RESEARCH ARTICLE. Abstract. Introduction

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1 DOI: Occuptionl Rdition Exposure nd Brest nd Esophgus Cnce Ris RESEARCH ARTICLE Nested Cse-control Study of Occuptionl Rdition Exposure nd Brest nd Esophgus Cncer Risk mong Medicl Dignostic X Ry Workers in Jingsu of Chin Fu-Ru Wng 1&, Qio-Qio Fng 2&, Wei-Ming Tng 3, Xio-Sn Xu 1, Tnmy Mhptr 3, Snchit Mhptr 3, Yu-Fei Liu 4, Ning-Le Yu 1&, Qun-Fu Sun 4 * Abstrct Medicl dignostic X-ry workers re one occuptionl group tht expose to the long-term low-dose externl rdition over their working lifetime, nd they my under risk of different cncers. This study ims to determine the reltionship between the occuptionl X-ry rdition exposure nd cncer risk mong these workers in Jingsu, Chin. We conducted Nested cse-control study to investigte the occuptionl X-ry rdition exposure nd cncer risk. Dt were collected through self-dministered questionnire, which includes but not limits to demogrphic dt, personl behviors nd fmily history of cncer. Retrospective dose reconstruction ws conducted to estimte the cumultive doses of the x-ry workers. Inferentil sttistics, t-test nd 2 tests were used to compre the differences between ech group. We used the logistic regression model to clculte the odds rtio (OR) nd 95% confidence intervl (CI) of cncer by djusting the ge, gender. All 34 brest cncer cses nd 45 esophgel cncer cses tht detected in cohort conducted mong helth workers between 1950~2011 were included in this presented study, nd 158 cncer-free controls were selected by frequency-mtched (1:2). Our study found tht the occuptionl rdition exposure ws ssocited with significntly incresed cncer risk compred with the control, especilly in brest cncer nd esophgel cncer (djusted OR=2.90, 95% CI: for brest cncer; OR=4.19, 95% CI: for esophgel cncer, nd OR=3.43, 95% CI: for totl cncer, respectively). The occuptionl X-ry rdition exposure ws ssocited with incresing cncer risk, which indictes tht proper intervention nd prevention strtegies my be needed in order to bring down the occuptionl cncer risk. Keywords: Nested cse-control study - occuptionl rdition - medicl dignostic X ry workers - cncer risk Asin Pc J Cncer Prev, 16 (11), Introduction The only confirmed ftl helth hzrds of humn induced by low dose rdition is the ionizing rdition crcinogenesis (Chrles, 2001). Although the rdition does not ply so prominent role s chemicl crcinogen in ll humn cncer cuses, due to the ppliction of nucler technology in humn production nd life, especilly in medicl dignosis nd tretment field occupies more nd more specil position, the potentil hzrds of rdition on humns re incresing. Therefore, reserch on the reltionship between rdition nd cncer hs been the oncology, rdition biology, rdition protection nd epidemiologicl reserch focus (Thompson et l., 1994; Sun et l., 1996; Yu et l., 2001; Wng et l., 2002). Number of niml studies confirmed tht long-term low dose rdition exposure my induce tumorigenesis (Httori et l., 1988; Yoshid et l., 1997; Nishimur et l., 1999; Sito et l., 2001). However, due to the presence of species, individul nd orgniztion-specific genetic differences, it is not yet estblished in vitro study using the theoreticl model to evlute its reltionship with humn tumors. Epidemiologicl studies of rdition crciongenesis re importnt in order tht people exposed to mn-mde sources rdition should be protected from its hrmful effects, nd humn crcinogenic risk of rdition reserch minly bsed on it. Erly studies, string with the ongoing cohort study on the Jpnese bomb survivors, focused on cute exposures to high doses of rdition nd becme the most importnt informtion on quntittive estimtes of rdition-relted cncer risk. Shimizu et l. (1990) conducted follow-up study on Ngski, Hiroshim tomic bomb survivors long-term effects from 1950 to 1985 found tht the 1 Deprtment of Rdition protection, JingSu Provincil Center for Disese Prevention nd Control, 2 Deprtment of Respirtory Medicine, Nnjing Children s Hospitl Affilited to Nnjing Medicl University, Nnjing, 4 Ntionl Institute for Rdiologicl Protection, Chin CDC, 2 Xinkng Street, Deshengmenwi, Xicheng District, Beijing, Chin, 3 Deprtment of Epidemiology, Fielding School of Public Helth, University of Cliforni, Los Angeles, USA & Equl contributors *For correspondence: wngfuru@jscdc. cn; wngfuru1983@126.com Asin Pcific Journl of Cncer Prevention, Vol 16,

