Cancer Causes & Control

, Volume 17, Issue 4, pp 539–545 | Cite as

Circadian Disruption, Shift Work and the Risk of Cancer: A Summary of the Evidence and Studies in Seattle

  • Scott DavisEmail author
  • Dana K. Mirick
Special Section on Cancer and Rhythm Original Paper


There is increasing interest in the possibility that disruption of normal circadian rhythm may increase the risk of developing cancer. Persons who engage in nightshift work may exhibit altered nighttime melatonin levels and reproductive hormone profiles that could increase the risk of hormone-related diseases, including breast cancer. Epidemiologic studies are now beginning to emerge suggesting that women who work at night, and who experience sleep deprivation, circadian disruption, and exposure to light-at-night are at an increased risk of breast cancer, and possibly colorectal cancer as well. Several studies have been conducted in Seattle recently to investigate the effects of factors that can disrupt circadian rhythm and alter normal nocturnal production of melatonin and reproductive hormones of relevance to breast cancer etiology. Studies completed to date have found: (1) an increased risk of breast cancer associated with indicators of exposure to light-at-night and night shift work; and (2) decreased nocturnal urinary levels of 6-sulphatoxymelatonin associated with exposure to 60-Hz magnetic fields in the bedroom the same night, and a number of other factors including hours of daylight, season, alcohol consumption and body mass index. Recently completed is an experimental crossover study designed to investigate whether exposure to a 60-Hz magnetic field under controlled conditions in the home sleeping environment is associated with a decrease in nocturnal urinary concentration of 6-sulphatoxymelatonin, and an increase in the urinary concentration of luteinizing hormone, follicle stimulating hormone, and estradiol in a sample of healthy women of reproductive age. Presently underway is a study to determine whether working at night is associated with decreased levels of urinary 6-sulphatoxymelatonin, and increased urinary concentrations of the reproductive hormones listed above in a sample of healthy women of reproductive age, and to elucidate characteristics of sleep among night shift workers that are related to the hormone patterns identified. A proposal is under review to extend these studies to a sample of healthy men to investigate whether working at night is associated with decreased levels of urinary 6-sulphatoxymelatonin, and increased concentrations of urinary cortisol and cortisone, urinary levels of a number of androgen metabolites, and serum concentrations of a number of reproductive hormones. Secondarily, the proposed study will elucidate characteristics of sleep among night shift workers that are related to the hormone patterns identified, as well as investigate whether polymorphisms of the genes thought to regulate the human circadian clock are associated with the ability to adapt to night shift work. It is anticipated that collectively these studies will enhance our understanding of the role of circadian disruption in the etiology of cancer.


Breast cancer Circadian rhythm Electromagnetic fields Environmental carcinogens Light Melatonin Pineal Shift work 


  1. 1.
    Angersbach D, Knauth P, Loskant H, etal. (1980) A retrospective cohort study comparing complaints and diseases in day and shift workers. Intern Arch Occup Environ Health 45:127–140Google Scholar
  2. 2.
    Colligan MJ, Frock IJ, Tasto D (1980) Shift work – the incidence of medication use and physical complaints as a function of shift. Occupational and Health Symposia – 1978. Washington, DC: US Dept of Health, Education and Welfare. (NIOSH Publication 80–105)Google Scholar
  3. 3.
    Minors DS, Scott AR, Waterhouse JM (1986) Circadian arrhythmia: shiftwork, travel and health. J Soc Occup Med 36:39–44PubMedGoogle Scholar
  4. 4.
    Knutsson A, Hallquist J, Reuterwall C, etal. (1999) Shift work and myocardial infarction: a case–control study. Occup Environ Med 56:46–50PubMedGoogle Scholar
  5. 5.
    Steenland K, Fine L (1996) Shift work, shift change, and risk of death from heart disease at work. Am J Ind Med 29:278–281CrossRefPubMedGoogle Scholar
  6. 6.
    Tuchsen F (1993) Working hours and ischaemic heart disease in Danish men: a 4-year cohort study of hospitalization. Int J Epidemiol 22:215–221PubMedGoogle Scholar
  7. 7.
    Knutsson A, Akerstedt T, Jonsson BG, etal. (1986) Increased risk of ischaemic heart disease in shift workers. Lancet 2:89–92PubMedGoogle Scholar
  8. 8.
