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Night shift work is associated with increased risk of several cancers, but the risk of skin cancer among night shift workers is unknown. We documented 10799 incident skin cancers in 68336 women in the Nurses’ Health Study from June 1988 to June 2006 and examined the relationship between rotating night shifts and skin cancer. We used Cox proportional hazard models, adjusted for confounding variables (phenotypic and established risk factors of skin cancer), and performed stratified analysis to explore the modifying effect of hair color. Working 10 years or more on rotating night shifts was associated with a 14% decreased risk of skin cancer compared with never working night shifts (age-standardized incidence rate: 976 per 100000 person-years (PY) vs 1070 per 100000 PY, respectively; adjusted hazard ratios = 0.86, 95% confidence interval = 0.81 to 0.92, Ptrend < .001). This association was strongest for cutaneous melanoma; working 10 years or more of rotating night shifts was associated with 44% decreased risk of melanoma, after adjustment for melanoma risk factors (age-standardized incidence rate: 20 per 100000 PY vs 35 per 100000 PY, respectively; adjusted hazard ratios = 0.56, 95% confidence interval = 0.36 to 0.87, Ptrend = .005). Hair color, a surrogate for an individual’s susceptibility to skin cancer, was a statistically significant effect modifier for the observed associations; darker-haired women had the lowest risk (Pinteraction = .02).
Night shift work has been associated with increased risk of several cancers, but the risk of skin cancer for shift workers is unknown.
A total of 10799 incident cases of melanoma and basal cell and squamous cell carcinoma were documented among women in the Nurses’ Health study between June 1988 and June 2006. Women who worked in night shifts for 10 years or more were compared with those who worked in night shifts for shorter periods or never.
Working 10 years or more on rotating night shifts was associated with a statistically significantly decreased risk of skin cancer. Women with darker hair color, a surrogate for an individual’s susceptibility to skin cancer, had the lowest risk.
The inverse association between the risk of skin cancer and both longer durations of night shift work and darker hair color suggests that both genetic and environmental factors may act in melatonin suppression during night work.
The question about shift work was asked only once and may have been misclassified in some instances. Details of ultraviolet light exposure could not be considered and may be confounding variables.
From the Editors
Melatonin has antimutagenic and oncostatic activity, and light exposure during night shift work can induce desynchrony in circadian rhythms and reduced melatonin production (1,2). Shift work is therefore thought to have important health impacts (3), and a growing body of literature provides evidence to link night shift work with increased risk of several malignancies, including breast (4–13), endometrial (14), prostate (15,16), and colorectal cancers (17), and non-Hodgkin lymphoma (18). With the exception of Parkinson disease (PD) (19), night shift work has also been associated with increased risk of chronic nonmalignant diseases such as gastrointestinal disorders, cardiovascular disease, and diabetes (3).
To examine whether night shift work is associated with an increased risk of skin cancers, as hypothesized by Kvaskoff and Weinstein (20), we used data from the Nurses’ Health Study (21–23), a large prospective study of nurses in the United States. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard models. To examine the proportional hazard assumption, we constructed interaction terms between rotating night shift work and calendar year and used likelihood ratio tests to assess the significance of these interaction terms. We performed stratified analysis to explore the modifying effect of hair color—as a proxy for phenotypic predisposition of skincancer—on the association between night shift work and skin cancer. To obtain P values for the tests of interaction, we performed likelihood ratio tests. All statistical tests were two-sided.
In 1982, we collected information from Nurses’ Health Study participants on natural hair color at age 20, history of painful sunburn that blistered, childhood or adolescent tendency to tan after repeated sun exposure, and childhood or adolescent tendency to burn after 2 hours or more of sunlight exposure. The information on number of melanocytic nevi larger than 3 mm in diameter located on limbs was collected in 1986. First-degree family history of melanoma (parents and siblings) was asked in 1982 and updated in 1992, 1996, and 2000. In a 2008 questionnaire, we asked how many hours per week (2–5, 6–10, and ≥11) were spent outdoors in direct sunlight in the middle of the day in summer months, including work and recreation at different age intervals (25–35, 36–59, and ≥60 years), and educational levels (high school, college, and nursing school).
Among the 68336 women who formed the baseline population for this analysis, a total of 10799 incident cases of skin cancer were documented during 18 years of follow-up, comprising 9632 basal cell carcinoma (BCC), 849 squamous cell carcinoma (SCC), and 318 melanoma case patients (Supplementary Table 1, available online). Women who reported having melanoma, SCC, BCC, or any other cancer before 1988 were excluded. The analysis was restricted to non-Hispanic white women because the number of case subjects in the other racial/ethnic categories was small.
Higher duration of working rotating nightshifts was associated with a statistically significantly lower risk of skin cancer (Ptrend < .001) overall (Table 1). Women who had worked for more than 10 years on rotating night shifts had a 14% lower risk of skin cancer compared with never night shift workers (multivariable HR = 0.86, 95% CI = 0.81 to 0.92). The age-standardized incidence rates of skin cancer were 976 per 100000 person-years among those with 10+ years of rotating night shifts and 1070 per 100000 person-years among those who never workedrotating night shifts, translating into 8% fewer cases. When follow-up was restricted to 10 years (1988–1998), assuming a shorter induction period for skin cancer, results remained largely unchanged (multivariable HR = 0.90, 95% CI = 0.82 to 0.98, Ptrend = .02). When we examined the effect of night shift work on different types of skin cancer, although the risk for each skin cancer was reduced, the strongest association was observed for melanoma. Working 10 years or more of rotating night shifts was associated with a 44% decreased risk of melanoma, after adjustment for melanoma risk factors (multivariable HR = 0.56, 95% CI = 0.36 to 0.87, Ptrend = .005) (Table 1). The age-standardized incidence rates of melanoma were 20 per 100000 person-years among those with 10+ years of rotating night shifts and 35 per 100000 person-years among those who never worked rotating night shifts translating into 57% fewer cases.