2 Fu-Ru Wng et l incidence of solid cncer begn to drmtic rise, nd the incresed incidence of brest cncer mong women is prticulrly prominent. However, it my not be possible to extrpolte directly from the effects of cute high doses to the long-term low-dose ionizing rdition exposure. Medicl dignostic X-ry workers re one occuptionl group tht expose to the long-term low-dose externl rdition over their working lifetime, nd they my under risk of different cncers. Word widely, there re over 2.3 million medicl rdition workers, nd bout hlf of their work time is exposed to humn-mde sources of low-dose rdition (Yoshing et l., 2004). However, the lck of informtion on individul rdition doses of previous studies limited the findings. Therefore, there is pressing need to conduct relevnt studies mong medicl rdition workers to ddress this identified issue. A cohort study ws conducted on survivl nd cncer incidence mong medicl dignostic X ry workers during 1950~2011 in Jingsu, Chin. Bsed on this finished cohort study, nested cse control study ws conducted, in order to investigte the occuptionl X-ry rdition exposure nd cncer risk, prticulr for brest nd esophgel cncers, two cncers which were considered to be sensitive to ionizing rdition (Thompson et l., 1994; Wng et l., 2002). Mterils nd Methods Study popultion A cohort study involving helthcre workers ws conducted in 13 cities of Jingsu province, from 1950 to We selected the medicl dignostic X-ry workers working t the deprtment of rdiology in selected hospitls from 1950 to 1980 s the rdiology group (3,961subjects until June 30, 2011). Control group were those medicl workers who were selected from the deprtment of internl medicine, ENT, peditrics, who hd not engged in rdition work in the sme hospitl during the sme period (3,742 subjects until June 30, 2011). All 34 brest cncer cses (ICD-10 34) nd 45 esophgel cncer cses (ICD-10 25) tht detected in the designed cohort conducted between 1950 nd 2011 were selected into this nest cse control study. In order to be n eligible cncer cse, cler dignosis hospitl, dte of dignosis or the bsis of dignosis were needed. In totl, there re 79 cncer ptients in the cse group. We rndomly selected 158 cncer-free controls by using cumultive (cse-non-cse) smpling strtegy t the end of the study (June 30, 2011), by frequency-mtched (1:2), which ws mtched on gender, ge (±5 yers), ge t prticipte in the work (±5 yers) nd residentil re, while exposure sttus ws not mtched. After informed consent ws obtined, we interviewed the subject, or his reltives, or other insiders by trined interviewers using pre-tested stndrd questionnire to obtin informtion on demogrphic dt, disese history, personl hbits, environmentl exposure history, nd fmily history of cncer in first-degree reltives (prents, siblings nd children). We used the following order to select respondents: respondents themselves, their spouses, their children, their collegues nd other insiders Asin Pcific Journl of Cncer Prevention, Vol 16, 2015 We tried to mke the survey content comprehensive nd concise nd ll investigtors hd been ccepted the epidemiologists nd psychologists trining. We unified the investigtion stndrds nd selected investigtor who hd pssed the qulified test. Ethicl considertion This study ws pproved by the Survey nd Behviorl Reserch Ethics Committee of the Jingsu Provincil Center for Disese Prevention nd Control. Respondents were ssured of their informtion nd confidentility, nd they were informed of