Myths & Realities: Is Shiftwork Tumorgenic?

June 23, 2010

By David Ecker, MD

Faculty Peer Reviewed

Over the last several decades, Westernized countries have become 24-hour societies.  Approximately 21 million workers in the US are on non-standard work shifts, including almost 4 million on regular overnight shifts.[1] In 1972, Taylor and Pocock published a mortality study, in which they reported a significantly increased incidence of neoplasms in shift workers compared to the general population.[2] After several published cancer incidence studies, Kerenyi explicitly proposed that changes in light exposure could be an important etiologic factor in the rapid growth rate of human cancers in developed countries over the last century.[3]

Shift workers are exposed to artificial light during the traditional night while in the workplace.  This common occupational exposure has inspired several studies seeking to elucidate a connection between exposure to light at night and cancer.  Schernhammer published the first large, prospective study examining the link between night work and breast cancer.[4] They followed 78,562 pre- and postmenopausal women participating in the Nurses’ Health Study for 10 years.  They described an increase in both total breast cancer and estrogen receptor-positive breast cancer among nurses, who work on rotating night shifts at least three nights per month in addition to days and evenings in that month.  Specifically, they reported a 23% increased breast cancer risk in premenopausal women after 1-14 years of shiftwork and a 36% greater risk in postmenopausal women that worked more than 29 years on rotating night shifts.  At the same time, Davis published a retrospective case-control study describing an increased breast cancer risk in women who recalled working the graveyard shift at least some time in the 10 years prior to their breast cancer diagnosis.[5] Furthermore, that risk was augmented by more years of graveyard shifts worked.

In 2005, a systematic review and meta-analysis was performed in order to overcome incomplete adjustment for confounding factors and the overall small sample sizes of the studies that had reported a relationship between occupational exposure to light at night and breast cancer risk.[6] Of the 13 studies that met inclusion criteria, 7 studies examined flight attendants and 6 studied other forms of night work.  In pooled results, there was a statistically significant 48% increase in the risk of breast cancer among shift workers.  Separate analyses of both groups yielded nearly identical results; thus supporting the supposition that light exposure at night, regardless of occupation, increases the risk of breast cancer.  Subsequently, additional epidemiological studies demonstrated similar results.[7], [8]

As interest intensifies around a relationship between the disruption of normal circadian rhythm with the risk of developing cancer, epidemiologic studies are linking occupations characterized by night shiftwork with other types of cancer.  Excess prostate cancer has been reported in pilots, firefighters, and police.[9], [10] Additionally, Schernhammer reported that working a rotating night shift at least three nights per month for 15 or more years may increase the risk of colorectal cancer in women, with a longer extent of shiftwork associated with increasing risk.[11] The women in the Nurses’ Health Study had increased risks of cancer in the right colon, left colon, and rectum, when those cancers were considered individually.

In total, indirect evidence has emerged that associates the disruption of circadian clock activity with cancer in humans.  This has prompted a sizable amount of basic science research dedicated to investigating whether this disruption actually favors tumorgenesis on a molecular level.  Many elegant experiments have elucidated the “circadian photoreceptor” and have established the suprachiasmatic nucleus as the master circadian clock.  Additional experiments have shown that interlocking transcriptional networks autoregulate a large number of genes at distinct circadian phases.  Furthermore, gene expression can be shifted out of phase when animals experience a rapid shift in their light-dark cycle.[12]

Obviously this research could have dramatic implications for the workforce.  Light exposure at night would be the most common workplace carcinogen.  Would shift work require hazard pay?  Would insurance carriers alter their coverage?  Would the night workforce shrink?  Until conclusive data links light exposure at night to tumorgenesis, the unknown risks will leave shiftworkers in the dark.

Dr. Ecker is a Second Year Resident at NYU Langone Medical Center

Theresa Ryan, MD, Oncology Editor, Clinical Correlations

Commentary By: Theresa Ryan, MD, Oncology Editor Clinical Correlations

The above editorial concerning “Is Shiftwork Tumorgenic?” raises some interesting questions. The author has reviewed several retrospective studies that seem to suggest a relationship between shift work and malignancy. These studies have suggested various mechanisms for such a relationship, the most common being environmental lighting leading to a change in melatonin production, which in turn leads to a change in reproductive hormone levels; these in theory could stimulate the growth of hormone responsive tumors such as breast cancer.  Alternatively, this change in melatonin production could nonspecifically increase the rates of malignancy by altering other “oncostatic” mechanisms.  Thus, there is some biologic rationale to this theory; however the proposed mechanisms do not necessarily indicate an inciting mechanism. A secondary mechanism i.e. melatonin production becomes altered in established malignancy may also account for these measured changes.

As this question has wide-ranging implications for individuals who perform shift work, it is important to recognize the limitations of retrospective studies such as these. For one, they are dependent on a worker’s recall of duty hours. This may be subject to faulty recollection.  Another potential problem is confounding variables. One such variable would be the “unhealthy shift worker” effect i.e. individuals with less healthy lifestyle and lower socioeconomic status may be preferentially attracted to or more likely to consent to shift work. These factors are already known risks associated with malignancy.  For example, in the colorectal study, shift workers were of lower socioeconomic class, tended to be heavier and smoked more than the control group. Finally are the “unknown” confounders. It is certainly possible that other risk factors including unrecognized hormone and lifestyle factors associated with shift work are the driving cause behind malignancy rather than shift work in and of itself.  This remains an interesting question and as shift work continues to become a growing avenue of employment, it raises a responsibility in the medical community to answer this question.

References:

[1]McMenamin, TM.  A time to work: recent trends in shift work and flexible schedules.  Monthly Labor Review.  2007 Dec; 3-15.

[2]Taylor PJ, Pocock SJ.  Mortality of shift and day workers 1956-68.  Br J Ind Med.  1972; 29: 201-7.

[3]Kerenyi NA, et al.  Why the incidence of cancer is increasing: the role of ‘light polution’.  Med Hypotheses.  1990; 33: 75-8.

[4]Schernhammer ES, et al.  Rotating night shifts and risk of breast cancer in women participating in the Nurses’ Health Study.  J Natl Cancer Inst.  2001; 93(20): 1563-8.

[5]Davis S, et al.  Night shift work, light at night, and risk of breast cancer.  J Natl Cancer Inst.  2001; 93(20): 1557-62.

[6]Megdal SP, et al.  Night work and breast cancer risk: A systematic review and meta-analysis.  European J Cancer.  2005; 41: 2023-32.

[7]Schernhammer ES, et al.  Night work and risk of breast cancer.  2006; 17(1): 108-11.

[8]Davis S, Mirick DK.  Circadian disruption, shift work and the risk of cancer: a summary of the evidence and studies in Seattle.  2006; 17: 539-45.

[9]Band PR, et al.  Cohort study of Air Canada pilots: mortality, cancer incidence, and leukemia risk.  Am J Epidemiol.  1996; 143: 137-43.

[10]Demers PA, et al.  Cancer incidence among firefighters in Seattle and Tacoma, Washington (United States).  Cancer Causes Control.  1994; 5: 129-35.

[11]Schernhammer ES, et al.  Night-shift work and risk of colorectal cancer in the Nurses’ Health Study.  J Natl Cancer Inst.  2003; 95(11): 825-8.

[12]Liu AC, et al.  Mammalian circadian signaling networks and therapeutic targets.  Nature Chem Biology.  2007; 3(10): 630-8.

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