Document OoeN38LeLMo4owRQwmkLy39e

Sent by: EPANITZMDFPANITZMDJD 609 921 3051 12/06/96 1 :OOPM Job 1 6 3 Page 2 AMERICAN JOURNAI..OF INDUSTRIAL MEDICINE 29:474 490 ( I 996) Review of Occupational Lung Carcinogens Kyle Steenland, PhD. Dana Loomis, PM), Carl Shy, Pkb. and Neal Simonsen, P ~ D INTRODUCTION lSalmnal Irislilute lor OscuprtimalSafety and Health [UIOSH),CiiidnnaC.Ohio (KSt DeDarlrnenl of Epiaeiriobgy. Univoteily01 Norlh Qrollna. (D.L , C.S, N S.) Mkrrss rspilnl rcqiests to Or Kve Steelland. Natlond hliMe lor OccLpalionirlSale& and Hedth 4676 CalumMa Parkway. A-13. Cincinnati. OH 45226. Acceplcd Inr publicationMay 8. 1995 til' 1 8 6 Wiley-Lis, Inc. 'This aticle is a US Government work and. as such, k in If18 puhlic cOomain in tho Wited Slates of America. Sent by: EPANITZYDFPANITZMWD 609 921 3051 12/08/96 1:OlPM Job 1 6 3 Page 3 Occupational Lung Carcinogens 475 U6L I. Detitite and Probable Lung Carcinogens as Classlfied by Ihe Irbrikiattunal Ageacy for Research 011Cancer (IARCJ' Human nilaur U A C 111. AGENTS Limitad Limiled Limiled s ulfiihf Sunicignt 1939. 1983a 1989 1987b 1980. 19871 1977, 1987a 1984.1987a 1990 me 1985.1987a Sent by: EPANITZMDFPANITZMDJD 809 921 3051 12/06/96 1:02PY Job 163 476 Steenland et al. TABLE II. Cohort and Case-Control Studies of silicotics Page 4 Finfand. msislant across W s t r & Yes; 72 cases, area of uoffewindustry, OR = 1 4 {0.7-2.8) b r m o d included them. It i s possible th;d Ihc n~inedogiccharxteristics of crystalline silica vary suffiiiently such that some varielies of silica induce lung cncer but wrne do not. Asbestos `lkiisc of asbestos has been increasingly restricted as its h i e e r s became known. The Nationd Inslitute ofOccupalional Health (NIOSH) estimates that in thc 1980)s ap- proximately 7(WI,[wIO US. workers wcw cxpned to ashes tos, primarily maintenance and construction wnrkem exposed to asbestos insulation, and mechanics expnsrd to asbestos in brake linings INIOSH. 1991j. Nicholson e( at. 119821 estimated that From IWI Ln 19'79. 27.5 millicln workers were potentially e x p o d , i8.8 million of whom had cxposul.l: in excess of the quivalent of 2 months in primary rnnrlukcturingof ashcntm.mse authors estimated that txcess lung cancer dentlrs due IO asbcstttrs ewwsure Sent by: EPAIVITZMDFPANLTZMDJD 609 921 3051 12/08/96 1:02PW Job 163 Page 5 -. Occupational Lung Carcinogens TAR. IN. cohort and Case-Control Studies of Silica-Exposed Workers 477 Neubefgsr et dl. (1986) Guend ei d. (1989) K&h et ai. (1990) Sksialycki et al. 41990) HWO ana Siuis-Crmer (1991) Steenland and Brown (1995) Checkoway 64 al. (19%) SHR = 1.48 11.22-1.74) SDVl = 1.16 (0.96-1.39) SMR = 1.27. shed wwkrrs SLUR = 2.00 (1.48-2.69) SlNR = 156 [l.D5-2.21) SHR = 2.81, 25t yc emp DR = 1.3 (1.0-1 8) OR = 1.7 for 20, exp SMR = 1 3 1 (1.03-173) SMR = 151 (1.04-2.12) SMR = 1.77, hired 4957 OR = 19 7 (1.17-3.30) DR = 2.1 (0.7-7.0) DR = D.S (0.3-1.0) OR = D.1 (02-23) Sh(R = 1.t3 (0 93-1.36) SMR = 1.43 (1.N-t.64) w a 1950 NO, 1,630 A1~trians nanlikouE dust, no cbanr la SUR a b r c ~ c k l h p -i Mo; 5,414 U m l e WO-s empbyed 1950-1982, high exposurus, especMy :or &ell W O ~ b l S No; 2.071 Danish stone wwkn with h h histarlul ram 01 silicosis. 44 intidcmt tung canczrs No; but smakhg habits probably sinibr b referents. 1,026 granite workers. 31 l u r ~ CallCets Yes; caws (n = 161) rsstrifted lo rtoradmocarcinma (no risk for adenocarcinoma n = 37) Yes; 3,669pottery warlurs a p d ~60, surwyed tnr d d and smd*rp ill 197u-\971. posm dose-respmsc YL.s; 1,022 brick ~ O r l o r S . silica~eandjmcosirerrce~o.28 lung CanCBR, Yes; case-control sludy among 2.209 Oold miners, t h.4 response, 77 cases, low radon exposure Yes, tase-~Mltrosl tudies among Chtnese pottery. tungsten, and iron worlrers. ORs Yes, 3,328gdd miners, high hm?.cal axpowres, no dpse-~esponse!.0w radnnlrsenic No; 2,570 diatomlceouseacth miners with hlgh pas exposures. 59 lung urnem. positive doseresponse Sent by: EPANITZMDFPANITZMDJD 609 921 3051 12(06/96 1:03PM Job 163 478 Sreenland et af. TABLE IV. Cohort Sttrdies of Asbeslolics Page 0 -- SMR = 9.1 (7.5-11.0) Finkelskin et al. (1961) Cookan el d.(1985) SMR = 7.9 (3.9-14.1) ! M A = 5.1 (3.2-7.9) c:incer in hurrums. Ttaerc is some debate about nresotb- (slope x fiberhnl-years). OSHA (Code c l Fcilnil Reg~d:~. litgna. Stme have wggcstcd th;tt thc mesothctlioma ob- tionr. 1994) estimated ail zwerake slop acrms eight stiidiw served amwig chrysotile-exposed workers may have &en as 0-01 (95% C1 O.O(M-0.03). It should k mtirl t k r t g(!cwwl due to the s m l i amounts nl tremolite that invariably con- estimation of exposure-rcspnsc is difficult k a u w ( ! \ taminalc chrysotile. innst studies have few historical mcasurClflcnts. and (3 Like silica, mhestos is not a clasqic gene mulagen in even in tho= Mudies that d0,conversion of his;oric:rl cLrtn in k t e r i a l systems. although it dues have he capacity IO units aC millions of particle of dust per rvhic f m (rnppcfl to induce gross chrrmimnd aberrations and transfarmation cunent gravimetric units is p~~~htct~wtic. in mammalian cclls. A.Fhesfc*; m y induce cancer directly in For ssbtos. like