Arsenic in drinking water is a well-established cause of lung. Arsenic, Tobacco Smoke, and Occupation

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1 Originl Article Arsenic, Tocco Smoke, nd Occuption Associtions of Multiple Agents with Lung nd Bldder Cncer Ctterin Ferreccio, Yn Yun, Jcqueline Clle, Hugo Benítez, c Roxn L. Prr, c Johnn Acevedo, Alln H. Smith, Jne Liw, nd Crig Steinmus Bckground: Millions of people worldwide re exposed to rsenic in drinking wter, nd mny re likely coexposed to other gents tht could sustntilly increse their risks of rsenic-relted cncer. Methods: We performed cse-control study of multiple chemicl exposures in 538 lung nd ldder cncer cses nd 640 controls in northern Chile, n re with formerly high drinking wter rsenic concentrtions. Detiled informtion ws collected on lifetime rsenic exposure, smoking, secondhnd smoke, nd other known or suspected crcinogens, including sestos, silic, nd wood dust. Results: Very high lung nd ldder cncer odds rtios (ORs), nd evidence of greter thn dditive effects, were seen in people exposed to rsenic concentrtions >335 µg/l nd who were tocco smokers (OR = 16, 95% confidence intervl = for lung cncer; nd OR = 23 [8.2 66] for ldder cncer; Rothmn Synergy Indices = 4.0 [ ] nd 2.0 [ ], respectively). Evidence of greter thn dditive effects were lso seen in people coexposed to rsenic nd secondhnd tocco smoke nd severl other known or suspected crcinogens, including sestos, silic, nd wood dust. Conclusions: These findings suggest tht people coexposed to rsenic nd other known or suspected crcinogens hve very high risks of lung or ldder cncer. (Epidemiology 2013;24: ) Arsenic in drinking wter is well-estlished cuse of lung nd ldder cncer, nd tens of millions of people worldwide re exposed. 1 Exposure to other gents such s tocco Sumitted 19 Septemer 2012; ccepted 19 Mrch 2013; posted 12 Septemer From the Deprtmento de Slud Púlic, Universidd Ctólic de Chile, Sntigo, Chile; Arsenic Reserch Group, School of Pulic Helth, University of Cliforni, Berkeley, CA; nd c Hospitl de Antofgst, Antofgst, Chile. Supported y US Ntionl Institute of Environmentl Helth Sciences grnts 5R01ES nd P42ES The uthors report no conflicts of interest. Supplementl digitl content is ville through direct URL cittions in the HTML nd PDF versions of this rticle ( This content is not peer-reviewed or copy-edited; it is the sole responsiility of the uthor. Correspondence: Crig Steinmus, University of Cliforni, School of Pulic Helth, 50 University Hll, MC7360, Berkeley, CA E-mil: crigs@erkeley.edu. Copyright 2013 y Lippincott Willims & Wilkins ISSN: /13/ DOI: /EDE.0013e31829e3e03 smoke or occuptionl crcinogens, like sestos or silic, could crete lrge sugroups of people in rsenic-exposed res whose cncer risks re especilly high. Numerous pulic helth gencies hve clled for reserch nd policies tht tke into ccount the cumultive effects of multiple gents. 2 To dte, however, reltively few regultions nd policies hve done this, primrily ecuse of lck of dt. We used dt from lrge cse-control study in northern Chile to investigte the possile cumultive risks of rsenic, tocco smoke, nd other known or suspected crcinogens. METHODS Study Are The study re consisted of regions I nd II in northern Chile, two contiguous regions with popultion of 922,579 people. 3 In the lte 1950s, river wter from the nery Andes mountins contining high concentrtions of nturlly occurring rsenic ws diverted to the lrgest city in the re (Antofgst) for drinking, leding to 13-yer period ( ) with n verge concentrtion of 860 µg/l in the city s wter supply. Instlltion of tretment plnt reduced this to <10 µg/l tody. 4 Other cities in the re offer wide rnge of exposure (Tle 1). The mjor occuption in this re ws mining of copper nd other minerls, nd this produced vriety of exposures, including silic, dusts, welding fumes, sestos, nd solvents. Prticipnt Selection nd Interviews Cses included people who 1) hd primry lung or ldder cncer first dignosed etween Octoer 2007 nd Decemer 2010; 2) lived in the study re t the time of dignosis; 3) were over ge 25 yers when dignosed; nd 4) were le to provide interview dt or hd close reltive who could. Lung nd ldder cncer were selected ecuse lung cncer is the min cuse of rsenic-relted deth, 5 nd ldder cncer is ssocited with higher reltive risks thn ny other rsenic-relted cncer. 