their right to withdrw from the study t ny time. Informed consent ws obtined prior to dt collection. Retrospective dose reconstruction Before 1985 there ws no individul dose monitoring system for Chinese medicl x-ry workers. In order to estimte the ccumultive dose for the x-ry workers, the min chrcteristics of the occuptionl exposure were investigted. Exposure doses t x-ry mchines nd workplces were mesured by simulting the pst working conditions. The x-ry workers were chosen by strtified rndom smpling method nd interviewed concerning the detils of their occuptionl histories. A mthemticl model nd computerizing system for dose reconstruction of occuptionl exposure were designed nd developed (Zhng L, 1998). Using these dt nd methods, we estimted the reconstructed verge nnul dose nd cumultive doses of the x-ry workers by clendr yer of initil employment. Sttisticl nlysis Dt were entered by double-entry nd pssed the consistency test by Epidt All dt nlyzes were performed by using SAS 9.1 SAS Institute, Cry, NC, USA nd stt13.0. Descriptive sttistics, which include mens nd stndrd devitions, were used to summrize the demogrphic dt. Inferentil sttistics, t-test nd 2 tests were used to compre the differences between ech group. We used the logistic regression model to gin the odds rtio (OR) nd 95% confidence intervl (CI) by djusting the ge, gender, which were consider to be two importnt confounders between cncer nd rdition. In the originl study, informtion regrding smoking nd lcohol drinking, two importnt potentil confounders were not completely collected. To solve this problem, we performed sensitivity nlysis to further djust for these two vribles. The detiled ssumption nd SAS code for sensitivity nlyses re presented in supplementry informtion A. Results Tble 1 shown us the chrcteristics of the 79 cncer cses nd 158 cncer-free controls, including 34 brest cncer cses nd 68 controls, 45 esophgel cncer cses nd 90 controls. The cses nd controls ppered to be dequtely mtched on ge nd ge t prticipte work in ech group. As shown in Tble 1, there were no significntly differences between the cses nd controls

3 DOI: Occuptionl Rdition Exposure nd Brest nd Esophgus Cnce Ris Tble 1. Distributions of Select Vribles in Cncer Cses nd Controls Vribles Cse Control P Brest cncer N=34 N=68 Age, yr (Men±SD) 70.41± ± Age t prticipte in the work, yr (Men±SD) 24.32± ± Age t menrche, yr (Men±SD) 15.06± ± Age t mrrige, yr (Men±SD) 26.38± ± Age t menopuse, yr (Men±SD) 50.33± ± Age t first live birth, yr (Men±SD) 27.06± ± Abortion Negtive Positive Brestfeeding Negtive Positive Orl contrceptives Negtive Positive 4 3 Fmily history of cncer Negtive Positive Esophgel cncer N=45 N=90 Age, yr (Men±SD) 72.27± ± Age t prticipte in the work, yr (Men±SD) 28.80± ± Smoking Negtive Positive Drinking Negtive Positive Fmily history of cncer Negtive Positive 7 9 Totl cncer N=79 N=158 Age, yr (Men±SD) 71.49± ± Age t prticipte in the work, yr (Men±SD) 26.9± ± Fmily history of cncer Negtive Positive Two-sided p vlue from c2test or t test for difference in frequency distribution between cses nd controls Tble 2. Logistic Regression Anlyses on Associtions between Rdition Exposure nd Cncer Risk Vribles Cses Controls P Crude OR (95%CI) Adjusted OR (95%CI) b Brest cncer non-rdiology rdiology ( ) 2.90( ) Esophgel cncer non-rdiology rdiology ( ) 4.19( ) Totl cncer non-rdiology rdiology ( ) 3.43( ) Two-sided c2 test for difference in frequency distribution between cses nd controls; b Adjusted for ge, gender Tble 3. Correltion between Helth Work Environmentl Rdition nd Cncers fter Sensitivity Anlysis Vribles Model 1 Model 2 b Model 3 c Brest cncer 2.76 ( ) 2.84 ( ) 2.70 ( ) Esophgel cncer 4.00 ( ) 4.10 ( ) 3.92 ( ) Totl cncer 3.27 ( ) 3.36 ( ) 3.12 ( ) Model 1 ws djusted for smoking, b model 2 ws djusted for lcohol, nd c model 3ws djusted for both smoking nd lcohol in the medin ge t menrche, medin ge t mrrige, medin ge t menopuse, medin ge t hving first live birth, smoking, drinking nd fmily history of cncer. For the brest cncer group, the proportions of bortion history were 43.5% in cse group nd 37.5% in control group, while the verge ges t first bortion were 30.0 Asin Pcific Journl of Cncer Prevention, Vol 16,

