of recet cacer treds i selected workers. A NYAcad Sci 1990;609: Meijers JMM, Plateydt HT, Slage JMM, et al. Treds ad geographical patters of pleural mesotheliomas i the Netherlads Br J Id Med 1990;47: Mowe G. The tred i icidece of maligat mesothelioma i Norway ( ). 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Arch PatholLab Med 1981;105: Peterso JT, Greeberg SD, Buffler PA. No-asbestosrelated maligat mesothelioma: a review. Cacer 1984; 54: Iteratioal Agecy for Research o Cacer. Overall Evaluatio of Carciogeicity: a updatig of IARC moographs volumes IARC Moogr Eval Carciog Risks Hum Suppl 1987;7: Pretice R. Use of the logistic model i retrospective studies. Biometrics 1976;32: Schlesselma JJ. Case cotrol studies: desig, coduct, aalysis. New York: Oxford Uiversity Press, 1982: McDoald AD, McDoald JC. Maligat mesothelioma i North America. Cacer 1980;46: Peters GA, Peters BJ. Sourcebook o asbestos diseases: medical, legal, ad egieerig aspects, Vol 2. New York: Garlad Law, Peto J, Seidma H, Selikoff UJ. Mesothelioma icidece amog asbestos workers: implicatios for models of carciogeesis ad risk assessmet calculatios. BrJ Cacer 1982;45: Viaa NJ, Maslowsky J, Roberts S, et al. Maligat mesothelioma: epidemiologic patters i New York State. NYStatejMed 1981;81: Natioal Occupatioal Hazard Survey, vol 3: survey aalysis ad supplemetal tables. Ciciati: Natioal Istitute for Occupatioal Safety ad Health. Departmet of Health, Educatio, ad Welfare, (Publicatio No ) 23 Techical Committee o Idustrial Classificatio. Stadard idustrial classificatio maual (1972). Washigto: Executive Office of the Presidet, Office of Maagemet ad Budget, US Govermet Pritig Office, / US Bureau of the Cesus Cesus of the populatio: alphabetical idex of idustries ad occupatios. Washigto: US Govermet Pritig Office, US Bureau of the Cesus Cesus of the populatio: alphabetical idex of idustries ad occupatios. Washigto: US Govermet Pritig Office, Platdeydt HT. Observer variatio ad reliability of the histopathological diagosis of mesothelioma. A NY Acad Sci 1979;330: Spirtas R, Keeh RJ, Beebe GW, et al. Results of a pathology review of recet US mesothelioma cases. Accomplishmets i Ocology 1986;1: Gart J. Poit ad iterval estimatio of the commo odds ratio i the combiatio of 2 x 2 tables with fixed margials. Biometrika 1970;57: Thomas DG. Exact ad asymptotic methods for the combiatio of 2 x 2 tables. Comput Biomed Res 1975;8: Matel N. Chi-square test with oe degree of freedom: extesio of the Matel-Haeszel procedure. Joural of the America Statistical Associatio 1963;58: Bruzzi P, Gree SB, Byar DP, et al. Estimatig the populatio attributable risk for multiple risk factors usig casecotrol data. Am J Epidemiol 1985;122: Beichou J, Gail MH. Variace calculatios ad cofidece itervals for estimates of attributable risk based o logistic models. Biometrics 1990;46: Atma KH, Blum RH, Greeberger JS, et al. Multimodality therapy for maligat mesothelioma based o a study of atural history. Am J Med 1980;68: Armstrog BK, Musk W, Baker JE, et al. Epidemiology of maligat mesothelioma i Wester Australia. Med J Aust 1984;141: Ashcroft T. Epidemiological ad quatitative relatioships betwee mesothelioma ad asbestos o Tyeside. Cli 811 Pathol 1973;26: Baris YI, Artivili M, Sahi AA. Evirometal mesothelioma i Turkey. A NYAcad Sci 1979;330: Bigo J, Sebastie P. Di Meza L, Paya H. Frech mesothelioma register. A NY Acad Sci 1979;330: Breer J, Sordillo PP, Magill GB, Golbey RB. Maligat mesothelioma of the pleura. Cacer 1982;49: Chahiia AP, Pajak TF, Hollad JF, et al. Diffuse maligat mesothelioma: prospective evaluatio of 69 patiets. A Iter Med 1982;96: Elmes PC, McGaughey WT, Wade OC. Diffuse mesothelioma of the pleura ad asbestos. BMJ 1965;1: Greeberg M, Davies TAL. Mesothelioma register BrJ Id Med 1974;31: Hirsch A, Brochard P, DeCremoux H, et al. Features of asbestos-exposed ad uexposed mesothelioma. Am _J Id Med 1982;3: Law MR, Ward FG, Hodso ME, Heard BE. Evidece for loger survival of patiets with pleural mesothelioma without asbestos exposure. Thorax 1983;38: Liebe J, Pistawka H. Mesothelioma ad asbestos exposure. Arch Eviro Health 1967;14: McDoald JC, Armstrog B, Case B, Doell D, McGaughey WTE, McDoald AD, Sebastie P. Mesothelioma ad asbestos fiber type: evidece from lug tissue aalyses. Cacer 1989;63: Mile JEH. Thirty-two cases of mesothelioma i Victoria, Australia: a retrospective survey related to occupatioal asbestos exposure. BrJ Id Med 1976;33: Mowe G, Gylseth B. Occupatioal exposure ad regioal variatio of maligat mesothelioma i Norway, Am_Id Med 1986;9: Newhouse ML, Thompso H. Mesothelioma of pleura ad peritoeum followig exposure to asbestos i the Lodo area. BrJ Id Med 1965;22: Oels HC, Harriso EG, Carr DT, Beratz PE. Diffuse maligat mesothelioma of the pleura: a review of 37 cases. Chest 1971;60: Rubio GF, Scasetti G, Doa A, Palestro G. Epidemiology of pleural mesothelioma i orth-wester Italy (Piedmot). Br Id Med 1972;29: Stumphius J. Epidemiology of mesothelioma o Walchere Islad. BrJ Id Med 197 1;28: Tago I, Blot WJ, Stroube RB, et al. 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