    Kawachi I, Colditz GA, Stampfer MJ, etal. (1995) Prospective study of shift work and risk of coronary heart disease in women. Circulation 92:3178–3182PubMedGoogle Scholar
  9. 9.
    Alfredsson L, Karasek R, Theorell T (1982) Myocardial infarction risk and psychosocial work environment: an analysis of the male Swedish working force. Soc Sci Med 16:463–467CrossRefPubMedGoogle Scholar
  10. 10.
    Tenkanen L, Sjoblom T, Kalimo R, etal. (1997) Shift work, occupation and coronary heart disease over 6 years of follow-up in the Helsinki Heart Study. Scand J Work Environ Health 23:257–265PubMedGoogle Scholar
  11. 11.
    Mammalle N, Laumon E, Lazar P (1984) Prematurity and occupational activity during pregnancy. Am J Epidemiol 119:309Google Scholar
  12. 12.
    McDonald AD, McDonald JC, Armstrong B, etal. (1988) Prematurity and work in pregnancy. Br J Ind Med 45:56–62PubMedGoogle Scholar
  13. 13.
    Nurminen T (1989) Shift work, fetal development and course of pregnancy. Scand J Work Environ Health 15:395–403PubMedGoogle Scholar
  14. 14.
    Arendt J, Deacon S (1997) Treatment of circadian rhythm disorders–melatonin. Chronobiol Int 14:185–204PubMedGoogle Scholar
  15. 15.
    Axelsson G, Rylander R, Molin I (1989) Outcome of pregnancy in relation to irregular and inconvenient work schedules. Br J Ind Med 46:393–398PubMedGoogle Scholar
  16. 16.
    Xu X, Ding M, Li B, Christiani DC (1994) Association of rotating shiftwork with preterm births and low birth weight among never smoking women textile workers in China. Occup Environ Med 51:470–474PubMedGoogle Scholar
  17. 17.
    McDonald AD, McDonald JC, Armstrong B, et al. (1988) Fetal death and work in pregnancy. Br J Ind Med 45:148–157PubMedGoogle Scholar
  18. 18.
    Axelsson G, Ahlborg G Jr, Bodin L (1996) Shift work, nitrous oxide exposure, and spontaneous abortion among Swedish midwives. Occup Environ Med 53:374–378PubMedGoogle Scholar
  19. 19.
    Axelsson G, Lutz C, Rylander R (1984) Exposure to solvents and outcome of pregnancy in university laboratory employees. Br J Ind Med 41:305–312PubMedGoogle Scholar
  20. 20.
    Hemminki K, Kyyronen P, Lindbohm ML (1985) Spontaneous abortions and malformations in the offspring of nurses exposed to anaesthetic gases, cytostatic drugs, and other potential hazards in hospitals, based on registered information of outcome. J Epidemiol Community Health 39:141–147PubMedGoogle Scholar
  21. 21.
    Uehata T, Sasakawa N (1982) The fatigue and maternity disturbances of night workwomen. J Hum Ergol (Tokyo) 11:465–474Google Scholar
  22. 22.
    Ahlborg G Jr, Axelsson G, Bodin L (1996) Shift work, nitrous oxide exposure and subfertility among Swedish midwives. Int J Epidemiol 25:783–790PubMedGoogle Scholar
  23. 23.
    Bisanti L, Olsen J, Basso O, etal. (1996) Shift work and subfecundity: a European multicenter study. J Occup Environ Med 38:352–358PubMedGoogle Scholar
  24. 24.
    Hansen J (2001) Increased breast cancer risk among women who work predominantly at night. Epidemiology 12:74–77CrossRefPubMedGoogle Scholar
  25. 25.
    Davis S, Mirick DK, Stevens RG (2001) Night shift work, light at night, and the risk of breast cancer. J Natl Cancer Inst 93:1557–1562PubMedGoogle Scholar
  26. 26.
    Schernhammer ES, Laden F, Speizer FE, etal. (2001) Rotating night shifts and risk of breast cancer in women participating in the Nurses’ Health Study. J Natl Cancer Inst 93:1563–1568PubMedGoogle Scholar
  27. 27.
    Schernhammer ES, Laden F, Speizer FE, etal. (2003) Night-Shift Work and Risk of Colorectal Cancer in the Nurses’ Health Study. J Natl Cancer Inst 95:825–828PubMedGoogle Scholar
  28. 28.