6 Cses were scertined from ll pthologists, hospitls, nd rdiologists in the re. Few people leve the study re for medicl cre ecuse the nerest lrge medicl fcilities outside the re re in Sntigo, 675 miles wy. The lrge mjority of cses were histologiclly confirmed (98% for ldder cncer nd 72% for lung cncer), with the remining dignoses sed on comintion of rdiologic (computed tomogrphy) Epidemiology Volume 24, Numer 6, Novemer 2013

2 Epidemiology Volume 24, Numer 6, Novemer 2013 Cncer Synergism of Arsenic nd Other Agents TABLE 1. Historic Arsenic Concentrtions in Drinking Wter (µg/l) in Northern Chile y Yer Averge Arsenic Concentrtion (μg/l) Yers Region City or Town Popultion I Aric 168, Putre 1, Iquique 196, Hur 2, Pic 5, Pozo Almonte 9, II Tocopill 21, Mri Elen 6, Clm 125, Sn Pedro 4, Antofgst 270, Mejillones 7, Tltl 10, Recent migrnts 82,312 <10 <10 <10 <10 <10 <10 <10 Popultion dt re sed on the Chile census conducted in nd physicin s clinicl findings. Cses or their next of kin were usully interviewed within 3 4 months of dignosis. Controls without lung or ldder cncer who otherwise met the ove criteri were rndomly selected from the Chilen Electorl Registry, frequency mtched to ldder or lung cncer cses seprtely y sex nd 5-yer ge group. 6 When cse ws identified, control ws selected from list of potentil controls comprising rndom susmple of the Electorl Registry for the whole study re. The Electorl Registry contined >95% of people over ge 50 yers when compred with the Chile ntionl census. All prticipnts were interviewed in person using stndrd study questionnire. For decesed sujects, the nerest reltive ws interviewed. Prticipnts were sked to identify ll residences they occupied for 6 months or longer. Questions regrding tocco exposure covered ge when smoking egn, periods of quitting, totl yers smoked, typicl numer of pcks smoked per week, nd exposure to secondhnd smoke s child nd dult, including the numer of people in the house who smoked nd the numer of hours per week nd yers exposed. Sujects were lso sked out their typicl wter intke t the time of interview nd 20 yers efore, ut these dt hd little impct on clssifying exposure ecuse the rnge in wter rsenic concentrtions (over 80-fold) ws much greter thn the rnge in wter intke. Sujects were lso sked whether they hd een exposed to other known or suspected crcinogens (Supplementry Tle 1, either t home or work, the jos or hoies in which these exposures occurred, nd the numer of hours per week nd yers exposed. These chemicls were selected nd clssified priori sed on lists of known or suspected ldder, lung, or kidney crcinogens (kidney cncer ws ssessed seprtely) from the Interntionl Agency for Reserch on Cncer, 7 or recent dt suggesting links to cncer Exposure Assessment Lifetime rsenic exposure ws estimted y linking ech suject s residences within the study re to the wter rsenic concentrtion of the wter supply of the city or town of ech residence, so tht n rsenic concentrtion could e ssigned to ech yer of suject s life. Arsenic mesurements were ville from government gencies, reserch studies, nd other sources, covering >97% of ll drinking wter sources in the re Until recently, few people in this region drnk ottled wter or used wter filters. Arsenic concentrtions were lso ville for ll lrge cities in Chile outside the study re, nd these were lso linked to residences, lthough lmost ll wter in Chile outside the study re hs rsenic concentrtions <10 µg/l. 4 Almost ll sujects spent most of their lives either in regions I nd II or in one of the other lrger cities in Chile, so we were le to ssign n rsenic drinking wter concentrtion to >95% of ll residences. Severl indices of rsenic exposure were developed using the yerly concentrtions, including the highest rsenic concentrtion to which the suject ws exposed for ny one yer; the highest concentrtion for ny contiguous 5, 20, or 40 yer period; cumultive exposure in µg/l-yers (clculted y summing the yerly concentrtions); nd verge exposure (clculted y tking the verge of the yerly exposures). Becuse the ltency period of rsenic-relted cncer is severl decdes, 18 nd ecuse Antofgst hd the lrgest popultion nd highest exposures in the re, some nlyses were limited to rsenic exposures efore 1971, the yer when high exposures in Antofgst ended. (Limiting exposures to 2013 Lippincott Willims & Wilkins 899

