Document NEKqJmawyXB2VwLoV5r439XwE

~DI 1 i^'10^ - Estimating H^a;ch Risks in Siuciss oi me Health Effects of Asbestos,,' * PHIU? S. cNTSRUlN- institute: cf occupational A;MO EMVJaCN:.: ental hEP.ITf-i MONTREAL CANADA SUMMARY ------ -------------------------------- --------- --------------------------------- ---------------------------------------------- Xaidriuiolrj-ic \:uui':s rcv/irat.VA cancer hj.'ird*. at?:l with .,f- i~. i.-; !...'.rn% -i*.*. >.:<';<:. " c si'.i v: ' : '*' ;*e .:. i. .< .' .. : * t magnitude of titexcess. While m.i m u* be it agreement a> u> the ex.-tanc? ! in cx- <tts. there r, considerable disagreement a. to i:* magnitude. lor II studies. estimate &: relative ri.k for respirators cancer range ftom about 1.2 10 *.*.2. l our feature* of these 11 studies can L>v identi fied that account for Mime of the satiation tit results: wins studies include worker* whjic e.iio- sure to asbestos was too rvteuc ro fie likely to produce cancer by the end of ibe M;oi--t:p p.-rle-l. and results are diluted l>> the presence of these worker*: in mou studies, the wrong copulation wav used lor estimating expected mm.diers uf deaths: in some studies, death cvrtifieatcs for the atudv population were corrected based ott a lev Ur* of other medical records, but then comparisons were made with expected deaths derived from uncorreeted death certificates; finally, in r.or. stud io. |cvd and duration of exposure is unknown, and this is clearly a factor that determines tvs magnitude of the respiratory cancer risk. For 0 of the ll studies it sas possible from published material to correct results roughly for the fu>t 3.of these factors and much of tr.c satiation chs- appeared. Problems in the 11 studies reviewed here should be considered in planning and reporting on epidemiologic investigations in the future. Asbestos represents an interesting environmental haaard in that it is apparently sufficient for rite production of one disease (cancer), and both necessary and sufficient for that of another (as* beatosis). That is. asbescosts is caused only by asbestos exposure, whereas cancer has many auses, one of which is apparently asbestos ex* posure. Tn (he instance of asbestous, a single case represents the health risk, whereas for cancer, the risk can be measured only in relation to all other risks. This paper is confined to a discus* slon of the problem of estimating cancer risks associated with asbestos, because it is here that (Received in original farm July 25, 197) end in re* vised form Sovtmker 17,197)) 1 From the Department of Biostau.tic*. University of Pittsburgh, Pittsburgh. Pa. a Pretemed at a joint meeting oi the American and Canadian Thoracic Societies. Muntreal, Canada. May 13.1S73. there appear to be some methoJalogic difficul ties in work that has been dons to date. When a number of agents contribute to a sin gle disease, as for respirators- cancer, it is cus tomary to measure the contribution of a single agent by calculating Use ratio of the risk with the agent present to the risk with the agent ab sent. Tltis calculation is illustrated in table 1* where death is the measure of risk. The relative risk can be estimated by calculating the ratio of the probability of dying among persons exposed to the agent of interest to the probability of dying among those not so exposed. This can also be expressed as the ratio of an observed number of deaths in an er.jimed population to art ex pected number based on the experience in a nonexposed jioptdation. There is also another way of measuring risk, and that it the absolute risk, i.e.. the absolute difference between the two probabilities. Both of these measures are of intetvst iti studies of the health effects of atVstov. In 11 studies in the United States and Canada. AMSfttC.SN Kf VII \v OI RI.MM1.WOXY HIM \F.. VOttM*. UJ. I*?* 175 Am o/x, t 175 WfH.t? t. f.XTMLIXI. TA3LS \ M2TN003 ?0R CALCULA7 EXC=S.S mortality IN A PPOSr-iC ri`-s $ruo V 0a f` a: 0*d Tat* c x ao*-*a No; ToMl b #* e d e+d b*d N PQ - ----- c*d Pctarfra r!