    Pukkala E, Auvinen H, Wahlberg G (1995) Incidence of cancer among Finnish airline cabin attendants. BMJ 311:649–652PubMedGoogle Scholar
  29. 29.
    Rafnsson V, Tulinius H, Jonasson JG, etal. (2001) Risk of breast cancer in female flight attendants: a population-based study (Iceland). Cancer Causes Control 12:95–101CrossRefPubMedGoogle Scholar
  30. 30.
    Tynes T, Hannevik M, Andersen A, etal. (1996) Incidence of breast cancer in Norwegian female radio and telegraph operators. Cancer Causes Control 7:197–204CrossRefPubMedGoogle Scholar
  31. 31.
    Band PR, Spinelli JJ, Ng VTY, etal. (1990) Mortality and cancer incidence in a cohort of commercial airline pilots. Aviat Space Environ Med 61:299–302PubMedGoogle Scholar
  32. 32.
    Irvine D, Davies DM (1992) The mortality of British Airways pilots 1966–89:a proportional mortality study. Aviat Space Environ Med 63:276–279PubMedGoogle Scholar
  33. 33.
    Band PR, Le ND, Fang R, etal. (1996) Cohort study of Air Canada pilots: mortality, cancer incidence, and leukemia risk. Am J Epidemiol 143:137–143PubMedGoogle Scholar
  34. 34.
    Krstev S, Baris D, Stewart PA, etal. (1998) Risk for prostate cancer by occupation and industry: a 24-state death certificate study. Am J Ind Med 34:413–420PubMedGoogle Scholar
  35. 35.
    Irvine D, Davies DM (1999) British Airways flightdeck mortality study, 1950–92. Aviat Space Environ Med 70:548–555PubMedGoogle Scholar
  36. 36.
    Rfnassan V, Hrafnkelsson J, Tulinius H (2000) Incidence of cancer among commercial airline pilots. Occup Environ Med 57:175–179Google Scholar
  37. 37.
    Pukkala E, Aspholm R, Auvinen A, etal. (2002) Incidence of cancer among Nordic airline pilots over five decades: occupational cohort study. BMJ 325:567–569CrossRefPubMedGoogle Scholar
  38. 38.
    Pukkala E, Aspholm R, Auvinen A, etal. (2003) Cancer incidence among 10,211 airline pilots: a Nordic study. Aviat Space Environ Med 74:699–706PubMedGoogle Scholar
  39. 39.
    Krstev S, Baris D, Stewart P, etal. (1998) Occupational risk factors and prostate cancer in U.S. blacks and whites. Am J Ind Med 34:421–430PubMedGoogle Scholar
  40. 40.
    Demers PA, Checkoway H, Vaughan TL, etal. (1994) Cancer incidence among firefighters in Seattle and Tacoma, Washington (United States). Cancer Causes Control 5:129–135CrossRefPubMedGoogle Scholar
  41. 41.
    Hill SM, Blask DE (1988) Effects of the pineal hormone melatonin on the proliferation and morphological characteristics of human breast cancer cells (MCF-7) in culture. Cancer Res 48:6121–6126PubMedGoogle Scholar
  42. 42.
    Cos S, Fernandez F, Sanchez-Barcelo EJ (1996) Melatonin inhibits DNA synthesis in MCF-7 human breast cancer cells in vitro. Life Sci 58:2447–2453PubMedGoogle Scholar
  43. 43.
    Cos S, Fernandez R, Guezmes A, etal. (1998) Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells.Cancer Res 58:4383–4390PubMedGoogle Scholar
  44. 44.
    Cos S, Mediavilla MD, Fernandez R, etal. (2002) Does melatonin induce apoptosis in MCF-7 human breast cancer cells in vitro? J Pineal Res 32:90–96CrossRefPubMedGoogle Scholar
  45. 45.
    Mediavilla MD, Cos S, Sanchez-Barcelo EJ (1999) Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci 65:415–420CrossRefPubMedGoogle Scholar
  46. 46.
    Siu SW, Lau KW, Tam PC, etal. (2002) Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor, and androgen sensitivity. Prostate 52:106–122CrossRefPubMedGoogle Scholar
  47. 47.