3 Ferreccio et l Epidemiology Volume 24, Numer 6, Novemer 2013 only those occurring 5, 20, nd 40 yers efore cncer dignosis or study recruitment produced similr results.) For ech rsenic exposure index, sujects were divided into four groups sed on qurtiles for ll sujects. This resulted in rsenic ctegories similr to the highest rsenic wter concentrtions in the four mjor popultion centers of our study re: Aric, Iquique, Clm, nd Antofgst. In the ssessment of direct (firsthnd) smoking, seprte nlyses compred never-smokers to ever-smokers nd neversmokers to hevier smokers (smoking n verge of >10 cigrettes per dy for 6 months, the medin mong smokers). Anlyses of secondhnd smoke were limited to never-smokers. Secondhnd smoke exposure ws clssified s yes or no sed on whether the suject reported ny exposure for t lest 6 months, nd seprte nlyses were conducted for childhood nd dult exposure. Becuse there were reltively smll numers of never-smokers, rsenic exposure ws divided into only two ctegories in these nlyses. Exposure to other known or suspected crcinogens ws initilly clssified s yes or no sed on ny reported exposure. Sujects with proxy interviews were excluded from these nlyses. Women were lso excluded ecuse very few reported these exposures. We ssessed only those gents to which ten or more cses nd controls comined reported exposure. Few sujects were exposed to known occuptionl ldder crcinogens so only lung cncer results re presented. Sttisticl Anlysis Interctions etween rsenic, tocco smoke, nd the other exposures were evluted using the Rothmn Synergy Index. 19 In rief, reltive risks were estimted seprtely for people who were exposed only to rsenic (RR A ), people exposed only to the second gent (RR S ), nd people exposed TABLE 2. Demogrphic Chrcteristics of Controls nd Bldder nd Lung Cncer Cses, Northern Chile Controls Bldder Cncer Cses Lung Cncer Cses No. (%) No. (%) OR (95% CI) No. (%) OR (95% CI) Totl 640 (100) 232 (100) 306 (100) Sex Women 209 (33) 62 (27) (30) 1.00 Men 431 (68) 170 (73) 1.33 ( ) 215 (70) 1.15 ( ) Rce Other 195 (31) 35 (15) (23) 1.00 europen 445 (70) 197 (85) 2.47 ( ) 236 (77) 1.48 ( ) Age (yers) (42) 94 (41) (37) (30) 76 (33) 1.13 ( ) 111 (36) 1.38 ( ) (21) 39 (17) 0.85 ( ) 69 (23) 1.26 ( ) (6) 23 (10) 1.69 ( ) 10 (3) 0.62 ( ) (1) 0 (0) 4 (1) 1.37 ( ) Body mss index >30 kg/m 2 no 612 (96) 216 (93) (94) 1.00 Yes 28 (4) 17 (7) 1.72 ( ) 19 (6) 1.45 ( ) Smoking never 242 (38) 65 (28) (20) 1.00 ever 398 (62) 167 (72) 1.56 ( ) 247 (81) 2.55 ( ) Socioeconomic sttus (tertiles) low 231 (36) 73 (32) (41) 1.00 Medium 203 (32) 66 (28) 1.03 ( ) 103 (34) 0.93 ( ) High 206 (32) 93 (40) 1.43 ( ) 77 (25) 0.69 ( ) Wter rsenic concentrtions (µg/l) c (22) 23 (10) (16) (30) 27 (12) 0.84 ( ) 52 (17) 0.77 ( ) (23) 60 (26) 2.50 ( ) 69 (23) 1.38 ( ) (26) 122 (53) 4.44 ( ) 137 (45) 2.39 ( ) Undjusted ORs nd 95% CIs compring ldder or lung cncer cses to controls. Bsed on self-reported usul height nd weight reported for 20 yers efore dignosis (cses) or scertinment (controls). c Highest single yer exposure throughout the suject s entire lifetime from irth to dignosis (cses) or scertinment (controls). Ctegories re sed on concentrtions in the four lrgest cities in the study re: Aric, Iquique, Clm, nd Antofgst. d An OR ws not clculted ecuse there were no ldder cncer cses in this ge group Lippincott Willims & Wilkins