silica. the argument can he mi& !hit1 humans hy there mechanisms. or indireclly by the produc- lung cancer cannot occur withnut preceding fibrosis. ?his lion o f free radicals conxeyueilt to immune responst hypothesis is difficult to assess epidemiuh~ic;rllyhccausr [Walker et al.. 19921. ( 1) those with fibrosis are those who dm hnd liipher dmw Asbestus is much like silica in that c t h i t sludks of and higher doses w w l d be exptxlcd to cause mcwc Itrnp suhjecls with sshcstosis have shnwn a atnsistenl end high cancer, and (2) few studies have gtmd data 011 thc Itiwc rate ratio for lung cancer. Table IV shows the rad@of variables necessary tn test this hypothesis. that is. d r w . cohort studies of asbestotics or men with mdiogmfihic nh- radiographic changes. and smoking (Browne. 19%). Rerrnt nwrndities. Rate ratios ranged fnnn 3-5to 9.1, heyond the studieswith reasonabledata on these three variables prnvkh. range of possible cunfounding by srncikiirg, The c o n h i d some evidence that only t1m.w with nhscrvahle mdiogriiphic. relative risk Tor these studies is 5.91 (95% (3 4.98-7.WI). fibrosis develop lung caiicer fHuglxs m d Wdll. IW!: I-icl- C o h t studies of workers exposed to asbestos have dell md McDonakJ. 1980; Slois-&mer and fkeauidcnhrwt. shown a consisten( excess of lung cancer. Tabb V lists the 19901. Howcuer. ea& of thcsc t h e stwlics has its O ~ I I larger oohort studies. concentrating on those with some es- IimitationP, and very large pcylulatkn.. are nccdcd IO tniiy timale ofclose and citing only the most r a r i t ttpdates. The confirm a negative hypothesis (that those withaat fibrcirir combined relative risk from TaMe V is 2.00 (95% CI 1.90- do not get lungcancer; see Ropgli el al., 14% and AhrJ h m . 2.1 11. Several of the studies shown in this table include 1994 for a recent discussion). estimelcs af a linear dose-rcaponsc,in the fonn of a pre- Most of the epidemiologic nliidics xhciwinp n Iring C:IW dicrion equation in which ~ h crate ratio (OT SMR) for lung ccr e l k t have been of wcirkcts cxposed ;it w r y high hi+ cancer between exposed and ncmexpnsed is equal tu 1.0 + torical levels, =vera1 orders of ni:ipiluctc hiptrr h n IWW Sent by: EPANITZMDFPANITZMDJD 609 921 3051 12/06/96 1 :04PY Job 1 6 3 Page 7 TABLE V. Cohon SWiss of Asbestos Workers -Jt* Lung eamer SWR [IYK CI) Sclikol?d al. (1979) S I R = 4.06 (3.93-4.98) Occupational Lung Carcinogens 479 C a l t m l tot cndling; cwlmmllt Hendwson and Enlerline (1979) SMR = 2.70 (2.07-3.45) Firikltem (1983) SMR = 7.4 (4411.6) SMR = 1.05 ( n - 1 . 4 ~ ) [mt yr sim hire] SlYR = 1.49 (1.161.87) I SUR = 2.96 (262-3.331 SMR = 1.31 (I.IQ-ll.S5} mmcipll CORort) Scrdman d ai. (1986) W R = 4.97 (4.05-603) SMlp = 1.31 {2.14-i.45) (>20 yr since hire) sus = 2 05 &I6-2.51) kmslrang el ai (1988) Newhouse and Sulliuar~(1989) SMR = 2.69 (2.15-3 64) SMR 5 I04 ( 88-1.18) P i o W et ai. (19901 SUR 2 1.1 (0.64-1.67) Bolta et al. (1991) SMR = 2 68 (2.111-3.26) SMR = 315 (1.95-4.61) SMA = 1.72 (1.32-2.21) McDortaM et d. (1993) SMR = t 82 (1 48-2.20) SMR = 1.33(122-1 .a) Dammi el al. (1934) SMR = 1.f6(1.44-2 09) Sent by: EPANITZMDFPANXTZMDJD 609 921 3051 12/06/96 1 :05PM Job 163 Page 8 _. 480 Steenland e t a1. curreid levels. Littlc cxcess lung caiicer i s e x p l e d to result fmni the low levels of expsare of today, although there continues to be controversy regarding he.ptendal of vcry law levels of exposure to cause mesothelioma ltlealth Ef- fccxs Institute. I99 I 1. ratloll pwgeny are riictal ions that adhere to p;,flic[es sus prided in the air. When inhnlctl these pntticlcs arc &P)s. itert on the surface of the respirarory tract. where they iri-:l~ cfiaie surrounding tissues with alpha particles, which ntp capable of breaking chromosomes. I r i mort studies. nrnhicnt Diesel Engine Exhaust r k w r eXxhaUst is a coniplcr mixlure of suhdawes, char.lcteri;.zd by polycyclic aromtuic hydrtxwhtms sur~ O l l l aMn ~elc~rn~en~tal cahcm core. The g;ls phase illcludcs cirrhon nionoxide and nitnigcn oxide... Diesel exhaust tias been shown io he a lung carcinogen in ariinials Ilstiinishi c: nl., 19861. The parliculate phase of the exhaust rather than It= gns pliase appears to be iniplicotd. exPo.qure tu radon pragcny i s measured in working 1eveis (Wf-1. and CUmUh[iW CXpOSUle iS expressed in working \ e v e ~ - i l ~ ~(~Wt LhMs . k product of cxpsure \eve\ in wt, and the numher of I7O-hour "working rnonHls-* expct. Sum). One W L is any combination of radw prnpny ill thnt ulrimale!y releases 1.3 x IO5 MeV or ellcr~ydurjlle decay. Exposure to radon progeny i s dso sometirncs ex- pressed in pictruriedlitcr (-Kill)a, unit niea!iuri,p dccny: 0.005 WLM is tlppsoxiinately equal to the progeny in cqoi- libriurn with IpCi/l of radon. Y i e current standard klr radon Oiitside of mining, there w e n approximately 1.4 mil- exposure in mines is 4 WLM per year. lion U.S. workers exposed to diesel exhaust in the early Occupational exposure.. t o r:drm and its progeny occur 19KoF. principally in the trucking and cvnstructiun industry in undergroundmining for urmiiim and ofhcr i e ~ n l sa, nd in lNIOSl1, 19901. There is currcntly