Night Work and Breast Cancer Risk Among Norwegian Nurses: Assessment by Different Exposure Metrics

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1 Amerian Journal of Epidemiology Advane Aess published Marh 31, 2011 Amerian Journal of Epidemiology ª The Author Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg Shool of Publi Health. All rights reserved. For permissions, please DOI: /aje/kwr014 Original Contribution Night Work and Breast Caner Risk Among Norwegian Nurses: Assessment by Different Exposure Metris Jenny-Anne S. Lie*, Helge Kjuus, Shan Zienolddiny, Aage Haugen, Rihard G. Stevens, and Kristina Kjærheim * Correspondene to Jenny-Anne S. Lie, National Institute of Oupational Health, P.O. Box 8149, N-0033 Oslo, Norway ( Initially submitted August 4, 2010; aepted for publiation January 11, Assoiations between night work and breast aner risk were investigated in a nested ase-ontrol study within a ohort of 44,835 Norwegian nurses. A total of 699 (74%) of the live ases diagnosed in and 895 (65%) ontrols, aner free at the time of sampling, were interviewed about work history and potential risk fators. The odds ratios for risk of breast aner in relation to different exposure metris were estimated by multivariate unonditional logisti regression models. No inrease of risk was found after long duration of work by nurses working 3 night shifts per month. Small, nonsignifiantly inreased risks were observed for exposure to 30 years in hospitals or other institutions (odds ratio (OR) ¼ 1.1), 12 years in shedules inluding night work (OR ¼ 1.3), 1,007 night shifts during the lifetime (OR ¼ 1.2), and lifetime average number of 4 night shifts per month (OR ¼ 1.2). Nonsignifiantly inreased risks of breast aner were observed in nurses who worked 5 years with 4 (OR ¼ 1.4) and 5 (OR ¼ 1.6) onseutive night shifts. Signifiantly inreased risks were seen in nurses who worked 5 years with 6 onseutive night shifts (OR ¼ 1.8, 95% onfidene interval: 1.1, 2.8). The results suggest that risk may be related to number of onseutive night shifts. breast neoplasms; ase-ontrol studies; hronobiology phenomena; Norway; nurses; risk Abbreviations: CI, onfidene interval; OR, odds ratio. Breast aner is the most ommon aner in women in Western soieties. Shift work, implying exposure to light at night and the subsequent redution in the synthesis of the hormone melatonin, has been suggested as a ontributing ause of this aner (1). In 2007, the International Ageny for Researh on Caner lassified shift work that involves disruption of iradian rhythms as a probable human arinogen, 2A (2), on the basis of limited evidene from epidemiologi studies and suffiient evidene from animal models. The inonsistent results from the epidemiologi studies might partly be due to different designs and to shortomings, suh as rude assessment of shift and night work harateristis and inomplete adjustment for onfounding fators. Previous studies have haraterized night work mainly by duration of work in jobs inluding night shifts. Studies onsidering additional fators haraterizing shift systems, suh as length of shift yle, diretion of shift yle, start time of the work shifts, and number of nights worked in suession, have been requested (3). The aspets of night work that might be assoiated with breast aner risk have not been suffiiently understood. It has been hypothesized, however, that night work may influene aner risk through sleep deprivation, iradian disruption, and depression of the hormone melatonin through exposure to light at night. Work shedules with longer sequenes of onseutive night shifts inrease iradian desynhronization (3). Some studies indiate that nurses have an inreased risk of breast aner (4 6). The objetive of the present study, whih was based on a Norwegian ohort of nurses (5), was to examine the relation of shift work and breast aner risk, inluding detailed evaluation of different exposure metris of night-shift work. 1

2 2 Lie et al. MATERIALS AND METHODS Study population A ohort of 49,402 female nurses who graduated from a 3-year nursing shool between 1914 and 1985 was established in 2004, on the basis of information from the Norwegian Board of Health s registry of nurses, as has been desribed in detail previously (5). A nested ase-ontrol study was arried out within this ohort. First-ourrene breast aner ases were identified by linkage to the Caner Registry of Norway by the 11-digit personal identifiation number given to all Norwegians alive in 1960 or later. The Caner Registry of Norway has virtually omplete reords of all individual ases of aner in the Norwegian population sine January 1, 1953 (7). The oding of aner is based on a modified version of the International Classifiation of Diseases, Seventh Revision (ICD-7), until 1993 and from that time forward on the International Classifiation of Diseases for Onology, Seond Edition (ICD-O-2). Cases were inluded if diagnosed during the period from January 1990 through Deember 2007, aged years at