*' ---- ASsftlur* r V< P\ - ?o the risk of developing respiratory cnnccr l:a* been estimated in a prospective way among workea exposed to asbestos. These studies should provide some estimate noc ortly of wheth* cr an excess in respiratory cancer exists hut of t!fe magnitude of this excess. The latest pub* Jished results from these studies, summarized in t3bie 2. are expressed as relative risks (1-14). Twelve studies are shown; however, my 1954 aw! JD57 reports relate to subgroupings from a single large cohort. All show an excess; however, the magnitude varies widely. At least 4 features of the published data account for this variation in results and. in a more general settle, can be regarded as problems in epidemiologic studies. (f) Some studies included workers with a very low probability of developing asbestos-related cancer. These were workers whose exposure to asbestos was too recent to be likely to produce cancer by the end of Use follow-up period. This can be labeled die latent period problem. (7) In i!io't studies. the wrong population wjj n*cd for estimating the cxpvctcd number of deaths, i.c.. I he p/f.'j.jhihsy (i'y) sIhjWU ;u uLle l of developing c.uucr in the absence of expo* Mire to asbestos. (?) In M*;ne Modiw death ccrt.-flc.-itt-s were cor rected bawd on a review of other medical rec ords: but comparisons then were made with ex pected uv.uh* derived hoiti uncnrrected death certificates. . (V) f;t u:o*t studies. the level anti iteration ol exunsurc were unknown, so tli.it relative risks could not be related to levels and duration of cxitov.;; r. r!xpcv:rc Ir*. e:* t.*?:*! rli-rau.vn are clearly factors that determine the magnitude o the health risk associated with asbestos (10. 12). The lateut period problem can probably best be demonstrated by looking at die experience of ;t population with a single exposure that is now known to be cincer-ituluriug, e g., the incidence of leukemia in the fiopukuion near the hypo tenter of the atomic bomb exploded a; Hiro shima and Nagasaki (figure l). Leukemia did not appear immediately, and, in fact, until 19-13 few cases occurred. The peak year was 1951, after which the incidence declined. The timlcrlytng distribution of cases of leuke* mia shown in figure 1 is probably the log normal distribution shown in figure 2. This illustrates how a single dose'of asbestos may work. Tor the exposure intensity represented here, little can* cer would be observed in the fine 6 years. The maximal respouse and the highest relative risk after the single exposure would be observed be* tween 13 and 21 yean. Whether the risk would, in fact, decline 23 years or more after cessation TABLE 2 RELATIVE RISKS FOR RESPIRATORY CANCER 03S5RVS0 IN STUOISS O? WORKERS EXPOSSO TO AS3SSTOS 0*t Pi#*t ?/*t*nt*d O' Pu*ishd Peculation Studied 8BAUN nd Trw* (1) CUN.V and tsoclt*s (2.3) OUN-V ind Vinr (3) MANCt/JO a/*d Coulter (4) SSUXOrP *ruf*foc<am 13.6) eNTCALt.Ne (7) rPLN and '8,* COO? 2 R and B.tirw (9. MCOONALO and associates (10.1 tl N " R L` >N and CO Miork *r\ (12) VIAOO-NSH 4-uJ 0 ^*0fX#n U31 S6LJ < 7?. and assoc.**** (141 ScLIXC'X ana (IS) 10SS 1959 1993 1363 1964 1967 1999 137* 1972 1972 1372 1372 Miner* lisswUCOr* Manufacturing lnw*>#(0'ft Mirwfaeturinj Manufacturing Intuljtort V-n*r* Manufacturing Mjnufwturinj Manufacturing Insulator* RMattv* Ai*2t 1.5 3-6 3.4 9.2 2.3 1.2. 1.3 7.3 1.4 2.7 2.3 8.2 5.6 0 1 -0201567 jTt.u'sj o.v >t>.\t.mi r>rtc.r\ot as.u>:os 177 Fig. 1. Incidence of Icukrinu a*. Ns,paki. ar.d cvu-xure i> conj-.'Ci'.'.r.*.!. iu ii'C-Ce Ci good epidemiologic observation* on this. it will be aj.met! in tin* discussion that the lung clear- Fig. 3. Respiratory cancer resulting front single aw ance mechanism or selective lectors are operative brstos cxpo.ureat 4 levels. in such a way a to reduce the risk approximately as shown in figure 2. For a Succession of doses-- as for workers exposed continuously to asbestos (and in the absence of anv interaction)--'we might think of a succession of curves. The area to the left of the dotted line in figure 2 would probably be approximately as shown, whereas the area to the right probably would look soma* Tlie problem is further complicated by the probable relationship between the intensity of exposure and the length of die latent periad. This j illustrated in figure 3. which chows a family of log normal curves corresponding to *mgle-tUe exposures at various intensities. Four assumptions were made in constructing these what different. The point is that the relative risk observed is partly dependent on when the exposure took place in relation to the period in which follow* up studies were carried out. The studies shown in table 2 varied widely in this regard, for some* follow-up did not start until 20 years