4 Epidemiology Volume 24, Numer 6, Novemer 2013 Cncer Synergism of Arsenic nd Other Agents TABLE 3. Odds Rtios for Bldder Cncer in Reltion to Arsenic Concentrtions in Wter, y Smoking Sttus, Northern Chile, Arsenic <11 µg/l Arsenic >335 µg/l ORs (95% CI) for Arsenic Within Cses/Controls OR (95% CI) Cses/Controls OR (95% CI) Smoking Strt Never smoker 6/ / (3.0 26) 8.9 (3.0 26) Smoked >10 cigs/dy 14/ (1.3 13) 33/18 23 (8.2 66) 6.2 (2.5 15) OR (95% CI) for smoking within rsenic strt 4.1 (1.3 13) 3.2 ( ) Mesure of interction on n dditive scle: Rothmn Synergy Index (95% CI) = 2.0 ( ). Mesurement on multiplictive scle: rtio of ORs (95% CI) = 0.64 ( ). These re the lower nd upper qurtiles of verge lifetime exposure up to 1971, the end of the high exposure period in Antofgst. Adjusted for ge, sex, socioeconomic sttus, nd secondhnd tocco smoke exposure. to oth (RR AS ), using people exposed to neither s the reference. A synergy index (S) ws then clculted s: S = (RR AS 1) / ([RR A + RR S ] 2). Using this method, S = 1 in the sence of synergy, nd S>1 when iologicl interctions re greter thn dditive. Confidence intervls (CIs) for S were estimted using the methods of Hosmer nd Lemeshow, 20 nd findings re presented s suggested y Knol nd VnderWeele. 21 Lung nd ldder cncer odds rtios (ORs) were clculted using unconditionl logistic regression. Potentil confounding vriles entered into regression models included sex, ge (10-yer ge groups), smoking, nd tertiles of socioeconomic sttus (SES) scores. SES scores were sed on 12 items including ownership of household pplinces, cr, computer, nd domestic help. Anlyses were done in SAS version 9.2 (SAS Institute Inc., Cry, NC). RESULTS The nmes of 370 persons with lung cncer nd 289 persons with ldder cncer were otined from locl pthologists, rdiologists, or hospitls. Of these, 46 persons with lung cncer nd 23 with ldder cncer were ineligile sed on ge nd residentil criteri. Of the remining, 18 persons with lung cncer (6%) nd 34 with ldder cncer (13%) (or their next of kin) could not e locted, hd moved outside the study re, provided insufficient residentil informtion, or declined prticiption. Among 872 controls selected from the Electorl Registry with vile ddresses, 232 (27%) no longer lived t the ddress nd could not e locted, were ineligile ecuse of illness, gve insufficient informtion, or declined prticiption. Sex, ge, nd SES were similr mong cses nd controls (Tle 2). Bldder nd lung cncer cses were more likely thn controls to e of Europen descent, smokers, nd exposed to higher rsenic concentrtions. Tles 3 nd 4 show the lung nd ldder cncer ORs for rsenic exposure strtified y smoking sttus. The ldder cncer OR in hevier smokers in the highest rsenic exposure ctegory (OR = 23, 95% CI = ) ws sustntilly higher thn tht in hevier smokers with low rsenic exposure (OR = 4.1, 95% CI = ) or in never-smokers with high rsenic exposure (OR = 8.9, 95% CI = ). The synergy index for rsenic nd smoking ws 2.0 (95% CI = ). The pttern ws similr for lung cncer, lthough with higher synergy index (S = 4.0, 95% CI = ). Dose response ptterns for rsenic in smokers nd never-smokers re shown in Supplementry Tle 2 ( Similr ptterns were seen in nlyses of those smoking >20 cigrettes per dy, rsenic exposure tertiles, cumultive rsenic exposure (Supplementry Tles 3 7, or durtion or pck-yers of smoking (not shown). Tles 5 nd 6 shows the ORs in never-smokers for rsenic exposure strtified y childhood secondhnd smoke TABLE 4. Odds Rtios for Lung Cncer in Reltion to Arsenic Concentrtions in Wter, y Smoking Sttus, Northern Chile, Arsenic <11 µg/l Arsenic >335 µg/l ORs (95% CI) for Arsenic Within Cses/Controls OR (95% CI) Cses/Controls OR (95% CI) Smoking Strt Never smoker 16/ / ( ) 2.0 ( ) Smoked >10 cigs/dy 28/ ( ) 46/18 16 (6.5 40) 4.2 ( ) OR (95% CI) for smoking within rsenic strt 3.8 ( ) 5.4 (2.1 14) Mesure of interction on n dditive scle: Rothmn Synergy Index (95% CI) = 4.0 ( ). Mesurement on multiplictive scle: rtio of ORs (95% CI) = 1.9 ( ). These re the lower nd upper qurtiles of verge lifetime exposure up to 1971, the end of the high exposure period in Antofgst. Adjusted for ge, sex, socioeconomic sttus, nd secondhnd tocco smoke exposure Lippincott Willims & Wilkins 901