    Rimler A, Lupwitz Z, Zisapel N (2002) Differential regulation by melatonin of cell growth and androgen receptor binding to the androgen response element in prostate cancer cells. Neuroendocrinol Lett 23:45–49PubMedGoogle Scholar
  48. 48.
    Marelli MM, Limonta P, Maggi R, etal. (2000) Growth-inhibitory activity of melatonin on human androgen-independent DU 145 prostate cancer cells. Prostate 45:238–244CrossRefPubMedGoogle Scholar
  49. 49.
    Xi SC, Tam PC, Brown GM, etal. (2000) Potential involvement of mt1 receptor and attenuated sex steroid-induced calcium influx in the direct anti-proliferative action of melatonin on androgen-responsive LNCaP human prostate cancer cells. J Pineal Res 29:172–183CrossRefPubMedGoogle Scholar
  50. 50.
    Moretti RM, Marelli MM, Maggi R, etal. (2000) Anti-proliferative action of melatonin on human prostate cancer LNCaP cells. Oncol Rep 7:347–351PubMedGoogle Scholar
  51. 51.
    Philo R, Berkowitz AS (1988) Inhibition of dunning tumor growth by melatonin. J Urol 139:1099–1102PubMedGoogle Scholar
  52. 52.
    Sze SF, Ng TB, Liu WK (1993) Anti-proliferative effect of pineal indoles on cultured tumor cell lines. J Pineal Res 14:27–33PubMedGoogle Scholar
  53. 53.
    Ying SW, Niles LP, Crocker C (1993) Human malignant melanoma cells express high-affinity receptors for melatonin: anti-proliferative effects of melatonin and 6-chloromelatonin. Eur J Pharmacol 246:89–96PubMedGoogle Scholar
  54. 54.
    Petranka J, Baldwin WS, Bierman J, etal. (1999) The oncostatic action of melatonin in an ovarian carcinoma cell line. J Pineal Res 26:129–136PubMedGoogle Scholar
  55. 55.
    Shiu SY, Li L, Xu JN, etal. (1999) Melatonin-induced inhibition of proliferation and G1/S cell cycle transition delay of human choriocarcinoma JAr cells: possible involvement of MT2 (MEL1B) receptor. J Pineal Res 27:183–192PubMedGoogle Scholar
  56. 56.
    Kanishi Y, Kobayashi Y, Noda S, etal. (2000) Differential growth inhibitory effect of melatonin on two endometrial cancer cell lines. J Pineal Res 28:227–233CrossRefPubMedGoogle Scholar
  57. 57.
    Tamarkin L, Cohen M, Roselle D, etal. (1981) Melatonin inhibition and pinealectomy enhancement of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in the rat. Cancer Res 41:4432–4436PubMedGoogle Scholar
  58. 58.
    Musatov SA, Anisimov VN, Andre V, etal. (1999) Effects of melatonin on N-nitroso-N-methylurea-induced carcinogenesis in rats and mutagenesis in vitro (Ames test and COMET assay). Cancer Lett 138:37–44CrossRefPubMedGoogle Scholar
  59. 59.
    Anisimov VN, Popovich IG, Zabezhinski MA (1997) Melatonin and colon carcinogenesis: I. Inhibitory effect of melatonin on development of intestinal tumors induced by 1,2-dimethylhydrazine in rats. Carcinogenesis 18:1549–1553CrossRefPubMedGoogle Scholar
  60. 60.
    Anisimov VN, Kvetnoy IM, Chumakova NK, etal. (1999) Melatonin and colon carcinogenesis. Exp Toxicol Pathol 51:47–52PubMedGoogle Scholar
  61. 61.
    Cini G, Coronnello M, Mini E, etal. (1988) Melatonin’s growth-inhibitory effect on hepatoma AH 130 in the rat. Cancer Lett 125:51–59Google Scholar
  62. 62.
    Mocchegiani E, Perissin L, Santarelli L, etal. (1999) Melatonin administration in tumor-bearing mice (intact and pinealectomized) in relation to stress, zinc, thymulin and IL-2. Int J Immunopharmacol 21:27–46PubMedGoogle Scholar
  63. 63.
    Subramanian A, Kothari L (1991) Melatonin, a suppressor of spontaneous murine mammary tumors. J Pineal Res 10(3):136–140PubMedGoogle Scholar
  64. 64.