4 Fu-Ru Wng et l nd 26.6 yers old respectively. The brestfeeding rtes were 75.0% in cse nd 87.0% in control, while the orl contrceptive using rtes were 25.0% nd 13.0% respectively. For the esophgel cncer group, the proportions of smokers were 53.6% in cse group nd 38.9% in control group, while the verge ges of smoking initition were 21.8 nd 23.8 yers old respectively. About 55.6% were drinkers in cse group, while bout 44.4% were drinkers in control group, with the verge ges of drinking initition t 24.3 nd 23.8 yers respectively. Results from logistic regression shown tht the occuptionl rdition exposure ws significntly ssocited with n incresed cncer risk, compred with the control (djusted OR=2.90, 95% CI: for Figure 1. The Norml Distributions of Cumultive dose (log (dose)) in Rdiology Group between Cncer Cse nd Controls Tble 4. Distributions of Cumultive dose in Rdiology Group between Cncer Cses nd Controls Group Cumultive dose (mgy) Cse Control Brest cncer P50% Men Esophgel cncer P50% Men Totl cncer P50% Men brest cncer; OR=4.19, 95%CI: for esophgel cncer, nd OR=3.43, 95%CI: for totl cncer, respectively). After further djusted for both smoking nd lcohol (model 3 in Tble 3), we found tht helth work environmentl rdition ws highly relted to brest cncer, esophgel cncer nd totl cncers, even the 95% CI of brest cncer includes one. To further nlyze whether there is dose-response reltionship between occuptionl rdition dose nd cncer, we conducted strtified nlysis focused on the objects hd occuptionl rdition exposure (rdiology stff). Finlly, we collected ll 97 rdiology stff, including 50 cncer cses nd 47 controls with cumultive doses dt. The distributions of cumultive dose in rdiology group between cncer cses nd controls were shown in Tble 4 nd Figure 1. From the Tble 4 nd Figure 1, we cn found tht both the P50% nd Men of cumultive doses in cse group re higher thn control in ech cncer group. Multivrite logistic regression nlyses results between vrint levels of cumultive dose nd cncer risk were shown in Tble 5. We strtified the dose group by P25% nd P75% of cumultive dose in ech cncer group respectively. Although we filed to find ny significnt ssocition between vrint levels of cumultive dose nd cncer risk, s the dose incresing, we found tht the odds rtio (OR) were rising in ech cncer group. Discussion In this nested cse-control study, we estimted the ssocitions between occuptionl X-ry rdition exposure nd risk of cncer, especilly brest cncer nd esophgel cncer mong Chinese medicl dignostic X ry workers. We found tht the long-term low dose occuptionl X-ry rdition exposure ws significntly ssocited with cncers, especilly brest cncer nd esophgel cncer, which my indicte tht occuptionl X-ry rdition ply n importnt role in cncer development. Epidemiologicl studies hve been crried out in severl countries for investigtion of cncer risk mong medicl rdition workers, such s rdiologists studied in Tble 5. Logistic regression nlyses on ssocitions between different cumultive doses in rdiology group nd cncer risk Cumultive dose group (mgy) Cses Controls P Crude OR (95%CI) Adjusted OR (95%CI) f Brest cncer < ~ b d 1.07 ( ) 1.07 ( ) c e 1.88 ( ) 1.48 ( ) Esophgel cncer < ~27.49 b d 1.07 ( ) 1.02 ( ) c e 1.25 ( ) 1.26 ( ) Totl cncer < b d 1.09 ( ) 1.12 ( ) c e 2.22 ( ) 2.62 ( ) Strtified by the P25% of cumultive dose; b Strtified by the P25% ~P75%of cumultive dose; c Strtified by the P75% of cumultive dose; d Twosided c2 test for difference in frequency distribution between cses nd controls; e P trend for cumultive dose between cses nd controls; f Adjusted for ge, gender 4702 Asin Pcific Journl of Cncer Prevention, Vol 16, 2015