diagnosis, and alive by February Of the 1,132 ases diagnosed in , 943 were alive and inluded in the study. For eah diagnosti year, ases were grouped into eight 5-year age strata (35 39, 40 44,..., 65 69, and years), and the proportion in eah stratum was alulated. Controls were frequeny mathed within eah 5-year age stratum for eah diagnosti year (1990, 1991,..., 2006, 2007) among the nurses in the ohort without breast aner prior to that speifi year and alive by February 2009 (i.e., aording to the inidene density method). For eah diagnosti year, 50% more ontrols than ases were seleted in eah age stratum. The study was approved by the Norwegian Data Inspetorate and the Regional Committee for Medial and Health Researh Ethis. Data olletion Information about the study was first published in the journal of the Nurses Assoiation of whih most nurses (>85%) are members. In order to minimize the risk of reall bias, (e.g., that the ases might exaggerate their shift work experiene ompared with the ontrols), the study was designed to investigate a broader spetrum of workrelated fators possibly related to breast aner risk. A few weeks before the telephone interviews started, all ases and ontrols reeived an information letter, inluding a delaration-of-onsent form and a heklist for work history. All women who had ever held a job as a nurse during at least 1 year were requested to partiipate in a telephone interview. From April to June 2009, trained interviewers at Statistis Norway interviewed all women who had given a written or an oral onsent. Interviewers did not have a priori information about the ase-ontrol status of the nurses. They used a strutured questionnaire that inluded detailed questions on work and other known or potential breast aner risk fators that might onfound the assoiation between night work and breast aner risk. Lifetime oupational history inluded information on years of starting and ending employment for eah job held longer than 1 year, type of work site (hospital, other institution, others), whether performing radiographi proedures (no, sporadi performane of radiographi proedures, daily performane of radiographi proedures), and type of work shedule (only days, only nights, both days and nights). A night shift was defined as a shift that lasted from at least 12 PM until 6 AM, alhough the shift may start earlier or end later. This is the normal night shift in Norway. The number of night shifts per month and the number of onseutive night shifts were asked for jobs inluding night work. Work history and other time-related variables were trunated at the year of diagnosis for the ases and year of seletion for the ontrols and hereafter alled year of diagnosis for both ases and ontrols. Twelve nurses who had never held a job as a nurse for as muh as 1 year were exluded. Altogether, 74% of the primary breast aner ases identified and alive (699/943) and 65% of the ontrols (895/1,384) were interviewed and inluded in the study. Assessment of night work Different exposure metris of night work were omputed on the basis of work history (Table 1). If nothing else is stated, the term night work in this study inludes working periods from rotating, as well as permanent, night shedules and inludes the work of permanent night workers. To evaluate the influene of permanent night work, we performed separate analyses, exluding nurses who worked only at night as permanent night workers (11%); these odds ratios were then ompared with the overall odds ratios when inluding all night workers, in order to evaluate the differene. The average number of night shifts per month was imputed for jobs reported to inlude night shifts if the average number was missing (10% of night-shift jobs) or for jobs where the reported average number exeeded 16 (1% of night-shift jobs). For imputation, we applied the average number of night shifts per month in jobs that started during the same 5-year period (before 1960, ,..., , 2000 and after) and in the same kind of work site (hospital, other institution, others). The imputed number of night shifts per month varied from 4.5 to 7.0. The referene ategory, in all but one analysis, onsists of nurses who never worked at night after graduation from the nursing shool. However, all women in this study had some exposure to night work during the 3 years at a nursing shool. Confounder assessment The following ovariates were evaluated as possible onfounders: age at menarhe, parity, breast aner in mother/ sister, use of oral ontraeptives, hormonal treatment during the reent 5 and reent 2 years before diagnosis, body mass index at age 18 years and time of diagnosis, weight gain >10 kg from age 18 years to diagnosis, age at diagnosis, period of diagnosis, alohol onsumption and tobao use, and duration of daily, oupational exposure to x-rays. A variable was inluded as a onfounder if the hi-square test showed an assoiation with night work, or if inlusion of the variable in the analysis hanged the risk estimate by 10% or more.