5 Ferreccio et l Epidemiology Volume 24, Numer 6, Novemer 2013 TABLE 5. Odds Rtios for Bldder Cncer in Reltion to Arsenic Concentrtions in Wter in Never-smokers, y Exposure to Childhood Secondhnd Smoke, Northern Chile, Arsenic <200 µg/l Arsenic >200 µg/l ORs (95% CI) for Arsenic Within Secondhnd Cses/Controls OR (95% CI) Cses/Controls OR (95% CI) Smoke Strt No secondhnd smoke exposure 20/ / ( ) 3.4 ( ) Secondhnd smoke exposed 7/ ( ) 14/ (2.8 17) 6.8 (2.2 21) ORs (95% CI) for secondhnd smoke within rsenic strt 0.9 ( ) 1.7 ( ) Mesure of interction on n dditive scle: Rothmn Synergy Index (95% CI) = 2.6 ( ). Mesurement on multiplictive scle: rtio of ORs (95% CI) = 2.1 ( ). Averge lifetime exposure up to 1971, the end of the high exposure period in Antofgst. Adjusted for ge, sex, nd socioeconomic sttus. exposure. The highest ORs were seen for persons exposed to oth rsenic nd secondhnd smoke. Synergy indices were >1.0 for oth ldder (S = 2.6, 95% CI = ) nd lung cncer (S = 2.1, 95% CI = ). No evidence of interction ws seen etween rsenic nd dult secondhnd smoke exposure (not shown). Among those reporting ny secondhnd smoke exposure, the medin numer of hours exposed per dy ws 4. Tle 7 shows lung cncer ORs in nlyses of rsenic nd other occuptionl or environmentl exposures. For ech of the gents ssessed, ORs re presented for three seprte groups, using sujects who hd low rsenic exposure nd who were not exposed to the other gent of interest s the reference group. These three groups (nd their corresponding ORs from left to right in Tle 7) re 1) sujects who hd reported exposure to the other gent ut hd low rsenic exposure; 2) sujects who did not report exposure to the other gent ut hd high rsenic exposure; nd 3) sujects who hd reported exposure to the other gent nd hd high rsenic exposure. Low nd high rsenic exposure in these nlyses were defined s the lowest (<11 µg/l) or highest (>335 µg/l) qurtiles of verge rsenic concentrtion in wter efore Very high ORs (eg, >10) were seen for sujects coexposed to rsenic nd severl of the other crcinogens ssessed. Synergy indices sustntilly ove 1.0 were seen for mny of the gents known or suspected to cuse lung cncer, including sestos (S = 2.7), silic (S = 2.0), wood dust (S = 3.1), welding fumes (S = 2.4), soot (S = 2.5), nd fierglss (S = 2.5). The ctegory ny crcinogen included ny of the known or suspected lung crcinogens listed in Tle 7 plus eryllium, is(chloromethyl) ether, chromium, nd cdmium. Synergy indices for rsenic nd gents not known or suspected to cuse lung cncer (such s enzene nd solvents) were mostly ner 1.0. Ctegorizing rsenic sed on other indices such s cumultive or highest exposure hd little effect on results. Results were lso essentilly unchnged when we limited nlyses to histologiclly confirmed cses, when we incorported numer of smokers in the home or totl yers of exposure to the secondhnd smoke exposure vrile, or when we sed exposure to crcinogens on numer of hours per week nd totl yers. Additionl djustments for ody mss index, rce, or mining work hd little impct on results. DISCUSSION Overll, these findings suggest tht people exposed to comintion of rsenic in drinking wter nd some other known or suspected crcinogen, including tocco smoke, sestos, silic, nd wood dust, hve lung nd ldder cncer risks tht re >10 times higher thn those who re unexposed. Synergy indices were sustntilly greter thn 1.0 for severl TABLE 6. Odds Rtios for Lung Cncer in Reltion to Arsenic Concentrtions in Wter in Never-smokers, y Exposure to Childhood Secondhnd Smoke, Northern Chile, Arsenic <200 µg/l Arsenic >200 µg/l ORs (95% CI) for Arsenic Within Secondhnd Smoke Cses/Controls OR (95% CI) Cses/Controls OR (95% CI) Strt No secondhnd smoke exposure 26/ / ( ) 1.4 ( ) Secondhnd smoke exposed 12/ ( ) 8/ ( ) 1.9 ( ) ORs (95% CI) for secondhnd smoke within rsenic strt 1.4 ( ) 1.6 ( ) Mesure of interction on n dditive scle: Rothmn Synergy Index (95% CI) = 2.1 ( ). Mesurement on multiplictive scle: rtio of ORs (95% CI) = 1.5 ( ). Averge lifetime exposure up to 1971, the end of the high exposure period in Antofgst. Adjusted for ge, sex, nd socioeconomic sttus Lippincott Willims & Wilkins