As a phenotypic proxy for a woman’s predisposition to skin cancer, we stratified our analysis by natural hair color. The inverse association between 10 years or more of rotating night shift work and all skin cancers was strongest among women with black or dark brown hair color (Table 2), and the test for interaction was statistically significant (Pinteraction = .02). We observed no effect modification by sunlight exposure level at baseline geographic residence or body location of skin cancer (available for melanoma and SCC only).
Our findings are in contrast with evidence from previous studies (4–18,27), which suggested that lower levels of melatonin among night shift workers attributable to longer duration of exposure to artificial light at night, could be responsible for the positive associations with the risk of cancers other than melanoma observed in these studies (1). Experimental studies provide strong evidence for some general oncostatic properties of melatonin both in vivo and in vitro (28). Melatonin, which is synthesized not only in the pineal gland but also in other locations such as the skin (29), has been reported to reduce the growth of cell lines of malignant melanoma as well as other tumors (29–36). However, effects may vary by melatonin concentration. In one study, low (or “physiological”) melatonin concentrations appeared to inhibit melanoma cell proliferation in vitro, whereas higher levels of melatonin had either no effect on melanoma cell growth or exerted stimulatory activity (30). In another study, pharmacological doses of melatonin were associated with increased melanoma cell proliferation, but lower doses had no (not even a protective) effect (37). Finally, nocturnal melatonin supplementation in mice that were exposed to constant light was associated with increased melanoma progression, whereas it had the opposite effect when administered under light–dark conditions (30). This last result supports the hypothesis that the effects of melatonin are dependent on photoperiod and time of day (physiologically higher levels at night), and genetic factors may also play a role in interindividual variation in absolute amount of physiological peak melatonin production during the night. Thus, although higher melatonin levels might be beneficial in individuals with stable circadian rhythms, in night workers, melatonin suppression may be more beneficial, perhaps especially among those with physiologically high peak melatonin production (which might be related to skin phenotype). There is some evidence suggesting that melatonin has an important role in hair physiology (38) and that dark hair is associated with higher tryptophan/melatonin levels (39). Another mechanistic explanation might pertain to melanin. Melatonin might be suppressed to a greater extent in those with high innate eumelanin levels if melatonin suppression were somehow associated with higher eumelanin activity (40).
To our knowledge, only one study to date, a Scandinavian register-based cohort study (41), has attempted to examine the risk of melanoma associated with shift work. That study, which did not report an association between night work and melanoma risk, was based on only 11 case subjects (41). Several studies of airline personnel reported a higher risk of melanoma related to this occupation (42,43), but whether the increased risk is more likely attributable to exposure to cosmic radiation, circadian disruption, or the lifestyle of airline personnel currently remains unclear (44).
Night shift workers have also been reported to be at higher risk of several nonmalignant chronic diseases, although PD has been an exception. Chen et al. (19) reported a 50% lower risk of PD among women who worked 15 years or more of rotating night shifts compared with those who never worked rotating night shifts (19). Notably, evidence has been accumulating to support a decreased risk of cancer among PD patients with the important exception of skin cancers, specifically melanoma (45,46). Gao et al. (47,48) reported a twofold increased risk of PD associated with fair hair color, a strong phenotypic risk factor of melanoma (47), and a family history of melanoma in a first-degree relative (HR = 1.85, 95% CI = 1.2 to 2.8) (48). Based on these findings, it appears possible that PD and melanoma share common genetic or environmental risk factors (49), hich might be influenced by circadian disruption (as encountered during night work).
Our study had several limitations. The question about shift work was asked only once and may have been misclassified in some instances; however, because of the prospective nature of our analyses, we expect any resulting bias only toward the null. Even though we adjusted for all known or suspected risk factors for skin cancer, the possibility for uncontrolled confounding remains. For example, a possible source of bias in our study was residual confounding as a result of nondifferential misclassification of variables related to ultraviolet light. However, in analyses stratified by residence, ultraviolet light exposure level at baseline, and by location of skin cancer, we found no important effect modification. Thus, actual sun exposure appears less likely to play a role in the observed inverse association between night shift work and skin cancer risk. The strengths of our study include large size, prospective nature, detailed information on location of skin cancers, and a detailed history of sun exposure in participants, as well as regularly updated information on confounders.
In conclusion, we found lower risks of skin cancer in women with longer durations of rotating night shift work. Because the risks of all three skin cancers that we examined (melanoma, SCC, and BCC) were lower, and no effect modification by history of sunlight exposure was apparent, the role of sun seems to be negligible in these associations. That the inverse association was strongest among women with dark hair raises the possibility for several mechanistic explanations, including a genetic component that may affect both the extent of melatonin suppression during night work and skin cancer risk.
National Institute of Health CA87969 (PI: Hankinson, S.E.,) and the Department of Dermatology, Brigham and Women’s Hospital.
The funders did not have any involvement in the design of the study; the collection, analysis, and interpretation of the data; the writing of the article; or the decision to submit the article for publication.
E. S. Schernhammer: funding, data collection, analysis, interpretation, and article preparation; P. Razavi: data analysis and article preparation; T. Y. Li: data analysis and article preparation; A. A. Qureshi: article interpretation and preparation; J. Han: data collection and analysis and article interpretation and preparation.
We are indebted to the participants of the Nurses’ Health Study for their dedication to this study. We thank the following state cancer registries for their help: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington, Wyoming.