after ex* posure began. For others* follow-up began close to the time of first exposure to asbestos. Terms* nation times and ages also, differed. Clearly* results should differ* and statements as to the magnitude of the cancer risk associated with asbestos cannot be made without reference to some latent period and termination times. curves: (/) response to asbestos exposure is linear, (2) an intensity of 20 fibers per ml corre sponds to a median latent period of 20 years, (i) response to a single clove has a log normal distribution with a geometric standard devia tion of IS. and (#) latent period is related :o the inverse cube root of dose. These assumptions are based oa papers by Jones and Crindon (13). Albert and Altshuler (16). and available dam on asbestos-exposed populations. From these data, the effects of applying various starting and stop* ping rules in epidemiologic studies can be esti mated. A requirement for entry into a study of 20 yean since first exposure would ensure miss ing nearly one half of the cases of respiratory cancer resulting from a very high exposure. Stop ping follow-up at any point because of age or time limitations would also provide a mislead* jng picture, a picture with a different kind of bias for each level of exposure. Obviously, follow-up must be stopped at some point, if only because all of the study ftfspnlation hat died. This leads to the interestin' notion that e'en if the lel.tiionship between asbestos and res^tra- tt:v c.inte: is linear there is a kins! of th.v*::old limit \ah;r. defined av i!..t du\e for which the latent period exceed* the life span of nvtn (55). l fig. 2. Kcspu.torv car.ccr rtxtihinj; from a jingle From tins, i: would appear that when expo exposure toasbesto*. sure levels aie uncertain. *rid'.*ni:ah>-;ic s;adics 01-20156g 173 THiLir z. ivn:xuN iliould probably include the cxo-rirr.ce of alt workers, rcr^ar<!!o> of tbe number of years since -; exposure: follow-up vhouLl continue tor 3 very long tine, anti results \UouId be reported in relation to the number of jean since first expovire. The second problem, time of ming the urong population for estimating the expected numbers of deaths, is >;imtra:cd by the data shown in table 5. derived from a study of retired asbestos workers (12). This shows the risk of dying from respiratory cancer H> years after retirement dur ing 2 time periods. i9` i io !i07 and i'siS :o iStif). The risk of dying was nearly 5 times greater after J*)o7 than before 1937. There ts no explanation for this insofar as the intensity of duration of ex posure to asbestos is concerned. The reason seems to lie simply in what was happening in the general population during this period, i.e., a Mold increase in respiratory cancer mortality. Asbestos was apparently interacting with other causes of respiratory cancer, so that the effects of other factors increased the effect of asbestos. Some data from an early study by Sslikoft and associates (5) seem to show* this quite well, and are given in table 4. The men in this study had a'U first been exposed 20 years earlier on entry to die cohort, and for each of the 4 time periods shown die population at risk was approximately the same size. Also, for men living in the 4 time periods shown, ids unlikely that exposure levels differed very greatly. One of die tilings that did change, however, was time, and with it. the effects of factors other titan asbestos on incidence of respiratory cancer. Note that both observed and expected deatlis increased at the same rate (a Mold increase in each case). There was also a 5-fold inoease in the absolute risk associated with respiratory cancer. The relative risk, how* ever, was unchanged. During this period, time multiplied die mortality rate by a factor of 3; asbestos, by a factor of 7. The combined effect TA3LS 3 P.zZ?l?