no OSHA ~&mku-dspe- prucessing oms and radioactive mulenuts. Must iirnnium cifically fur diesel exhaust. although &re are standards for mines in the Uniicd States have cltlsetl, ; i d thc itunhcr of components ul' thc exhaust such in carhin monoxide or currently exposed miners i s relatively small. Howcvcr. ttww nitrogen dioxide. Environmental Protection A p w y (EPA) i s potential exposure to large n u i n k s of wrirkcrx ir) poorly regthlions have been gradualiy tightcned over the last de- ventilated buildings. Although radtni conccntratir)ns in cade to diminish the amount o Jicsel exhaust permitted linrnes and buildings are far lower lhrm i n mines. thc lol~p frmi) trucks. periods of t.irne that people spcnd iiL tmtnc nnd at wcwk can H u m a r epidcmirdogic studieg have been difficult t o result in significant cumulative expcaures, although geiirr- crinduct because there are fcw data documenting post expo- alIy far less than a miner's e x p s i ~ r eA. pcrson spiidirlg 7 0 sures. a d most such data are nonspecific measurements r9f years in a residence and 45 years wcxkirig lifetiine in build- surrogates for diesel exhaust. such as nitmgcn oxides. Re- ings, both with lhe tJ.S. average radon concentr:iticnl nf I .S cently a more specific measure. eleinentid carbon. has k n pCiA [Samet, 19891 would accurnulale approximately 20 developed (Zaebst et al.. 1992). WLM of exposure to radon progeny from the hoinc and Recent studies of diesel-exposed paputationshave im- approximately another 5 W L M from buildings. By mrrvilr- proved on earlier ones because smoking data have been iwn, the mdian exposurc to a uranium miner in the United a,llectcd and an attempt has heen made tn measure diesel States JIRSbeen about 430 WLM. exhaust currendy, and then to extrnpnlate hxck to likely Studies of uranium minus a d O ~ C Tminers c x p w d io historical levels. Table V I lists more recent stdies that have rdon daughters have cwisistenlly shown exces.ses due la had relatively gmwd discumenlutioit of exposureor h v e heel; lung cancer (Homung and Meinhank, 1987: Damher end based (WI self-reporteddiesel exposure. Most hnve been able Lnrsson. 1982; Howe et al.. 1986; Morrison et al.. 1988: tci adjust for smoking as well. I k stud& would indicate Radford and St. Clair Renard. 1984: Sevc et al.. 1993:Solli a combined relative risk of about ! 3 t (95% C1 1.13 -1.441 et a].. 1985; Tinmarche et al., 1993; Hodgson and Joncs. for dieset-cxp~sedpopulations vs. nonexpuserl plpillations. 1990: Woodward et al.. I99l; Sarnel t't al.. 1991: Xunn c! 'I'hesc studies are reasonably consistent. and the weight oC al.. 19931. Animal data conlinn these ohstmatinns ICross e l the evidence to date tends to confirm [ARC'S 1989 judgc- al.. 1982a,b1.fn a11 of the miljur cohorts of miners tha4 have m n t that occupational diesel exhaust i s a probable lung heen studied. rnudality increases monotonically with runiu- carcinogen. lative exposure in WLM. The excess rclative risk 01' luitg cancer among miners i s gcncrafly 1-2s per WLM )Satnct Radon Progeny Radon ("'Rn) i s radioactive niihle gas I'ornied during the radioactive decay series thrwgh which unnium (='U> decays to stable f e d 'rhe radioactive decay of radon gas itself prtduccs short-lived radioaciive isobipx of bismuth. polmirim. and lead, known as nckm progeny ur "radon cirughters." Unlike radon gas. which i s chemically inert. the and Homung, 19901. The ohsenation o f excess fuiig cancer mortality at \ow cumulative exposures (lessthan SI) W1.M) is an important finding in seven! studies of mirters [Radftml and SI.Clair Renard. 1984; Scvc el a\., 1976; Howe et al.. 1986;Morrison d a!., 1988:Tirimarche et al.. 1943: Wrrtwl ward et ai., 1 9 9 11. These.observed risks at iow lcrek and the linear fit of the dose-response function can he takrn ax stippnortiog the view that radon carcirngcnesisis a sioclrostic .. . . -_,_ Occupational Lung Carcinogens 48 I T A U VI. Recent Studies of Lullg Cancer and Dksd Exhaust steenbnd el ai. (1990) Bofletta e1 al, (1930) 6.000dewduras K. Qenwdpopulation OR = 1.41 (i.os-t.es) long-term railroad worken m. nonexposed SMR = 1.18 (OM-1.01) s1-- vs nonexpossd SMR = 1.15 (0.67-1.84) ys.-a OR = 1.89(1.04-3.42) --haul diesel Iru& driwrs YS. IlOMxposed OR = 1.21 (a78-z.o~) d.,1993).which fumd h m t risk for highest exposed bawd on 50 cases and dieset krsl amslwnpNan survey; Rlt Cor lunq W C W Incidence = 1.I3(1.36-2.07) yes; I,= ca~89Z,D+ YLpS o x p o ~ d exposure survey jab utaqakq lindings similar in subsequent cohort s t d y Yes sekrepoited d w expmue in m. Cancw Soc.cohort of 1 mrllion. 174 enposed Jwlp depths.RR increased with durillion ol exposurr. SMR = 1 24 for Much drivers, SMR = 1.59 for railroad workr~ No,but inlar;rl analysis showed bi(#wA rlsk far 6% buEgsraOe worlc%rs Mphly expasad (OR = 2.4). parallel SXpcKure surmy. 