The relationship between night work and breast cancer

Background Since the International Agency for Research on Cancer classified shift work that involves circadian disruption as “probably carcinogenic to humans,” there has been growing concern on the relationship between night work and breast cancer. In Korea, about 10–15% of workers are engaged in night-shift work, and breast cancer is one of the most common cancers in women. The purpose of this study was to review epidemiologic evidence on the relationship between night work and breast cancer. Methods We reviewed 21 original articles and 5 meta analyses on relationship between nightwork and breast cancer, and investigated the compensation criteria of Denmark. Results The association between breast cancer and night work has been reported by numerous epidemiologic studies, including cohort studies, case-control studies, and meta-analysis. However, a dose-response relationship has not clearly emerged among workers exposed to less than 20 years of night work. Conclusion Although there are some limitations to the epidemiological studies so far, further consideration of breast cancer cases in patients with high exposure to night work is needed to assess breast cancer as a work-related disease.

Shift work that involves circadian disruption has been classified as "probably carcinogenic to humans" (group 2A) by the International Agency for Research on Cancer (IARC) [1,2]. This decision, made in 2007, was based on sufficient evidence from experimental studies, but limited evidence from epidemiological studies. Since then, attention to breast cancer in night workers has been growing. In addition, in Korea, the number of cases of patients with breast cancer who have been exposed to night work and who thereby apply for compensation for breast cancer as an occupational disease is increasing. The International Labor Organization reports that more than two and a half billion people are engaged in shift work that involves night work [2].
Considering the higher incidence of breast cancer and prevalence of night work, it has become a major priority to examine evidence of night work-related breast cancer.
The aim of this study is to review epidemiologic evidence on the relationship between night work and breast cancer.

Methods
To review scientific evidence for a relationship between night work and breast cancer, we searched databases, including Ovid-MEDLINE, EMBASE, and PubMed, without date or language restrictions. We looked over the references from included studies and existing systematic reviews. We reviewed original articles including 7 cohort studies, 14 case-control studies and 6 meta analyses, and additionally, we attempted to obtain more information on each of the studies from systematic reviews, including the IARC monograph [2] and meta-analyses.
To understand the epidemiology of breast cancer, the status of night work in Korea, and compensation criteria for breast cancer in night workers in other countries, we reviewed government reports and various grey articles in addition to scientific articles.

Results and discussion
Incidence and risk factors for breast cancer According to Korea National Cancer Incidence Database, the crude incidence rate of breast cancer was 68.2 per 100,000 patients, which was the second most common cancer in women following thyroid cancer in 2013. The age standardized incidence rate of breast cancer per 100,000 patients increased from 12.5 in 1999 to 26.2 in 2013. The annual percentage change was calculated as 5.6%, which was also the second most rapid increase in cancer following thyroid cancer.
Risk factors of breast cancer include exposure to endogenous and exogenous female sex hormones, lifestylerelated factors such as drinking alcohol or having low levels of physical activity, and hereditary factors [3]. These established risk factors, however, contribute to only about 50% of the cases of breast cancer [4]. As a

Definition of night work
The meaning of the term "period of night work" varies from country to country. For example, definitions of night time range from 00:00 to 05:00 in France and the UK, between 20:00 and 06:00 in Belgium, and between 20:00 and 07:00 in Portugal [2]. According to the Labor Standard Act, night work in Korea is defined as work between 22:00 and 6:00. Generally, these definitions have been established for the regulation of work hours and compensation for work performed at non-standard working hours.
With the increasing amount of research on the health effects of night work, there is a need for a consistent definition of night work for purposes of epidemiologic investigation regarding the biological effects of disruption to circadian rhythms in night workers. Accordingly, the IARC assembled a workshop to discuss how "shift work" should be assessed. In this workshop, the IARC proposed which domains of non-day shifts and shift schedules should be examined, including (1) shift systems, (2) years on non-day shift schedules, and (3) shift intensity (i.e., time off between work days). The suggested definition of night work is "at least three hours of work between 00:00 and 05:00" [5].

Exposure to night work in Korea
Shift work that involves night work is essential for some public services, such as the provision of transportation, gas, electricity, and health care. Shift work is inevitable for the technological needs of some industries, including power plants, oil refineries, and the steel industry. In some cases, shift work is utilized to achieve higher productivity by operating machines for 24 h, typically in manufacturing industries. Several surveys include the investigation of night work in Korea. Night workers are estimated to comprise about 1.27 million workers (11.2% of total workers), 1.97 million workers (14.5%), and 1.34 million workers (10.2%) in the Survey Report on Labor Conditions by Employment Type (2010), the Korea National Health and Nutrition Examination Survey (2007-2009), and the Korean Labor and Income Panel Study (2008), respectively [6]. In these surveys, manufacturing industries (employing approximately 456,000 night workers), transportation (200,000 workers), and human health and social care activities (90,000-130,000 workers) are the main industries with significant proportions of night workers. In the Korean Working Condition Survey, 13.2% of the working population is recognized as night workers, with night work defined as at least two hours of work between 22:00 and 05:00. In this survey, among employed workers, 17.4% of male workers and 7.5% of female workers are night workers [7]. According to the fourth European working condition survey, the prevalence of shift work, including night work, was approximately 20% of employees in European countries in 2005 [2]. The prevalence of night work in Korea is lower than in European countries, with one potential reason for this being the extremely long working hours of Korean workers in general. Moreover, in 2012, the most common shift system in Korea was a two-team, 12-h shift system (prevalent in 60% of businesses with shift systems), followed by a two-team, 24-h shift system (in 14.6% of businesses) [8]. This means that the majority of night-shift workers in Korea are exposed to a higher intensity of night work or, in other words, a greater amount of night-shift work per month and year.