6 Epidemiology Volume 24, Numer 6, Novemer 2013 Cncer Synergism of Arsenic nd Other Agents TABLE 7. Lung Cncer Odds Rtios in Men in Reltion to Exposure to Other Agents, Exposure to High Concentrtions of Arsenic in Wter, or Both, Using People not Exposed to the Other Agent nd with Low Arsenic Concentrtions in Wter s the Reference Group, Northern Chile, Other Agent Unexposed Exposed Unexposed Exposed Arsenic Low Exposure Low Exposure High Exposure High Exposure Synergy Index N OR (95% CI) N OR (95% CI) N OR (95% CI) N OR (95% CI) S (95% CI) Any crcinogen c,d 6/ Ref 11/ ( ) 19/ (1.8 15) 27/ (3.8 38) 2.2 ( ) Asestos 16/ Ref 1/7 1.6 ( ) 40/ (2.9 12) 6/3 16 (2.8 95) 2.7 ( ) Silic 11/ Ref 6/ ( ) 30/ (2.6 15) 16/15 13 (3.9 43) 2.0 ( ) Wood dust d 9/ Ref 8/ ( ) 34/ (3.2 18) 12/7 26 ( ) 3.1 ( ) Welding fumes 12/ Ref 5/ ( ) 33/ (2.4 13) 13/10 12 (3.7 38) 2.4 ( ) Coke oven 14/ Ref 3/ ( ) 34/ (2.7 13) 12/ (2.2 19) 1.1 ( ) Soot 13/ Ref 4/ ( ) 41/ (2.9 14) 4/5 16 ( ) 2.5 ( ) Fierglss 15/ Ref 2/ ( ) 40/ (2.9 13) 4/6 14 (2.6 81) 2.5 ( ) Benzene 16/ Ref 1/4 1.0 ( ) 44/ (3.1 13) 2/4 8.7 ( ) 1.5 ( ) TCE 16/ Ref 1/3 2.4 ( ) 43/ (3.5 15) 3/5 6.7 (1.1 40) 0.73 ( ) Other solvents 16/ Ref 1/6 1.9 ( ) 45/ (3.3 14) 1/2 4.2 ( ) 0.48 ( ) Acrylic 15/ Ref 2/5 4.6 ( ) 44/ (3.3 15) 2/3 10 ( ) 0.97 ( ) Any solvent e 15/ Ref 2/9 1.6 ( ) 42/ (3.3 15) 4/7 7.6 (1.4 41) 1.0 ( ) Vpors 13/ Ref 4/ ( ) 41/ (3.6 18) 5/3 15 (2.3 96) 1.8 ( ) Other chemicls 10/ Ref 7/ (1.1 13) 32/ (3.6 20) 14/ (2.5 24) 0.64 ( ) Mining 12/ Ref 5/ ( ) 36/ (3.2 17) 10/ (2.0 24) 0.90 ( ) N indictes numer of cses/controls; Ref, reference group; TCE, trichloroethylene. High rsenic exposure is defined s n verge lifetime rsenic concentrtion in wter up to 1971 of >335 µg/l. Low rsenic exposure is defined s n verge lifetime rsenic concentrtion in wter up to 1971 of <11 µg/l. All ORs re djusted for ge, smoking, nd socioeconomic sttus. c Includes ny of the known or suspected lung crcinogens listed in this tle (sestos, silic, wood dust, welding fumes, coke oven emissions, soot, nd fierglss) s well s eryllium, is(chloromethyl) ether, chromium, nd cdmium. d Further detils on these nlyses re shown in Supplementry Tles 8 nd 9 ( e Includes enzene, TCE, nd ny other solvent. of the coexposures ssessed here, suggesting tht the comined effects of these multiple crcinogens re greter thn dditive. This study hs severl dvntges for studying the helth effects of rsenic. First, the study took plce in n re with history of high concentrtions of rsenic in drinking wter nd good dt on pst exposure. Otining ccurte dt on historicl exposures is importnt ecuse the ltency for mny crcinogens is severl decdes or more. Northern Chile is the driest hitle plce of erth, nd over 97% of ll wter is otined from smll numer of pulic wter systems tht supply ech city or town. Historicl records of rsenic concentrtions re ville for ll of these systems, with mny dting ck 40 yers or more nd showing very stle concentrtions over time. Becuse of this smll numer of wter sources nd good historicl records, lifetime rsenic exposure cn e ccurtely estimted simply y knowing the cities or towns in which person hs lived. The second mjor dvntge is tht the rsenic exposures were very high (eg, >800 µg/l) nd hve een linked to high reltive risks of lung nd ldder cncer. 5,22 Higher reltive risks hve greter sttisticl power nd re less likely to e ecuse of confounding or is thn reltive risks ner The third dvntge of this study is tht detiled informtion ws collected on other known or suspected crcinogens including smoking, child nd dult secondhnd smoke, sestos, silic, nd wood dust. This informtion llowed us to investigte the comined effects of multiple crcinogenic exposures. Multiple exposures were ssessed in this study, nd it is possile tht some of these findings could e ecuse of chnce or correltions etween exposures. Evidence ginst chnce eing n explntion include the fct tht mny of the OR CIs excluded 1.0 nd tht synergy indices tended to e high for gents lredy known or suspected to cuse lung cncer (eg, sestos), ut not for gents not linked to lung cncer (eg, solvents). Tocco smoke, sestos, silic, coke production, nd soot re ll estlished cuses of lung cncer. 