17 lung c m f deahs Yes; 9 S ~ass5in teamsters Ma,risk wbt for mschanics ami drivers. @araUd8xpomre sum. &--d-kRI rapart d engine Lype. OR = 1.55 for lono-haul &hisbased on teamster records Yes; 477 cases,sell-reparfedd i a d e*posure. t trend with increasing duration ~ m i x s swith nu risk thrcshold (NCRP, 19841. With this pre.wniptiue, data fmrn studies ul' riiiners with vmy large cuinulaiive exposures have h x n used to esrirnate risks for rnltwirluals c.xpoxd ut much bwer levels in homes and wirkplaccs. Arsenic Arsenic occurs in orgaiik a d ioorgmic forms. fnwgnnic urwnic ~rrnyw c u c a. ur.sennle jAs(V)] or arsenite IAs(I1I)I. Melabolistn of As(V) wsults in As(ll1). which is ~hcidi etoriticd by Inettiylotitm. A n n i i c is unusual in Lst there is in;deyuate animal evidence of its carcinogenicity. whik tlw human epidrniiologic data are quite slrmg. Arscnit. app;irs to interfere w i d DNA repair a d has heen shuwn t u ciliise chroniovomitlukrrillions but h s nut QUI% nrutetions in hctcriai systems. inhalatiurr studies in rodents hive txxen uekil\ive, but mine studies with inlmracheal injcction have had positive results ISmith et ai., 1992). The Imncipal occupiltions exposed to substinatid inorganic iirscnic lcvels in Ihe past arc workers in copper smeltu.5, worhcrs iniii~dirciuringarsenical pesticides. and suine tnimrs. In the early I9HOs there were an estiinatzd 50.(WKI U.S. workers exposed u) airborn arsenic [NIOSfl, I9?H)l outside of Iht:mining industry. The curmt OSHA slanOirrl for uiibtme iiingvnic cnsenic i s 1 0 pglrn'. Thcrc i s scim limited evidence that inorganic arsenic in drinking water is carcinogenic; excess lung ailcer hirs bee0 found in Taiwan in association with chinking water contmination [Smithet al.. 19921- The piiiripd buniar, epidemiologic studies are shown in 'fiible VII. Thew slimlies show a conaisteilt lung cancer risk at high levels, with a clear dose-rcspnnsc:.TIK combined relittive risk from the& studies is 3.69 (3.0114.46).It would appear Cmni the epihinlogir: data that Ihc excess lung cancer risks in warher ppul;nions arc priinarily due to high exposures, which wcumd largdy in thc posl. No excess lung cancer was noted in the study by Enterline et al. [ 19871 at srncltcrs wherc exposwcs were ertimalcd IO be BL the current OSHA I C V ~ I . I Op&. Acry Ioni trile Sent by: EPANITZMDFPANITZMWD 609 921 3051 12/06/96 1 :07PY Job 63 482 Sreenland et al. TABLE VU. Selected Studies of Inorganic Arsenic and Lung Cancer Study Ott el al. (1974) Larg tinter SMR (%% CI) SMR = 3.45 {2 11-5 32) Lee-Fetdstein (19E6) SMR = 2.85 (2.57-3.16) Enterline et 34. {1987) SMFl = 1.31 (1.07-2.65) Enterline e l al. (191) SMR - 1.98 (1.64-2.38) Taylar at ai. (1989) OR - 15.2 (6.9-52.71 Jarw, et al. (1-9) SMR z 3.73 (3.064 501 ConIra( lor smoking; comment Na; 603 men in pesticide phnt. 20 lung cancers. 100-5.900 palm3 in 1 ~ 1 9 5 0 sc. dose-response No; 8,000 workers at copper smelter. 302 lung cancers. t dose-response, range of mmswe 400-62,mOmdm' Yes: 6.000 worfrcrs a1 8 copper smtllsrs. 93 iung mncm exess Seen only at the one pant with the h i g k t mean exporum (69 pub"], dher plants had 7-13 p g l d NO; 2.80I)workers at copper smelter. 104 tuna cancers. positive dca-response. 10-2.100 pg/m3 exposures Yas; caseantcol sludy among tin ninsrs. 107 cases, poailive dose iesponss. mean emosurss 420 11g/m3hebm 1951,10-60 pQ/rn3thereafter Yes, via laler casecontral study of 107 cases (Jarup and Pershagen. 1991). 3.W in cohw a1 copper srn#tmr. + dose-response. e k p o s ~ r e ~ 5U-50,OOO I.I$II~ tefore 1940.50-5.oM1 irq/m3 in 1940s, SO-2Oll p@m3thereafter Page 10 rently senw primarily ~3 s key component in acrylic fibers used in textile mniiracluring. and is also used in pipes, fittings, and other praciucts. NIOSH eslirnotes that in thc early 19XUs, 335,CHNI. 1J.S. workers were ptenrially erposed to acrylonitrile on the job (NIOSH, 1990), primarily viu inhnlelion. Absiabed acrykmitrik is pnmrily excreted through the urine following metabolism by the liver. The OSHh standard is 2 ppin (TWA}. Rats exposed to acrylonitrile by inhainrion or ingestion have sttown elevated tumor rates. although rates were elevated for sites other lhan the lung. A finding of 8 lung cancers vs. 4.4 expected [,mte ratio t i f 1.83,9SS CI 11.78-3.6R) in a cohort of workers at an acrylic fiber plant prompted initial concern abt.xit lurrg carcinogenicity IO'Rcrg. 1980<11-Since this 19111 study, there have k e n three relevant studies with reasonable sample s i 7 ~A. further folltnv-up through I984of the original cohort studied by O'Berg et ai. iChen et al., 198Sa,h] failed to observe P substanrial lung cancer excess (SMR of 1.06). Collins et 11. [ 19891 reported on 1774 acrylonitrile-exposed wmkcrs employed between 195 I and 1973 at one acrylanitile nrd one acrylic fiber producfion plant. The SMR for tung CPIICCT was I 00.Swaeci et al. 119921 Fdlciwed 2.842 Dutch workcrs mtplnyed at eight plants producing or using acrylonitrile. 2 1 S~MR for lung cancer was 0.82 (95% C.1. 