    Jochle W (1964) Trends in photophysiologic concepts. Ann N Y Acad Sci 117:88–104Google Scholar
  65. 65.
    Shah PN, Mhatre MC, Kothari LS (1984) Effect of melatonin on mammary carcinogenesis in intact and pinealectomized rats in varying photoperiods. Cancer Res 44:3403–3407PubMedGoogle Scholar
  66. 66.
    Blask DE, Sauer LA, Dauchy R, etal. (1999) New actions of melatonin on tumor metabolism and growth. Biol Signals Recept 8:49–55PubMedGoogle Scholar
  67. 67.
    Blask DE, Dauchy RT, Sauer LA, etal. (2002) Light during darkness, melatonin suppression and cancer progression. Neuroendocrinol Lett 23:52–56PubMedGoogle Scholar
  68. 68.
    Dauchy RT, Sauer LA, Blask DE, etal. (1997) Light contamination during the dark phase in “photoperiodically controlled” animal rooms: effect on tumor growth and metabolism in rats. Lab Anim Sci 47:511–518PubMedGoogle Scholar
  69. 69.
    Dauchy RT, Blask DE, Sauer LA, etal. (1999) Dim light during darkness stimulates tumor progression by enhancing tumor fatty acid uptake and metabolism. Cancer Lett 144:131–136CrossRefPubMedGoogle Scholar
  70. 70.
    Hahn RA (1991) Profound bilateral blindness and the incidence of breast cancer. Epidemiology 2:208–210PubMedGoogle Scholar
  71. 71.
    Feychting M, Osterlund B, Ahlbom A (1998) Reduced cancer incidence among the blind. Epidemiology 9:490–494PubMedGoogle Scholar
  72. 72.
    Pukkala E, Verkasalo PK, Ojamo M, etal. (1999) Visual impairment and cancer: a population-based cohort study in Finland. Cancer Causes Control 10:13–20CrossRefPubMedGoogle Scholar
  73. 73.
    Verkasalo PK, Pukkala E, Stevens RG, etal. (1999) Inverse association between breast cancer incidence and degree of visual impairment in Finland. Br J Cancer 80:1459–1460CrossRefPubMedGoogle Scholar
  74. 74.
    Kliukiene J, Tynes T, Andersen A (2001) Risk of breast cancer among Norwegian women with visual impairment. Br J Cancer 84:397–399CrossRefPubMedGoogle Scholar
  75. 75.
    Reppert SM, Weaver DR (2001) Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol 63:647–676CrossRefPubMedGoogle Scholar
  76. 76.
    Katzenberg D, Young T, Finn L, etal. (1998) A CLOCK polymorphism associated with human diurnal preference. Sleep 21:569–576PubMedGoogle Scholar
  77. 77.
    Johansson C, Willeit M, Smedh C, etal. (2003) Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology 28(4):734–739CrossRefPubMedGoogle Scholar
  78. 78.
    Archer SN, Robilliard DL, Skene DJ, etal. (2003) A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep 26:413–415PubMedGoogle Scholar
  79. 79.
    Ebisawa T, Uchiyama M, Kajimura N, etal. (2001) Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep 2:342–346CrossRefPubMedGoogle Scholar
  80. 80.
    Parry BL, Newton RP (2001) Chronobiological basis of female-specific mood disorders. Neuropsychopharmacology 25:S102–S108CrossRefPubMedGoogle Scholar
  81. 81.
    Zhu Y, Brown HN, Zhang Y, etal. (2005) Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol Biomarkers Prev 14:268–270PubMedGoogle Scholar
  82. 82.
    Fu L, Pelicano H, Liu J, etal. (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111:41–50PubMedGoogle Scholar
  83. 83.
    Davis S, Kaune WT, Mirick D, Chen C, Stevens RG. (2001) Residential Magnetic Fields, Light-at-Night, and Nocturnal Urinary 6-sulphatoxymelatonin in Women. Am J Epidemiol 154:591–600CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  1. 1.Program in Epidemiology, Division of Public Health Sciences Fred Hutchinson Cancer Research Center, Department of Epidemiology, School of Public Health and Community MedicineUniversity of WashingtonSeattleUSA
  2. 2.Program in Epidemiology, Division of Public Health SciencesFred Hutchinson Cancer Research CenterSeattleUSA

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