5 the UK(Doll, 2005) nd the U.S (Mtnoski et l., 2008), rdiologicl technologists studied in the U.S (Little et l., 2014; Moskowitz et l., 2014) nd Jpn (Yoshing et l., 1999), nd rdiotherpy stff studied in Denmrk (Andersson et l., 1991). Brest cncer is believed to be one of the most redily cused by ionizing rdition (Snijders et l., 2012). It seems likely tht femle brest cncer is relted to occuptionl x-ry exposure, nd, s the literture suggests, frctiontion of the dose cnnot pprecibly lower the risk of rdiogenic brest cncer (Boice et l., 1991; Howe et l., 1996). The risk of esophgel cncer ws lso significntly elevted mong the medicl x-ry workers, nd incresed risk of esophgel cncer hs been reported mong those who exposed to high dose rdition, such s tomic bomb survivors (Little et l., 1999). The elevted OR of esophgel cncer mong the medicl x-ry workers with long-term low dose externl rdition lso demonstrted tht cumulted nd long-term ionizing rdition might bring up cncer risks. In ddition, it hs incresingly been recognized tht gene muttion my increse cncer risk. A lrge number of reserches show tht humn peripherl blood lymphocytes hypoxntine-gunine phpsphoribosyl trnsferse (HPRT) gene, which is chemicl nd ionizing rdition sensitive mutgen loci (Nickls et l., 1991; Zimmer et l., 1997; Hmdn et l., 1999; Helledy et l., 2000), ws closely relted to the p53 nd bcl-2 gene (Liu et l., 1997; Phillips, Gebow et l., 1997), which hd been demonstrted strongly ssocition with cncer development (Murry et l., 2012; Zeestrten et l., 2013),especilly with brest cncer nd esophgel cncer (Bellini et l., 2012; Wlerych et l., 2012). Therefore, it is worthy to emphsize tht the occuptionl X-ry rdition exposure might interct with phosphoribosyl gene muttion contribute to cncer susceptibility. Further welldesigned lrge studies, prticulrly refer to gene-rdition exposure interctions were wrrnted to confirm the rel contribution of occuptionl X-ry rdition exposure in cncer development. Although this study hs mny interesting findings, limittions of this reported study limited our bility to ssess cncer risks. First, there were only 79 selected cncer cses. Despite the originl cohort hd reltively lrge smple size, the totl number of cncer cses is still smll, becuse of the lower cncer incidence rte. This smll smple size my limit our bility to detect the correltion between interested exposure nd selected cncers, due to the lck of power. Second, our study my be bised by some unmesured (for exmple, smoking nd drinking, obesity nd night shift work) nd unknown confounders, which further limited our bility to explore the true correltion between the interested cncers nd rdition, even we conducted sensitivity nlysis bsed on litertures. In conclusion, our present study found tht the long-term low dose occuptionl X-ry rdition ws ssocited with incresing cncer risk, especilly for brest cncer nd esophgel cncer. This indicted tht proper prevention nd intervention strtegies re needed to bring down the cncer risk mong helth cre workers DOI: Occuptionl Rdition Exposure nd Brest nd Esophgus Cnce Ris who exposed to occuptionl rdition. Further longfollow up time cohort study with completed individul dosimetry dt is clled to confirm the ssocition between occuptionl X-ry rdition exposure nd cncer risk. In ddition, mechnism studies tht focus on pthogenesis of rdition crcinogenesis effect, especilly on brest cncer nd esophgel cncer, nd interction reserch on rdition nd genetic fctors to cncer development re needed. Acknowledgements This work ws supported by Socil development projects nd Technology Support Progrm of Jingsu Province (NO.BE ), Twelfth Five Science nd Eduction Helth Project Innovtion Pltform for Public Helth Emergency Prepredness nd Response (NO. ZX201109) nd Ntionl helth industry reserch nd specil projects (NO ) References Andersson M, Engholm G, Ennow K, Jessen KA, Storm HH (1991). 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