0.17Ti.33). Ncither the Collins et at. nor the Swneii et a!, sludies showed a consistent dose-response. In suruniary. thc epidemiologic cvirlctrce does not indicate that ncryloiiilrilc exposure is related to lung cancer. Chromium Chromium i s a nieml that CUI exist in any n x i c l i t ~ i c i o state between 2 and +6.Most chromiumcon\prwwi%colitain the metal in the +3 (trivalent) cr +6 (hexnualcnt) slate. a i d mast natural clrroniium is found as oxides in chmniitc ore. CrIV1) causes cancer in anitnal studies. hut Tr(ll0dntc not IIARC, 1390; Cohen et al., IYYJ!. Chmmiunr adds rust a i d acid resistance 3% w d l as IiurJness to alloys. Stainless steel accuuntcd for 82% n f d l chromium coiisuined in rhe United States in 1987 [IARC. l!Kol. Worker exposures o ~ c u rirr the prrrduciion of chrnless steel. other chrome alloys, chrome-coiitainiiig piginene. chrnine plating. and welding (of sfainlevi steel). NIVSIi I cl(H71 cstimates t h t in the early l%%. S!i1,t?W wtirkrrc 111 IIIC IJnikd States were exposed (n hexavalent chiarniurn. OSHA considen Cr(V1) to be carcinogenic. and the OSHA standard for chromic acid and chromates containing t N V I 1 i s 0. I mgfm3. Historical ~ X ~ O S U I E S in chminatr prrduchr .and chromate plating were generally IO times higher than the current standard [IARC, lY90[. Over 50 epidemiologic itwentigations nddrcqcine luiig S e n t by: EPANITZMDFPANITZMDJD 609 921 3051 12/08/96 1 :OBPM Job 163 Page 11 Occupational Lung Carcinogens 483 TABLE WM. Selected Studies of Chromium-Exposed Workers stue snn (I#% a) cM&Olbf SaldriW, CORRBM .-~~ E ~ d % : l ~(i1t8~74) h ) S et at p 7 a J SUR I)13 (I 33-1I 63) SMR 2.0341 55 2 631 tkJ, IblpUilcltj L a r i U l w,p l ~ i, & y ~ t l l uw/ w, d u u t ~ wu;y Wilh mation Alderson at al. (1981) SMA 2.42 (2.00-2~90) Some; U.K. chromate plant. heavy smokers rarer in cohort than in rebrnts SarOh el al. ( 1 W ) Kofdkrset al. (1982) SMR 9.23 (8.27-13.10) SMfl 2.10 (1.56-2.76) No; chromate producers, lnwase wim durarlon No: rclspimiwy cancer, chromate plant Frenizel-Beyne (1983) WR 2.04 (1.23-3.19) ido; D~QIIESI~ p m . maximum risk at high exposwe D a w s (1984) SHR 1.82 (1.37-2.43) No: 3 pipment p h t s . no i n c m 4 at lacp rxposureg, ~ c n a k i ~pgrahibit.d in workpke Sorohan et at (1487) SMR 1.511 (t.l?-i.B4) No;C~IDNIBand nickel platers, incraasr with duration Hayes e l ai. (19R9) SMfl 1.43 (0.93-2.13) No; pigment worters, increase with duration Takahashi a( a1 (1990) SMfl 1.87 (0111-3.69) Somr; plaers. 1.7 tor platers usmq other metals, - eslilnated 30% increase due to smoking SMR = swardlzed mmdii mala CI - conlidsnce intaival. Results PIT fa$ hup cmar morrahly unkrs ahmwlse mtee In the comments cmcer in occupaiional groups exposod io chromium compcmxIs have qp%wxi io date. Extensive tabulations of sludy resulcs urc wailable in the lARC review [19901. 'lhe largest and bcs-desigiied studies of chromium production workers, prcduccrs of chrorrwe paints, and chromate plating wcwken: are included in T~bkV M . The overall rekitive risk is 1.78 (2.47-3.52).Those studies that addressed tobisco smoke. asksins. and nickel exposure ruled out thew bcltxs the major source UT the observed association. Beryllium Okcupatiunnl cxplwirc to haylliuin occurs principally in minirig. refining, and in the manufacture of crramics. arid elwtnmic and xrospxe equipment. NiOSH estimates that 44,(xuI workers were zxposed to beryliium dust or fumes in the Ilnikd States in thc carly 19130s [NIOSH. IWOj. In I'HY, a new slantlard lor beryllium exposure (2 pgim3 TW.4) was i n t t r n i d IO avoid berylliosis. Bcfurc this time, herylliutn expusurcs were cnnsideerably higher than this limit. which is still the O S H A slimdad (NIOSH recuminclads 0.2 pdmJ).A study 01' US. be~ytIi~m-irHp~laynt aiiduutect in 1947-48 by the NIOSH showed heryk'lium ulixcnlri!iiDl~s ranging from 41I pgtrd in the general air wrrounding inixing operations to 43,000 p@m3 in the bruthirig mne of alloy operdiicns f NIOSH, 19721. In a 1980 revicw. IARC Il9SOl concluded that there is dticimt cvidence that herylliuni mebl and seven1 brrylhum cimpouodh were lung carcinogeris in rdts and 111011keys, but t t u t cpiderniuiogic evidence of lung nrciiwgenicity was limiicd, bslsed on ihree nudieb. Since 1980, two cohort mortality studies have been nprtcci, in w h rif which il significant excess of lung cancer was ohervecl. SitxnIand and Wurd [ 1 9 9 1 1 expanded the itrwtaliqy thllow-up of ihc Belyllium Casc Registry cohnd ti1 include 689 wontcn a d men of ull races. The [ungmncw SMR was 2.m (95% CI. 1.33-2.89). H a d on limited smoking data (32% of she cohort) and ihe magnitude of the observed excess, the autliorsk l i i v e d it would he unlikely that sraoLing was P major confounder of' the &served excess lung cancer, and selection bias was also judged unlikely. W a d vt ul. j1!?!2] reported (he rrsulfs of a cohort niortality study of '1,225 mde workers from seven berylliurir plants in Ohio and PeniisyIvsnia. The overall SMR for lung canax was I .24 (95% CI. I . IO- I.39). Plane having a high SMR for pneurnuconiosis md therefore presumably higher beryllium exposue consistently also had an clewled SMK for lung cancer. Lung cancer SMRs increased with increasing Iaenry. AHer LI smoking lwijustment based on limircd smoking data. tlir authors concluded that snloking was IIIIlikely IO fully accauni fiw thr: observed excess. nie SMR ut ihe plllnt with ihe highest eapsures a d tongcst latency rendncd elrvnrrd (smoking-adjusted S M R = I .19).Iir 199.3. a working gioup of t k [ARC conclulied [hiit Ilke evidence was IMW sufficient IU concliide lhar beryllium is carcinogenic t o hunrans [IARC, I993 1. The principal current LLSS uf nickel and nickcl salts arc in the production of stainless steel, nonfcrrous i~lkiyysd, e v - froplating, and in the mmufiictiiw of bflcries IIARC. Sent by: EPANITZMDFPANITZMDJD 609 921 3051 12/06/96 1:09PY Job 163 Page 12 484 Steeniand et al. 199901. Data fruin NIOSH 119901 indicate that abotli Until recently, the various epiden~ic~logicasliutfies 147.01)o workers in the US were exposed to nickel and cadmium exposed workers did not enable any definite con- nickel compwnds in the mriy 1980s (metallic nickel and clusioii to be reacheddue to conctwnilant exposums to dhcr nickcl alhiys excluded; see later). The OSHA standardi s 0.1 mupatinnnl carcinogens, iiininly nickel and arsenic I Bot. m g h ' Por soluble compounds. and I m g / d for nickel fetta. 19921. New evidcnce comes from a study or B (.I.S. ineta\ ant1 insoluble nickel cumpounds. plant whcrc cadmium oxide. sulfide, awl nlrial were ICCOV- fARC IIY W l comcluded that there is suflkient evidence errd from the waste of lead and zinc sndtcrs bcgimitig in in experimental animals for the carcinogenicity of metallic 1926 [Thun et al.. 1986; Sliiyner ct al.. 1992, 1V931. T l t ~ nickel. and for nickel oxides and sulfides. From epidcmio- rnost recent follow-up showed a lung cancer relative risk of logical studies of nickel-exposat workers, IARC considered 1.49 (9S% C1, 0.96-2.22);the relative risk increawd with the evidence sufficient f k the carcinogenicity of nickel sul- estimated cuniulative exposure to cadmium and w m sratis fate and Tnr "the combinations of nickel svlfidcs and o x i r k tically significant for workers in the highest. exposwe cat encountered in the nickel refining industry". Ilowever, the egory (RR = 2-72: 95% CI. t .24-5. IS). In order Lo cnntnil evidence in humans for h e carcinogenicity of metallic for the potential cml'nunding effect of arscnic, suhpnups nf nickel mud rtickcl alfuys was deemed to he inwlcquate. workers known lo haw little arsenic expclsurc wcre studied The innst current mid comprehensive review of car& and also slimed 3 sigtiifkinl excess of tung cancer. I r i nogcnic effects among nickel-exposed workers is presented 1933. a working group of ihe IARC concluded that there in the 1990 report of the International Committee OR Nickel now was sufricicnt evidence in humans for the corcinogr- Carcinogenesis in Man IICNCM. 194101- T h i s mporl PIC- nicity of cadmium IIAKC, IYY31. sents updatcd analyses of nine cnfiori studies and urre case- contrul study of nickel. Lung cancer and nasal cancer were AITRIBUTABLE RISK consisteritly and significantly increased among exposed workers at nickel refineries. Using data froiii this report Thcre ~ T aCpproximately 90.000lung cailcer &ah.. per (Table g3), the combined relative risk acnxss 13 studies is year among U.S. mdes and approximately I(W).IMIO iicaly 1.56 (95% CI 1-41. 1.73). diagnosed cases per year. 'The comparable figures for U.S. fn cnntfiist t o these positive results, cohofl nlortdlity females are approxiinotely 45.000 and 6O.(HW1. studies of workers engaged in the manufacture of' high- There have been seveml estimates 01 ilie prnportimr ol' nickel alloys showed no consisteiit significant overall ex- male lung canccrs that arc due to occupational exposums c c . ~nl l ~ i gcancer IICNCM, IWOJ. and positive studies Recent extimetas of 9% (Morobiu et al., 1992) and 3- 172 were often polentially confounded by other lung m i n o - [Vineis et ai., 19881 have come from large ciise-coiitrd pens. The rrtfe of nickel in lung canccr excesses observed skidies and refer the propurtion of lung cancers ;tttrihut- among stainless steel welders i s itlsn unclear, as these weld- able to work inoccupations with excess risk of lung cancel. ers are also cxposed lo chrorniuin VI. mther than LO lung cancer attributable to specilic rrcupcl- Cadmium tional carcinoaenn. In earlier work. Doll aiitl Peto 119811 eslimatcd tlrat approximately IS% of male lung cancers and 5% of female lung cmcers were duc 10 rxrupatinnel cxpw Cadmiuin is principally used in electroplating,in cnm- sure, without using any lorrrm! mefhcrdology. piundsthat serve os ctabilimrs fur plastics and as pigments, Estimates based on B caw-cnritrcd study usinp ticcups- in electrodes in hatterics, a i d in alloys. IIARC. 1976; tional catcgories rather than e x p s i i r e 10 specific snhrf;tnccs Schaller and hngerer, 19921. Most exposure occurs via in- have the advantage that they will take into consideraticin ti;iiation. In tile past. cadmium concentrations in workplaces occupations at excess lung cancer risk. even though Ore were high; air levels of I - If1mg/m' were found iri alkaline occupational agent is unknown. However. the cnse-cori!roll hu~teryfactories in the 1950s. but with inodern tcchiiolqyy wcupatiun apprcmch usually relies on a sttigle lnrgr .;tiiiIy. it is pssihle to redlice air cadmium conccntr:iiiuns to less or on a few largc stitdies in which the spine crr-ciiFdionol than 0.02 mglm' (Schaller and Angerer. 