*TOriY CANCSR OSATH3 ANO CEATH RATES AMONG MSN GSTO YEARS O? AGE S:udy P*<iod 1341-1957 1953-1949 No- 0* 8 37 R; e-f 1.000 PsMOrt* 2.3 6.6 of time and asbestos, then, was approximately 21. i.e.. 0.3 expected deaths in the nrrind 1943 :o 1947. arid 13 ubssrsed deaths ::i :ht -'.':r:ecl 7*5-3 to 1952. Asbestos apparently has the ability o multiply the effects of other agents in producing respiratory cancer. This has been observed by Berry and associates (17) with regard to asbestos and cigarette smoking. The interaction between asbestos and other factors that cause respiratory cancer probably applies to geographic as well as temporal variations. Thus, the absolute lung cancer risk, ass^ ciatcd with' asbestos exposure would be higher in an area with a high lung cancer death rate than in an area with a low lung cancer death rate. The relative risk would probably be the same, however. In nearly all U.S. studies, the ex pected number of deaths from respiratory can cer was based on "the level of mortality that char acterized the entire United States, rather than the local area in which Use asbestos workers lived. The result was that the relative risk, ob served was directly related to the local dexth rats for respiratory cancer. This relationship is shown in figure 4 for 6 studies in which men whose first exposure occurred 20 years previously were fol lowed, ie.. where the latent periods are roughly comparable on entry 10 the study. As might be expected, dtis shows that if asbestos interacts with other factors that cause lung cancer, and if local death rates are ignored in calculating expected deatlis. when the local death rate is TABLE 4 RELATIVE AND ABSOLUTE RISKS FROM RESPIRATORY CANCER* Study od ostve C0tClt'J flirt Abtolut* flirt (rste/I.CCO ptrzont) 1*43-1947 1948-1953 1933-1997 1953-1942 6 8 13 18 *0t> from S*i>Hotf *r*j 0.9 1.4 2.0 2.4 (Si. 7.S S.7 65 7.5 3.8 3.3 5.3 7.8 ( i ( <r STCiiliS OF Jl.-vcni >MK(.UO> A;w.VGS 179 Fig. 4. Relative rbk fc: respiratory cancer and local death rates in 6 studu-v hiijh, the relative risk, is hi-^rs; when tits local death rats is low, ths calculated relative'risk is low. If local rates of respiratory cancer death, rather than the U.$. death rate, had been used in calculating the expected deaths, variation in relative riik due to variation in local death rates would have been eliminated. The third problem is that in most studies, cause-ohdeath statements on death certificate* were corrected by checking hospital records, pathologic reports of biopsies and autopsies, and coroners' reports. In some cases, data on respiratory cancer were published both as they were recorded on death certificates and as cor* rected, and these show that corrected death cer tificates produce larger numbers of respiratory cancer deaths than uncorrected death certificates A comparable correction cannot be made, how ever, for calculating the expected death date. As a result, some of the published comparisons between observed and expected deaths are also comparisons between corrected and uncorrected death certificates, and this inflates the relative risk. The relative rivks, with the death certificate correction removed, are shown in table 5. The tabic includes data bust: C studies f *r vhi-.h h- tent pcrtotU w.-re roughly t'*ntpa:.b!-.\ For th studies by Srlikof: and to-'-orktrv. observed han^ cancer deaths .verr u-duted by tm.UinUiiv- by 373, b.ucd u;t a reported tOMvetio:t for their U.S. Insulation Worker* Study, and phrtsral rtevi- thelioma deaths by a factor of U. 13.5. based on a .study by Dutic (!3, 19j. The first column of re tire* in table 5 >!kw relative risks a> calculated from published rejsurts. The secund column shows the relative risks that would have user. calcji.i-.ed if d tad; cevtlf.cates Itad not hern car- r:c:-;d. The .a*. .h:n:s u;e-. ;!.? risks that would have been observed if. in addi tion, local, rather than national, death rates had been used in calculating expected deaths. These adjustments bring the findings from the various studies much closer together. Finally, some of the variation hi the relative risk for respiratory cancer among studies is un doubtedly due to differing exposure levels. As shown in figure 3. studies that include only workers with 20 years since first exposure would result in higher relative risks than studies in which workers were included with shorter times since first exposure, owing to fulfillment of latent period requirements--particularly at lower dose levels. In addition, however, relative risks would be higher because of die longer period of expo sure and, thus, the larger dose. Intensity of ex posure appears to nuke an additional but inde pendent contribution. The latter is illustrated in table 6. These data are based cn the retired pop ulation of asbestos workers mentioned earlier; relative risks are shown by number of years since first exposure at time of entry to the cohort (time of retirement) and average exposure levels dur ing work, both factors dearly contributed to the respiratory cancer risk. Actually, 3. rather tlun 2. factors were probably operating here: latent pe* TABLE 5 RELATIVE fi!5*S AND CORRECTED RELATIVE RISKS FOR RESPIRATORY CANCER FOR 6 STUDIES. 