3 Night Work, Breast Caner, and Norwegian Nurses 3 Table 1. Names and Definitions of Seleted Exposure Metris of Night Work for Norwegian Nurses, Inluding 699 Breast Caner Cases Diagnosed in and 895 Controls Name of Exposure Metri Duration of employment in hospitals or other institutions Duration of work in shedules inluding 3 night shifts per month Duration of work in shedules inluding night work Cumulative no. of lifetime night shifts Lifetime average no. of night shifts per month Duration of work in shedules inluding a minimum of 3 7 onseutive night shifts Definition Sum of years spent in suh institutions a Sum of years spent in jobs inluding a minimum of 3 night shifts per month Sum of years spent in jobs inluding either permanent night work or rotating night shifts Sum over all jobs (no. of years spent in a job inluding night work multiplied by 12 months and by average no. of night shifts per month) Cumulative no. of lifetime night shifts divided by total no. of months of employment For nurses who ever worked a minimum of 3 7 onseutive night shifts for <5 years and 5 years b a Surrogate measure used in a previous study of Norwegian nurses (9). b The remaining nurses were ategorized aording to ever or never having worked night shifts. Ten nurses reported age at menopause lower than 30 years. For 5 of them, the age at menopause was altered to the reported year of starting postmenopausal hormones. For the remaining 5 nurses, age at menopause was oded as missing. Of 36 nurses who did not report age at menopause, 11 nurses aged 60 years at the time of diagnosis were ategorized as postmenopausal. The year of starting or stopping was missing for 13 jobs but was imputed for 8 of these jobs, on the basis of the year of starting and stopping for the jobs preeding and following the atual one. Statistial methods The relative risks of breast aner were estimated as odds ratios with 95% onfidene intervals by using multivariable unonditional logisti regression models. In addition to the mathing variables age at diagnosis (35 49, 50 59, 60 69, years) and period of diagnosis ( , , , ), the ovariates parity (nulliparous, 1 2, 3 hildren), breast aner in mother and/or sister (no/yes), and alohol onsumption at the time of diagnosis (<2 times per week, 2 times per week) were entered in the final model. Adding other variables did not lead to substantial hanges in the risk estimates. When ategorizing the ontinuous variables duration of work in shedules inluding night work and umulative number of lifetime night shifts, we hose the third quartile among the ontrols (i.e., 12 years, 1,007 nights) as the utoff point for the highest exposure ategory. For the other variables, the ut-off point of the highest ategory was hosen to seure a reasonable number of observations in that ategory. Potential differenes by time and life periods were evaluated by restriting exposure to the time period before 1970 and before age 40 years. As some studies have reported different risks for pre- and postmenopausal women (8), separate analyses were made for the postmenopausal group. Furthermore, analyses inluding only reently diagnosed ases from 2004 to 2007 were performed, to evaluate any effet of exlusion of deeased ases. Two-sided P values of less than 0.05 were onsidered to indiate statistial signifiane. Trend tests were performed on the basis of ategorial lassifiation. All statistial analyses were arried out by using STATA, release 11, statistial software (StataCorp LP, College Station, Texas). RESULTS Table 2 shows the distribution of established and possible risk fators by ase-ontrol status. Previously identified risk fators for breast aner are onfirmed, for example, early menarhe, a lower number of hildbirths, breast aner in mother or sister, and hormonal treatment use within the reent years before diagnosis. Sixty-seven perent of the ases and 66% of the ontrols were postmenopausal at the time of diagnosis. The average number of jobs and of jobs involving night work was 4.8 and 2.0, respetively, among the ases and 4.5 and 1.9 among the ontrols. The prevalene of ever having worked a night shift was 85% in ases and 84% in ontrols. Results from multivariate regression analyses of 4 previously used exposure metris (8 11) adjusted for age and time of diagnosis are presented in Table 3, with and without adjustment for parity, family history of breast aner, and alohol onsumption. A nonsignifiant dereased risk was observed in