1992). NIOSH es- calegorics have k n rnnlyred. As a resull, the relrlivr risks tiinates that 250,MMI workers were exposed lo cadmium In for spcific ompatinns may nut he very precise and a l w the early 1980s [NIOSH.19901. I'he current OSHA $mi- may not be rcpreaenliltive uf the population as a whole. &id is 0.1 m@m3 for cidmiurn fumes (cadmium oxides) Our nicthod hen: will he hascd on estimating the pro- arid 0.2 mg/rn' fur cadmium dust. podion of the population exposed to specific accupalianal Experintentally, cadmium induces Lunwm ul the pros- carcinogens and will use estimated relative risks for these (ate 1Waalkcs e l id., t992a1. lymphocytic leukemia carcinogens. The nuinber of exp)sed workers in the trlROs 1WaaIkes ct al., t992bj. and limp lurnws IHeinrich, 19921; and estimatedrelutive risks have been presented earlier. We a11 tumors were induced in rats, and the incidence of tunism use a standard formula for cajculating the nttrihutnblc. r i s k . was &F,G depeitiknt. also known as the etiologic fraction [Kleiiibum ct al.. S e n t by: EPANITZMDFPANITZMDJD 609 921 3051 12/06/96 1:lOPM Job 1 6 3 Page 13 Occupational Lung Carcinogens 485 TABLE IX. Summary of Relative Risks from Selected Studies ol Occupational Lung Carcinogans and Eslimated Number of Woners Exposed Cadmium Nickel Arseotc Chroirilurn Diesel banes silica 8efymunr Asbestosc -~_R l_l l t h s titlr 149 1.56 3.69 2.78 1.31 133 1 49 2.m With d wpesao worllem In mIli lwQr 258.000 (69%male) 147,000 (7896 male) 58,000 (78%male) 551.Mo (83% male) 1,350,oOo (96% male) 1,700,000(9Mb mak)' 44,000 (95% m ! e j 7W.W (93%male)" 'Eststwrnled lo be 61 mm, 65 millon wom61. 'Qata M e m s u n by sex Rol a e , ertimald 90% male. 'For dsb8slas. nu-r of anrlhulabietung cams CWE taken from PHchdsan at ai. j1982). Plap8#llonat worthru agsd zDd5 (126 mHUin). 0 20% 0 12% OW% 0 43% 107% 13% 0 03% 0 50% __ 19H2l. Fur IWO substances. asbestos and d n . wc rely on cstimites of the number nf attribulublc lung cancers made by oilier authors. Our nwihod has ihc disadvnntage that one must assume llrrc thc hismrical rclstive risks iwaihble from qidemiology are applicible 10 itre exposed workers of interest. For lung cancer in the IWXk, the exposed workers of inLettst would have gencreily been exposed 20-50 years earlier if we as- siuw these agcnrs are cancer iniriators, (x in more recenl ycrtuds, i T we USSUIW these ugerils are promoteru. We will iriake rhe brad assumption that the relative risks available from the eplderiiialogy (presented ar1it.r) are k&Ly apphcablr to (tic t ~ p c i ~wodrkers of interm. Wc will baw our cstiinutes on the proportion of the populationexposed from NIOSII t b a I'm the early 1980s. because these arc the hrst data available (NIOSH, IWll, and make another broad assutnpticm a u t the proportion of the popuhtkm exposed has reinairid catisc;mr over rime (clearly witrue forasbestos. see loicr). While on earlier NlOSll survey of exposures dom in J ~ cCarJy 1970s wo9 rrlsn available, disEussinns with NIOSfl ,v;lff,uggest that Ihc h e r survey hrtneiitd h m the a p e rieiicr of [helirsr one ( M t c r quality controi during the data culletxiori phase). so thdt [he l a l u survey may tr more rcliahic. Firs1 WE will consider seven agents: diesel exhaust. silica, arxiiic. chromium, nickel. cadmium. and heiyllium(PShesicts and cidrm are txilitxl q x m t e l y her]. Very small iiutifiw UP workers are cxpwed to otkr igrnis in Table I I<Y).IWX) rich). whilc the data indicating lung wrcinogc- rircity are doubffiil for orhers (e.g.. acrylonitrile). Approxit ~ t z l y6% ot' the lniilc U.S. popuhiion aged 20-65 (e=61 i w l l i w ) w;*s ~ ~ c u p i ~ ~ i ~c~xpiousletdyIO ~ s seeven agents ill llh: early 1980s (l'ahlc 1x1. Approximlcly 0.7% of thc lwlale popul,~tion(n = 65 million) Wi1S rxpcised. Appmxi- maiely 3% of male lutig CBIICIXS, OT 3,000 cases per year, we estimated to result from exposures to these seven agents. Another 300 cilses are estimated to i w u r among fcmules due to these exposures. For asskslcw we accept the estimates of 5,400 excess lung cancm deaths among malcs annually in the mid- 1WOs aiiribulahle to W ~ C S ~ O Rcxpmun? as wrimjled by Nichnlscwr et PI. (L9821,which corespcwnllr LO ;rbout 6.CWXl annuub &- ~ributableincident mcs. No coinpnmble figures SIC avail- able for fenwles, but if we usuine the same LU:L ride: feniale ratio, as we observed earlier, m h e r 600 lung cancem might tu attributable to asbestos expa.sulr arnnrrg women. I d m r ridon exposures at work may also cause s o w lungcilnctrs. based an the assmpUw~of no threshoid, analogr,us to the situation Cor 1ndiwr radon exposures at home ILubin, 19941. Esiimalcs of Ihe number of lung cancersdue to residential exposure to radon in honles are &out l0,OOrr per year I S a w t , I%Q\. Basedon relalive dose at home nnJ at work [appruximiltely 5:l. see [he marlier scclkm on rad ~ )oc.cupiltionul exposure to radon in buildings may account for anothcr 2,O(K)annuil cawen,presurrialily equally divided between inales a d feisrles. Excluding Lhe coniribution of rdoii at work. approxi- mately 9,OW annual lung cancer cifsus smung U S . males can be