Shift Work, Light-at-Night and Melatonin
USED IN: Night shift workers
THE GIST: Women exposed to artificial light during night-time hours, especially night shift workers, experience a higher incidence of breast cancer than other women. Scientists believe melatonin, a hormone that helps prevent tumor formation, offers the best explanation for the link, because the body produces high amounts of melatonin at night, and melatonin levels drop in the presence of light. In 2007, the International Agency for Research on Cancer concluded that shift work is “probably carcinogenic to humans,” and the World Health Organization deemed shift work a probable carcinogen.
State of the Evidence on Shift Work, Light-at-Night and Melatonin
In 2007, the International Agency for Research on Cancer concluded that shift work is “probably carcinogenic to humans,” based in large part on the growing association between shift working and increased incidence of breast cancer (Stevens, 2011; Straif, 2007).
Several occupational studies have demonstrated that women who consistently work night shifts have increased breast cancer risk, although not all reports have found evidence for this relationship. Methodological differences between studies, including definitions of “shift work” and “night,” as well as lack of consistent attention to confounding factors such as sleep deprivation or other lifestyle factors, may explain some of the differences in results between individual studies (Bonde, 2012; Costa, 2010; Stevens, 2011). Two major reviews of the literature, one examining only studies of night-shift nurses (Kolstad, 2008) and a second looking at studies of airline crews and other night-shift workers (Megdal, 2005), reached the conclusion that long-term experience (several years) in night-shift work increases risk for breast cancer.
Effects of night-shift work on breast cancer risk are greatest for women who worked rotating hours that include the overnight (as opposed to evening) shift and for those who work 12-hour shifts that frequently switch between day and night work, as compared to shorter work periods (Hansen, 2012). Risk of developing breast cancer increased for women who worked night shifts for more than 4.5 to 5 years, especially those who regularly engaged in night work for at least four years prior to their first pregnancy, therefore before their mammary systems had fully differentiated (Lie, 2011; Menegaux, 2012). These results are of concern, as about 15 percent of the U.S. workforce currently works at least some of the time on non-day shifts, and night-shift work disproportionately falls to African Americans (Costa, 2010).
The most thoroughly studied mechanism to explain the effects of night-shift work is called the light-at-night (LAN) hypothesis (Stevens, 2009). Increasing exposure to light, especially bright indoor lights, at times outside of normal daylight hours, decreases secretion of melatonin (Stevens, 2009). Melatonin is a hormone secreted by the pineal gland in response to decreases in ambient light. Normal high levels of melatonin at night are important for regulation of both pituitary and ovarian hormones (including the naturally secreted estrogen estradiol), and for suppressing the local production of estrogen resulting from the conversion of androgens into estrogen in the breast tumor cells (Cos, 2000; Knower, 2012).
Clinical studies have demonstrated that there is a decrease in the peak amount of melatonin secreted in women with metastatic cancer, as compared with healthy women, and larger tumors are associated with lower levels of melatonin (Cos, 2000). One proposed pathway by which reduced melatonin might affect breast cancer risk is enhancement of the production or secretion of estradiol and other ovarian hormones. However, one recent study that examined this possible link did not find a relationship between melatonin and sex hormone levels, once other factors like age, menstrual status and body mass index were factored into the analysis (Langley, 2012).
In support of the LAN hypothesis, blind women who are completely unable to perceive the presence of environmental light, and therefore have no daily decreases in melatonin levels, have a statistically significant lower risk of diagnosis of breast cancer than do blind women who do perceive light and have regular decreases in melatonin secretion over the normal 24-hour cycle. The former effect (no daily melatonin decreases) and its opposite in night-shift workers (no daily melatonin increases) both support the conclusion that the greater the secretion of melatonin, the lower the risk of breast cancer (Flynn-Evans, 2009).
In rodent models, higher levels of melatonin are associated with decreased incidence and size of mammary tumors, and when they do occur, the time before tumors developed is lengthened (Cos, 2000). In human mammary tumors that had been grafted into mice, perfusion of the tumors with blood taken from women at night (when melatonin is high) decreased proliferation and growth of mammary tumors, as compared to the use of samples collected during the day when melatonin levels are naturally lower (Blask, 2005).
Mechanistically, night pulses of melatonin enhance the activity of pathways that can prevent the development of cancer (Blask, 2009, 2011). These protective effects of melatonin are mediated by epigenetic changes in many of the genes involved in regulation of cell growth and proliferation, as well as in the synthesis and activation of the estrogen receptor (Zhu, 2011). Genes that are associated with the regulation of the daily melatonin cycle also regulate other pathways that may be involved in the development of breast cancer. Structural variation in one such gene, Per3, is associated with higher breast cancer rates in young women (Zhu, 2008). Per2, another gene associated with the control of daily rhythms, is also poorly regulated in many women with breast cancer, with normal structure and expression of this gene being associated with lower effectiveness of estradiol in altering cellular activity. In healthy cells, Per2 also may act directly as a tumor-suppressor gene, decreasing the activity of pathways associated with tumor formation (Gery, 2007).
The results of one recent study, designed to avoid skewing of results due to circadian rhythm (Grundy et al., 2009), directly measured light exposure as well as saliva and urine samples during both day and night periods of nurses who worked rotating shifts. When they worked at night, there was a slight inverse relationship between light intensity and melatonin levels, but the relationship disappeared when data for individuals from both phases of the rotating shift were analyzed together. These data suggest that this rotating pattern of two 12-hour days followed two 12-hour nights is not associated with substantial changes in melatonin levels and that other factors should be investigated (Grundy, 2012). Other possible consequences of shift work, including phase shift (shift in the timing of biological cycles), sleep disruption, lifestyle factors or decreased vitamin D production, may also be linked to increased cancer rates. They need to be studied as both single and possibly interacting factors in altered risk for developing breast cancer (Anjum, 2012; Fritschi, 2011).
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