the highest exposure group of duration of work in shedules inluding 3 night shifts per month (odds ratio (OR) ¼ 0.8). Odds ratios from 1.1 to 1.3 were observed in the highest exposure ategory for the other exposure metris in that table, after adjustment for all potential onfounders. Imputation for missing values of average monthly number of night shifts resulted in slightly lower estimates as ompared with no imputation. No signifiant trend was observed by inreasing exposure in any of these analyses. Table 4 displays the risk estimates for breast aner by duration of work in shedules inluding a minimum number of 3 7 onseutive night shifts. Signifiantly inreased odds ratios were observed among nurses who worked a minimum of 5 years in shedules with 6 (OR¼ 1.8) and 7 (OR ¼ 1.7) onseutive night shifts, respetively. A

4 4 Lie et al. Table 2. Charateristis of Female Norwegian Nurses, Inluding 699 Breast Caner Cases Diagnosed in and 895 Controls Charateristi Cases Controls Mean (SD) % Mean (SD) % P Value Age at stop time, years a 54.4 (7.7) 54.5 (7.9) 0.82 b Menarhe before age 12 years Age at menarhe, years 13.5 (1.4) 13.3 (1.3) 0.03 b Nulliparous No. of hildren 2.4 (0.9) 2.6 (1.04) 0.00 Age at first birth, years d 26.8 (4.2) 26.5 (4.0) 0.15 b Age at first birth 30 years d First degree family history of breast aner Ever use of oral ontraeptives or IUD Postmenopausal at stop time a Age at menopause 55 years e Age at menopause, years e 48.8 (4.8) 48.5 (4.7) 0.36 b Body mass index of 25 at age 18 years f Body mass index of 25 at stop time a,f Reent hormonal treatment use 5 years before diagnosis e Reent hormonal treatment use 2 years before diagnosis e Alohol onsumption at stop time a at least twie/week Ever smoked Daily exposure to x-rays Abbreviations: IUD, intrauterine devie; SD, standard deviation. a Stop time, year of diagnosis for ases and year of seletion for ontrols. b Derived from analysis of variane. Derived from the hi-square test. d Among the parous women only. e Among the postmenopausal women only. f Body mass index, weight (kg)/height (m) 2. signifiant, positive trend was found with inreasing duration in jobs inluding a minimum of 6 or 7 onseutive night shifts (P trend ¼ 0.01 and 0.05, respetively). The risk estimate for all nurses was found to be similar in the following subgroups, when using the exposure metri minimum 5 years with 6 onseutive nights : postmenopausal nurses (OR ¼ 1.8, 95% onfidene interval (CI): 1.1, 3.0); nurses, exluding permanent night workers (OR ¼ 1.6, 95% CI: 1.0, 2.6); and the ases diagnosed during (OR ¼ 1.7, 95% CI: 0.8, 3.8). Risk estimates did not hange when the exposure was limited to the time period before 1970 or age <40 years. DISCUSSION When applying different previously used exposure metris for night work, we found that estimates showed a slight (10% 30%) but nonsignifiant inrease of risk for breast aner in the highest exposure ategories. By using onseutive night shifts as the exposure parameter, we observed signifiantly elevated breast aner risks in the range of in nurses who worked 5 or more years in jobs inluding 6 onseutive night shifts, ompared with nurses who never worked night shifts. To our knowledge, this is the first study to reveal an assoiation between a higher number of onseutive night shifts and breast aner risk. The study is based on a large ohort of nurses eduated from 1950 to 1984 and inludes a high number of breast aner ases. Compulsory reporting of all aner ases to the national aner registry made it possible to identify all breast aner ases in the ohort for the period However, several validity questions have to be addressed. The study is based on living, prevalent ases. Seletion bias might affet the results when deeased ases are exluded. However, a subanalysis of ases diagnosed in showing approximately the same estimates as for all suggests that it is unlikely that the inlusion of long-term survivors has biased the results. Although the partiipation rate is onsidered fairly high in both groups, differential reruitment between groups, together with the 9% higher response rate among ases than ontrols, might also have ontributed to seletion bias. Responders and nonresponders were, however, similar with respet to soioeonomi status, oupation, age distribution, and sex. A detailed oupational history with information on lifetime night work experiene and data on well-known and suspeted risk fators was obtained by telephone interviews.