7 Wood dust is n estlished cuse of nsophryngel cncer ut hs lso een linked to lung cncer in severl studies Severl of the findings presented here re consistent with previous studies. For exmple, studies hve reported evidence of synergistic reltionships etween rsenic nd smoking in lung cncer, including previous study in northern Chile A recent study in Bngldesh reported evidence of synergistic reltionship etween rsenic, smoking, nd fertilizer use for premlignnt skin lesions. 27 The study reported here is novel in eing the first to exmine the comined effects of rsenic with secondhnd tocco smoke, sestos, silic, wood dust, nd severl other common crcinogenic 2013 Lippincott Willims & Wilkins 903

7 Ferreccio et l Epidemiology Volume 24, Numer 6, Novemer 2013 exposures. With regrd to ldder cncer, previous studies in Argentin nd the United Sttes y our reserch group hve reported somewht higher rsenic-ssocited ldder cncer reltive risks in smokers compred with nonsmokers, ut smple sizes were smll nd rsenic exposures nd reltive risks were low. 28,29 In contrst, the study reported here is the first to provide firly good evidence tht synergistic reltionship my exist etween rsenic nd smoking for ldder cncer. Although the exct mechnisms of the synergistic ssocitions identified here re unknown, severl possiilities exist. For exmple, simultneous exposures to different gents working y the sme pthwys could overwhelm repir or detoxifiction processes tht would normlly help prevent cncer. Alterntively, erly exposure to rsenic could cuse permnent iochemicl chnges tht then led to greter susceptiility to susequent exposures. In mice, Wlkes et l 30 found tht while rsenic exposure hd no effect y itself, the numer of skin tumors following exposure to 12-O-tetrdecnoyl phorol-13-cette incresed y three-fold in mice pretreted with rsenic in the fetl period. Also in mice, Dnee et l 31 found tht pretretment with rsenic incresed UV rdition relted mutgenesis in greter thn dditive fshion, nd tht rsenic inhiited the repir of UV-induced DNA dmge. Results such s these provide possile iologicl sis for the synergistic reltionships identified in our study. An interesting feture of our findings is tht rsenic exposures in our study re occur primrily y ingestion wheres the other exposures we evluted re primrily y inhltion. These interctions re not iologiclly implusile ecuse some reserch hs shown tht ingested rsenic cn ccumulte in the lung. 32,33 In ddition, previous nlysis hs shown tht the lung cncer risks linked to rsenic re relted to its internl dose s mesured y urinry rsenic concentrtions, nd the risks sed on internl dose re essentilly the sme regrdless of whether rsenic is inhled or ingested. 34 Becuse exposure informtion ws collected retrospectively, some exposure misclssifiction is likely. However, exposure ws ssessed similrly in cses nd controls, so some of this misclssifiction is likely nondifferentil, ising ORs nd synergy indices towrd the null. 35 Becuse rsenic exposure in this re cn e determined sed primrily on the cities or towns in which the sujects lived, nd errors in reclling residency informtion re expected to e miniml, the impct of misclssifiction of rsenic exposure is likely smll. Arsenic levels were not collected for residences outside Chile, ut the lrge mjority of sujects spent their whole lives in Chile nd none lived in res outside Chile with known high rsenic concentrtions. Arsenic exposure my lso come from food or ir, lthough previous nlysis in this re showed tht these exposures would mke up less thn 2% of the totl rsenic intke in sujects who lived in Antofgst during the high exposure period. 36 With regrds to misclssifiction of smoking sttus, studies ssessing plsm cotinine levels hve shown tht self-reported smoking sttus cn relily distinguish smokers from nonsmokers. 