iutribuied LO occupational exposure (approximutely 9%of all cases). Among fenrales. perhaps 900 cases annually rnay hc altrihitable t o occupational exposures, accwnring for 2%of the annual cases in ihe Uniaed Stales Asbeslus exposure iiccounts for the majority ot the airtributablecases. II' rudon exposure ai work is considered, the numbers incrcilsc to l[l,UI)o cases per year a m n g males and 1,9111 among ferrules. Our estiiiiates are jn line w i h #hees~iinatesof piior Sent by: EPANITZMDFPANITZMDJD 609 921 3051 12/06/96 1:llPM Job 163 Page 14/18 486 Steenland et ai. authors. However, it tiiust be stressed that oiir quatititalive estimate OF attrihutuhle cancers is likely to be quite imprecise and serves primarily as a bmad approximalion. The major limitalioia of our estimate include the reliance on histcirical relative risks, which may lead fo overestimation; the restriction tu confirmedcarcinogens, which may lead to untkrcstimtion; inaccurate estimates of [he pmpnrthn nf e x p x e d wwktrs in the relevant time period, which may teRd trt underestirnalion; and the lack of data 1u nppr0pl.iately consider the effects of the iatteraction between smoking and the agents in question. M a t occap~tkmallyd a t e d lung cancers cxcurring $0day are the result of heavy c~~psureins the past. 111 the Future thc mumber of attributable UPICS i s likely to diminish. u n h s new occupationalcarcinogens are introJuced intn the workplace. or unless we discnva uther unknown occupational lung carcinogens to which workem are being or have been exposed. On lhis last point. them are a number of animal carcinngens that have hcen identified in the laat 10-15 yews that are used in the workplace but have not k e n siudied cpideiniol+ally. %some of these may eventtmlly be iniplicaled as huntan occupational carcinogens. ACKNOWLEDGMENTS Holfcltrr P. Slelimnn. S. Garlinkel L ( 1 9 R X l : Diesel r r h d w l uxpcsnrc and m d i l y among n u h v in the Amcricw Cancer S ~ ~ i cIl'ryaqwctivc Study Am J Ind Med 14:403-415. BnITcniP. Hwnr R,W y d e r E (1990): Ca--cnntrol utudy on w r u p l i r m s l cxlmure to die-I exlxtiid and lung cancer risk. Ani J lad M r d 17.57 f-591. Bolts M, Miignani C. l m a c i n i T, Rcriolone 0.Castcignrin 13, Ccciw V. DcCiovaNmi D, W g t i i F (1991): MOrlalicy frtna twpimnry a d d i g c 4 r r cancm among acrhes~mcemen~urorktrc in Italy. Cplwu lkclcct frrvciu 1544s -447. k w n e K (19R6): 1s asbeslur or ~abestorirIhc cause d t l r incwasd risk of lrmg cancer in ashcRtos w d a s ? Rr 3 Ind Mcd 63:135-149. Cana P.Coew P. Cvliuh 0 (1W1):Mtirlaliry from lung m c e r ainniig Sadininn pttienls with silicosis. Br J lml Med dll: I22 129. Chcckouay II. llcyer N. Oemcrs P. Rrcsknv N (19931: Mcirblify .miinif workers in t k diaiomceous art11 industry. Rr J Ind Md KtM-SQ7. Chcn J . Fayemalbcr W.PCU S (IYIIRa): Mortality sluly of wnkcrs ex posed LO dimcthylfmmamkk and/or scrykwritrifc. 3 Omup Mcd ?(tR19621. Chcci 1, F:ayenuWher W.Fell S ClYRRh): Cinccr incidmcc 01 wwkcrr cxpnral rodimcthyl~orm3midLmdlrw nerytrmilrilc. J Occrip Mctl3ISR 13.Ria. Clicng W-N. Kong J (1992) A rctrr%;pcs.riw niortalilp cnhim *rmly 4 4 chrymilc rhbstos pmductr workers in 'Tisnjin 1972-1987. Envirrm Rch 59273-27n. Alice Greife and Randy Young 11 NIOSH kindly p w viclcd estimates of thc nunlhcrs of workers e x p c d . REFERENCES Chia 5. Clria K. Phwn W. Lee ff ( I W I ) : Siliccrsia and tung cancrr iiiiwnnp Cluncsc gmnkc workcrs. Scan J Work Envimii liurlth 17:I7IL174. Chiyntani K. Sailo K. Okuho T. ' r o h h d ? i K (1990): I . r n ~rawer I-itl amuog pneurmconionii palimM in Japan. with special rcfcrrncr III qilic-11tics. IARC Sci puhl 97:95-1M. Ahraham J (IQ'M): A~healu?iinhalation. not ashest4rrir. mimes lung cancer. Am J Ind Med 26:839-842. hldcrwin M. RatIan N, Bidstnip I. ( L98 I): Hcalth of wcwknun iii the c k m e t c - p d u c i n g induxlry in Britain. Br 1I d M e d 711:117-124 Amandus H. S l y C. Wing S.Shy C, HcinemanE. Blair A (1981 j: Silicusis a d fang camcr in North Carolina durty l r r h s wlrtkers. 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Health Phy 41:13~-153. Sent by : EPANITZMDFPANITZMDJ D 609 921 3051 12/06/98 1 :12PM Job 163 Page 15/18 Occupational Lung Carcinogens 487 S e n t by: EPANITZMDFPANITZMWD 609 921 3051 488 Stpenland et al. 12/06/96 1:13PM Job 163 Page 16/18 IARC (lYW4h): "Polynuclear Ammatic C m p n d r . Parl7, Industrial Exptsures in Aluminum Rrzdductinn.Coal Gasificatinn. Cdw Prcrdudion. a n d Irrm and Steel Founding. Monograph 34." Lyon. Francs: [ARC. IARC (19RSf:"Polynuclear Aroniatic Cmnpnds. Part 4, Riumens, C~+al-hrasnd I k r i r c d p c C d i 1 ~ 6S. luk ds. and Saois, MoncqppJi 3s." Lyrm. Fnnce: IART. IARC (1987.1):"Overall Evnluarirmr d C';lrEimgcniciy: An Updating ol IARC ~ n n o g n p b s1-42.supp(cnwnt 7.- L Y ~rm, acc:imc. [ARC (198761: "Silica and Swne Silicates. Mtrnclgiaph 42." Lyon. France: I ARC. IARC (19R8): "MRR-Made Minernl Fihrcs and Radon. M m p a p h 43:' Lvon. Fmncec:IARC. WRC i1990):"Chnnnium. Nickel. and Welding. Moao&nph 49." L y m , Frpnce: MRC. IARC ( 1993): "Rcryllium. 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