5 Night Work, Breast Caner, and Norwegian Nurses 5 Table 3. Odds Ratios of Breast Caner for Norwegian Nurses, Inluding 699 Breast Caner Cases Diagnosed in and 895 Controls by Seleted Exposure Metris Exposure Metri No. of Cases No. of Controls OR a 95% CI OR b 95% CI Duration of employment in hospitals and other institutions <1 year years , , years , , years , , 2.0 P trend Duration of work in shedules inluding 3 night shifts per month Never night work Never 3 nights per month , , years , , years , , years , , 1.4 P trend Duration of work in shedules inluding night work Never night work years , , years , , 1.8 P trend Cumulative no. of lifetime night shifts Never night work <1,007 night shifts , , 1.6 1,007 night shifts , , 1.7 P trend Lifetime average no. of night shifts per month Never night work <4 night shifts per month , , night shifts per month , , P trend Abbreviations: CI, onfidene interval; OR, odds ratio. a Odds ratios adjusted for age (35 49, 50 59, 60 69, years) and period of diagnosis ( , , , ). b Odds ratios adjusted for age (35 49, 50 59, 60 69, years), period of diagnosis ( , , , ), parity (0, 1 2, 3 hildren), family history of breast aner in mother or sister (no/yes), and frequeny of alohol onsumption at time of diagnosis (maximum 1 time/week, 2 times/week). Calulated by using the ategory number of the exposure variable as a ontinuous variable. Suh interview data are partiularly subjet to reall bias. In Norway, over the last years, there has been an inreasing publi onern about night work and breast aner risk. In order to minimize the risk of ases and ontrols reporting exposures differently on the basis of their status as either ase or ontrol, we designed the study to investigate a broader spetrum of work-related fators possibly related to breast aner risk. In addition, no differene was found between ases and ontrols on duration in jobs reported to inlude night work but where number of onseutive night shifts was missing. Still, we annot exlude that information bias may have ontributed to the results observed. A variety of potential onfounders were identified in the present study, among them ionizing radiation. However, no major onfounding was observed by oupational exposure to x-rays or by any other variable. By studying one profession only, the problem of other potential onfounders was redued. In the final models, age, period of diagnosis, parity, family history of breast aner, and alohol onsumption were inluded as ovariates. Among the validity issues addressed, we onsider potential reall bias as the greatest threat to the assoiations observed in this study. On the other hand, nondifferential mislassifiation of exposure, together with the lak of a ompletely unexposed referene ategory, may have biased risk estimates toward unity. Previous studies evaluating the assoiation between breast aner and night work differ with respet to lassifiation of the duration of night work, with utpoints for the highest ategories varying from 3.1 to 30 years. In 5 studies (8 12), long duration of night work was assoiated with

6 6 Lie et al. Table 4. Odds Ratios of Breast Caner for Norwegian Nurses, Inluding 699 Breast Caner Cases Diagnosed in and 895 Controls, by Exposure to Night Work, Expressed as Duration of Work Inluding a Minimum of 3 7 Conseutive Night Shifts Exposure Metri No. of Cases No. of Controls OR a 95% CI OR b 95% CI Duration of work in shedules inluding a minimum of 3 onseutive night shifts Never worked 3 onseutive nights , , 2.1 Worked <5 years with 3 onseutive nights , , 1.6 Worked 5 years with 3 onseutive nights , , 1.5 P trend Duration of work in shedules inluding a minimum of 4 onseutive night shifts Never worked 4 onseutive nights , , 1.5 Worked <5 years with 4 onseutive nights , , 1.6 Worked 5 years with 4 onseutive nights , , 1.9 P trend Duration of work in shedules inluding a minimum of 5 onseutive night shifts Never worked 5 onseutive nights , , 1.5 Worked <5 years with 5 onseutive nights , , 1.7 Worked 5 years with 5 onseutive nights , , 2.4 P trend Duration of work in shedules inluding a minimum of 6 onseutive night shifts Never worked 6 onseutive nights , , 1.5 Worked <5 years with 6 onseutive nights , , 1.7 Worked 5 years with 6 onseutive nights , , 2.8 P trend Duration of work in shedules inluding a minimum of 7 onseutive night shifts Never worked 7 onseutive nights , , 1.5 Worked <5 years with 7 onseutive nights , , 1.6 Worked 5 years with 7 onseutive nights , , P trend Abbreviations: CI, onfidene interval; OR, odds ratio. a Odds ratios adjusted for age (35 49, 50 59, 60 69, years) and period of diagnosis ( , , , ). b Odds ratios adjusted for age (35 49, 50 59, 60 69, years), period of diagnosis ( , , , ), parity (0, 1 2, 3 hildren), family history of breast aner in mother or sister (no/yes), and frequeny of alohol onsumption at time of diagnosis (maximum 1 time/week, 2 times/week). Calulated by using the ategory number of the exposure variable as a ontinuous variable. inreased risks. Shernhammer et al. (8) studied the assoiation between night work and breast aner among nurses partiipating in the Nurses Health Study and followed up in Based on a question in 1988 rergarding how many years in total the woman had worked rotating night shifts with at least 3 nights per month, a signifiant inrease of risk (relative risk ¼ 1.36) was found for the longest exposure (30 years), ompared with never working suh shifts. In the Nurses Health Study II (12), premenopausal nurses who reported 20 years of rotating night shifts showed a signifiant inrease of breast aner risk (relative risk ¼ 1.79) ompared with nurses who never worked night shifts. In a German population-based ase-ontrol study, Pesh et al. (10) found a nonsignifiant inrease (OR ¼ 1.66) of risk among women employed 20 years in shift work. In a previous study of Norwegian nurses (9), a signifiantly elevated risk was found among nurses who had worked for 30 years or more in hospitals and other

7 Night Work, Breast Caner, and Norwegian Nurses 7 institutions (OR ¼ 2.21, 95% CI: 1.10, 4.45). This result was not repliated in the present study, when applying the same surrogate measure of exposure (OR ¼ 1.1, 95% CI: 0.6, 2.0). The ases of the 2 studies were, however, diagnosed at different time periods: during in the former study versus in the present. Thus, the different results may be due to the progressive hange of shift systems observed in many ountries in reent deades, from traditionally slow-rotating to faster-rotating systems (3). Prior to 1970, shift shedules for Norwegian nurses often inluded 7 14 onseutive night shifts in addition to day shifts, and night shifts of 12 hours duration were quite ommon. In the present study, no signifiant assoiation was found between duration of work inluding night shifts (OR ¼ 1.3 for 12 years inluding night work; OR ¼ 0.8 for 30 years of work in shedules inluding 3 night shifts per month). The range of years worked for 5 years in shedules with both 6 and 7 onseutive night shifts was 5 39 years (mean, 11.4 years for 6; mean, 11.0 years for 7 onseutive night shifts). In a reent populationbased ohort study of Chinese women (11), no inrease or a nonsignifiantly dereased hazard ratio of breast aner was found by duration of night work. As ethni variability has been disovered in lok gene variants (13), potentially geneti differenes in response to night shift work may explain some of the differene, in addition to the differenes in diet and reprodutive fators (11). Risk estimates by the exposure metri, umulative number of lifetime night shifts, were slightly but nonsignifiantly elevated in the present study (OR ¼ 1.2) among nurses who worked 1,007 night shifts. Compared with women never working at night, Pesh et al. (10) observed an odds ratio of 1.73 (95% CI: 0.71, 4.22) in women who worked 807 night shifts, and Pronk et al. (11) found a risk ratio of 0.7 (95% CI: 0.4, 1.1) in women exposed to >1,632 night shifts. Using the exposure ategories of Pesh et al. (10) and Pronk et al. (11) in the present study resulted in an odds ratio of 1.2 (95% CI: 0.9, 1.7) among Norwegian nurses exposed to 807 night shifts and an odds ratio of 1.3 (95% CI: 0.9, 1.9) among Norwegian nurses exposed to >1,632 night shifts (not shown). The inonsistent findings from these studies may be explained by different study designs, variation in definition and distribution of night shift work (depending on ountry and period), and unstable estimates in some studies due to a low number of ases. In the present study, risk estimates by lifetime average number of night shifts per month were slightly but nonsignifiantly elevated in exposed nurses ompared with nurses who never worked at night. The 2 exposure metris, umulative number of lifetime night shifts and lifetime average number of night shifts per month, were both based on information on average number of night shifts per month for eah job. Beause the length of a nurse s work yle usually exeeds 4 weeks, the monthly average number of night shifts may have been inorretly reported and estimated. In the present study, the number of onseutive