37 The vlidity of self-reported secondhnd smoke exposure is less cler. Willemsen et l 38 found tht selfreported secondhnd smoke exposure correlted resonly well with ir nicotine concentrtions in office workers (R = 0.65). In n investigtion of 9320 US dults, Mx et l 39 identified positive predictive vlue of 80% nd negtive predictive vlue of only 64% etween self-reported secondhnd smoke exposure nd serum cotinine, lthough the cutoff point used to define positive cotinine level ws somewht low ( 0.05 ng/ml). Overll, some nondifferentil misclssifiction of secondhnd smoke (nd resulting is of ORs towrd the null) is likely. Differentil misclssifiction could occur if cses tended to recll their pst secondhnd smoke exposure with greter or less ccurcy thn controls. The extent of this is is unknown. But, the fct tht ldder nd lung cncer ORs for secondhnd smoke exposure in people without high rsenic exposure were close to 1.0 (0.91 nd 1.3, respectively) suggests tht this is, if present, ws not strong. Exposures to the other gents like sestos or silic could lso hve een misclssified. As mentioned ove, nondifferentil misclssifiction would most likely is ORs towrd the null. Severl studies hve shown tht most people re le to recll their pst occuptionl exposures with fir to good ccurcy, lthough results vry cross studies. 40 In study of 951 shipyrd workers, the prevlence of pleurl plques correlted much etter with self-reported sestos exposure thn with expert s estimtes sed on jo titles. 41 A study of drycleners reported sensitivities nd specificities >90% for self-reported trichloroethylene exposure compred with employer reports. 42 Differentil misclssifiction could conceivly occur if cses recll exposures differently thn controls, lthough n in-depth review of this topic concluded tht there is little evidence for this. 40 Our finding of higher ORs nd synergy indices for those gents known to cuse lung cncer (eg, sestos, silic, soot) compred with those gents not linked to lung cncer (eg, enzene, trichloroethylene), nd lck of evidence of synergy etween known crcinogens of the lung nd the risks of ldder cncer, is further evidence tht differentil recll did not cuse the positive results reported here. Sujects relted lmost ll of these other chemicl exposures to their workplces, nd few exposures from hoies were reported. Becuse we did not sk out specific hoies, it is possile tht some exposures were missed, lthough ny is from this ws likely nondifferentil. The ORs in this study chnged very little with djustment for smoking, other crcinogens, ody mss index, mining work, or SES. Reltively smll chnges were seen with djustment for ge nd sex. Confounding from other fctors like diet or rdon is possile. However, in order to cuse importnt confounding, vrile must e ssocited with oth the exposure nd outcome of interest, 43 nd there is no evidence tht rdon, diet, or other fctors re strongly enough relted to rsenic exposure in this study re to cuse the elevted ORs identified here Lippincott Willims & Wilkins

8 Epidemiology Volume 24, Numer 6, Novemer 2013 Cncer Synergism of Arsenic nd Other Agents Tens of millions of people re exposed to rsenic worldwide, nd mny of these people re proly coexposed to t lest one of the other gents ssessed here. Furthermore, lung nd ldder cncer re mong the most common cncers worldwide. These fctors, comined with the lrge mgnitude of the reltive risks identified here, highlight the lrge numers of excess cncer cses likely to e relted to these comined exposures nd the possile enefits of interventions imed t reducing these exposures. REFERENCES 1. Rvenscroft P. Predicting the Glol Distriution of Nturl Arsenic Contmintion of Groundwter. Symposium on Arsenic: The Geogrphy of Glol Prolem. London: Royl Geogrphicl Society; President s Cncer Pnel. Reducing Environmentl Cncer Risk. Wht We Cn Do Now? Annul Report. U.S. Deprtment of Helth nd Humn Services. Ntionl Institutes of Helth. Bethesd, MD: Ntionl Cncer Institute; Instituto Ncionl de Estdistics. 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