Biological plausibility
Numerous experimental studies support the notion that melatonin produces a potent circadian anti-cancer signal to cancer cells and protects normal cells from initiation [9]. In many experimental animal studies, an accelerated growth of mammary tumors has been found in response to exposure to constant light at night and/or in animals with a status of surgical pinealectomy [2]. During the natural darkness of night, pineal glands produce high levels of melatonin. However, reduced melatonin production has been reported among night-shift workers [10][11][12]. Consequently, the suppression of melatonin secretion by exposure to light during nighttime hours is surmised to be the main biological mechanism in the relationship between breast cancer and night work. In conclusion, the biological mechanism of the relationship between breast cancer and night work is explained with sufficient evidence from animal studies and experimental data.

Scientific evidence for the relationship between night work and breast cancer
The association between breast cancer and night work is reported in numerous epidemiologic studies, although the magnitude of association is not substantial. A doseresponse relationship is not clear among workers exposed to less than 20 years of night work. So far, the most significant limitations in epidemiological studies are different definitions of night work and varied exposure assessment across studies. Consistency in studies according to the objective assessment of exposure to night work is required.
Cohort studies (Table 1) An IARC evaluation from 2007 includes three cohort studies [13][14][15]. Two of the studies show an increased relative risk for breast cancer in the range of approximately 1.4-1.8 among female workers with more than 20-30 years of night work [13,14]. Since this IARC evaluation, four more cohort studies have been published. Generally, recent studies tend to obtain more detailed information on night work and possible confounders in comparison to older studies. Statistically significant risks are found in two of the four recent studies, with a range of approximately 1.8-2.0, in comparative analysis of groups exposed to extreme levels of night work [16,17]. The other two studies show no overall effects of night-shift work [18,19]. On the whole, four of seven cohort studies show increased risks of night work on breast cancer in sample populations of female night workers. Two studies with nurses' cohort showed significantly increased risk [13,14]. The other cohort studies were built with working population with various jobs [15][16][17][18][19].
Case-control studies ( Table 2) There are more case-control studies, including nested case-control studies, regarding the effects of night work on breast cancer than there are cohort studies on the topic. Including five studies evaluated by the IARC in 2007, six of fourteen case-control studies show significantly increased risks of cancer in high-exposure groups for night work [20][21][22][23][24][25]. Half of the studies were population based case-control studies, three studies were nested case-control studies in nurses' cohorts [22,23,26]. Two studies were nested case-control studies in cohorts of the other occupations including radio and telegraph operators and military employees [24,27]. In a study by Fritschi et al., only a lower-exposure group shows a significantly increased risk of cancer due to night work [28]. The other studies report non-significantly increased risks with odds ratios (ORs) not higher than 1.50, except for in two studies [26,27,[29][30][31][32][33].
Meta-analysis (Table 3) The first meta-analysis reported in 2005 includes six studies, and finds an increased risk for breast cancer among night workers (relative risk [RR], 1.51; 95% confidence interval: 1.36-1.68) [34]. After the IARC evaluation, four meta-analysis studies on breast cancer and night work were published in 2013. According to these studies, breast cancer risks due to night work are significantly increased, and the pooled RR ranges from 1.19 to 1.21 [35][36][37]. In two studies, the risk for breast cancer is estimated to increase 3-5% with every five years of exposure to night work [37,38]. A recent meta-analysis study didn't show effect of night work on breast cancer [39].

Criteria for compensation
In Denmark between 2007 and 2011, the work-relatedness of breast cancer with night work was recognized in 110 cases, and the patients were therefore eligible for compensation by the Danish National Board of Occupational Injuries [40]. The patients in these cases had occupational histories of more than 20 years of shift work that involved night work more than once a week. However, the Danish National Board of Industrial Injuries and the Occupational Diseases Committee reported a change in practice for claims regarding breast cancer and night-shift work in 2013. Following the new criteria, cases with at least 25 years of regular night-shift work may be submitted to the Occupational Diseases Committee for consideration of provision of worker compensation [41]. Except in Denmark, it is difficult to find a country in which breast cancer-related night work is officially compensated.

Conclusions
Breast cancer in patients with high exposure to night work should be understood to be an occupational disease, and patients should be eligible for workers' compensation, as in Denmark. In Korea, general working hours are longer and night shifts for shift workers are more frequent than in European countries. Therefore, various factors, such as total working hours, the frequency of night work, work schedules (including rotating schedules and rest periods after night shifts), and co-exposure to other occupational carcinogens additional to years of employment in non-day shift work must be considered. Furthermore, restrictions on the frequency of night shifts or exposure periods to night work might be considered in order to reduce the risk of breast cancer among night workers in Korea.