night shifts was probably easier to reall than the number of night shifts per month. A high number of nights worked in suession, usually in addition to morning and afternoon shifts, was probably exhausting, with great impliations for soial life. Thus, the number of onseutive night shifts is presumably the most informative exposure metri in this study. Beause nurses often hange their shift shedules during their working life beause of hanging jobs or organizational hanges, duration of work in shedules with a minimum number of onseutive nights seems to be the most optimal exposure metri, inluding information on both intensity and duration of night work. The observed signifiant inrease of risk in the highest exposed group (OR ¼ 1.81 for 5 years in shedules inluding 6 onseutive night shifts), ombined with a positive trend, supports an assoiation between night work and breast aner. Slowly rotating night shift systems inlude longer sequenes of onseutive night shifts, thereby ausing inreased iradian misalignments or desynhronization of many biologi funtions, inluding sleep (3). The more suessive nights of work, the more disruption of sleep (14). In summary, this study suggests that breast aner risk may be related to the number of onseutive night shifts. Beause this is the first study to assess the impat of number of onseutive night shifts, the assoiation needs to be repliated in other studies. In addition to epidemiologi studies, further researh is needed to establish the pathways and mehanisms mediating the possible effets of shift work in breast aner risk, inluding individual fators suh as geneti variations of lok genes. ACKNOWLEDGMENTS Author affiliations: Department of Oupational Mediine and Epidemiology, National Institute of Oupational Health, Oslo, Norway (Jenny-Anne S. Lie, Helge Kjuus); Setion of Toxiology, Department of Chemial and Biologial Work Environment, National Institute of Oupational Health, Oslo, Norway (Shan Zienolddiny, Aage Haugen); Department of Community Mediine and Health Care, University of Connetiut Health Center, Farmington, Connetiut (Rihard G. Stevens); and Department of Etiologial Researh, the Caner Registry of Norway, Oslo, Norway (Kristina Kjærheim). This work was supported by a grant from the Researh Counil of Norway (ontrat /V50) and by grants from the South-Eastern Norway Regional Health Authority (3b-107) and the Norwegian Caner Soiety (PK ). The authors thank Ivar Martinsen, the Caner Registry of Norway, for data preparation and management. Conflit of interest: none delared. REFERENCES 1. Stevens RG. Light-at-night, iradian disruption and breast aner: assessment of existing evidene. Int J Epidemiol. 2009;38(4): Stevens RG, Hansen J, Costa G, et al. Considerations of iradian impat for defining shift work in aner studies:

8 8 Lie et al. IARC Working Group Report. Oup Environ Med. 2011; 68(2): Costa G, Haus E, Stevens R. Shift work and aner onsiderations on rationale, mehanisms, and epidemiology. Sand J Work Environ Health. 2010;36(2): Lie JA, Kjaerheim K. Caner risk among female nurses: a literature review. Eur J Caner Prev. 2003;12(6): Lie JA, Andersen A, Kjaerheim K. Caner risk among 43,000 Norwegian nurses. Sand J Work Environ Health. 2007; 33(1): Pukkala E, Martinsen JI, Lynge E, et al. Oupation and aner follow-up of 15 million people in five Nordi ountries. Ata Onol. 2009;48(5): Larsen IK, Småstuen M, Johannesen TB, et al. Data quality at the aner registry of Norway: an overview of omparability, ompleteness, validity and timeliness. Eur J Caner. 2009; 45(7): Shernhammer ES, Laden F, Speizer FE, et al. Rotating night shifts and risk of breast aner in women partiipating in the Nurses Health Study. J Natl Caner Inst. 2001;93(20): Lie JA, Roessink J, Kjaerheim K. Breast aner and night work among Norwegian nurses. Caner Causes Control. 2006; 17(1): Pesh B, Harth V, Rabstein S, et al. Night work and breast aner results from the German GENICA study. Sand J Work Environ Health. 2010;36(2): Pronk A, Ji BT, Shu XO, et al. Night-shift work and breast aner risk in a ohort of Chinese women. Am J Epidemiol. 2010;171(9): Shernhammer ES, Kroenke CH, Laden F, et al. Night work and risk of breast aner. Epidemiology. 2006;17(1): Ciarleglio CM, Rykman KK, Servik SV, et al. Geneti differenes in human iradian lok genes among worldwide populations. J Biol Rhythms. 2008;23(4): Sallinen M, Keklund G. Shift work, sleep, and sleepiness differenes between shift shedules and systems. Sand J Work Environ Health. 2010;36(2):

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