20 YEARS AT ENTRY SINCE FIRST EXPOSURE Rf?ne R*Utn> Risk SJt* C iMXisais Co'rai<t D*t?v Rar* Co"aet4 () Enttrlii* Co9>* <01 113) SWi'olt (tat it) S3 7.6 0.3 3.0 3.0 29 7.9 7.0 0.7 a.i 3.0 3.0 1.3 8.0 S.S s.t 4.7 9.7 Ol-(V?n o 0 I'MILU* t. ;\ J KJLI.'f TABLES 3SLAT1VS ftl3< PCS RSS^.BATORV CamCs.9 AMONG S7I R = 0 AS3SST05 `.VOA.'IFRS 7 -r> Out! LV ,1 {/ f tn} < ?0 mooct > JO *r>oosl < 23 27^29 > 30 1.2 3.1 1.S 26 2.S A.7 dose expressed as time, anti dose expressed z> Thus iar. the effects of the first 2 has - See- irr.-josiible to separate. A<s: erznczs 1. Braun. D. C.. and Truar., T. D.: An cpidemiological study of lun^ ca.'tcer in aibesto miners, AMA Arch Ind Health. 1933.17,634. 2. Dunn. J. E.. Linden. C-. ami Srcslow', L.: Lung cancer mortality of men in certain occupations in California. Am J Public Health. I960. 30, 1475. 5. Dunn. J. ., and Weir, J. .*!.: Cancer experience of several occupational groups followed prospec tive*}. Am J Public Health. I96j, }S, 1357. 4. Mancuso. T. ., ami Coulter. E. J.: Methodology in industrial health studies. Arch Environ Health. 1953,5.210. 5. Selikoff, I. J., Churg. J., and Hammond. . C.: Asbestos exposure and neoplasia. JAMA, 1934, ISS, 22. 6. Selikoff.!. j., Hammond. . C., and Setdman. K.t Career risk of insulation worker* in (he United States, in Proceedings of 14RC tforkmg Croup to Review tat Biological Effects of Asbestos, Lyon, France, 1972, International Agency (or Research on Cancer, Lyon, 1973, p- 209. 7. Entetline, P. E.t Mortality among asbestos prod* vets workers in the United States, Ann NY Acad Sci. 1963.733. 156. 8. Enterline. P. E* and Kendrick, M. A.; Asbestos* dust exposures at various levels and mortality. Arch Environ Health, 1967, JS, 13). 9. Cooper. \V\ C.. and Balter. J. L.: Evaluation and control of asbestos cxpourcs in the insulating trade, in Proceedings of e Working Conference on the /tiofojtieet Effects of Asbestos, Drcsdrn, Cermany, 1963. 10. Mcl Vmj.it, J. C.. Mt Don j Id, A. 1).. Cihht. C, W.. J.. and y.pN\i:t?, C.. E.: Mortality in |l:t ClT}>M<!w j>1C'COi mino jml nnl'i nr b.C, Aith Knvirun Health. ir,7l, 33. 577. Jl. McDonald. J. C.. LetklaU. M. R.. Cihb*. Cl. \V,, McDonald. A. I ::*! R.ovd;er. C. .; The health of tlm^otik* mine a::d mill vtork.* cr* of Quvbi-e. Arch Envhon Health. 1974. 2S. 61. J2. F.n'tiline. P. .. Decotiilc. l\. atut Hemier-on, V.: Respiratory cancer in relation tu nccupatlur.al txpo.ure among retired a-ooto workers, Er j Ind Med. 1973. 30.162. 13. Wagoner. J. K.. Johnson. W. M., and Lumen. 7L: Malignan; am*, non-mah^r.-:-'. rv..ni ra; v- j. cae mortality pauenr> a:uoi:g j.1jcsu:> p;jduc- lion workers, in CongioWouaf Record-Sertuis Proceedings and Debates of tiie 93rd Congests. First Session, vol. 119. pt. -3. March 14. 1973. L'3. Gov't. Printing Office, Washington. D. C, p. 7323. 14. -Selikofr, I. J,, Hammond. E. C., and Churg, J.: Carcinogenicity of anionite asbestos. Arch Envi ron Health. 1972,23.1S3. 15. Jones. H. B., and Cfindon, A.: Environmental factors in the origin of cancer and estimation ot the possible hazard to man. fed Comtec ToxicoL J975.J8.25I. 16. Albert. R. E.. and Altshuler. B.: Considerations relating to the formulation of limits lor unavoid* able population exposures to environments! car* cinogcns. in Radionuclide Carcinogenesis, J. E. Ballou. R. K. Bu*ch. D.D. Maltlttm. and C. L. Sanders, ed., AEC Symposium Series, CQNF- 72050. NTIS. Springfield. Va,, 1973. p. 235. 17. Berry. C* Newhou*e. M. l~. and Turok, Ma Combined effects of asbestos exposure and smok ing on mortality from lung cancer In factory workers. Lancer. 1972.2.276. 1$. Roisiter. C. E.: Discussion summary. In Procced- ings of the tARC Iforking Croup to Review the Biological Effects of Asbestos, Lyon, France, 1972, International Agency, for Research ou Cancer. Lyon,1973. 19. Ductcl 5.: L'cxactttude des causes de tlecis : one comparaison avee les <Hagtto>:iquc* a l'autopsis dans une serie de mcsotltcliome* et autres tu* meurs tnaligncs du poumott. Can J Pub Health. 1971.67.395. 001330 > twiiios Infcr--aticrt Asxciuticn tbrt'n Africa 15.:) L StfKl 'i V/. Witfinst:*. 0. 0. 20325 01 -02 t57i