Shift work and cancer. Public PhD. trial lecture for Jakob Hønborg Hansen.

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  • In 2007 A report about cancer and shift work were published from the international agency of research on cancer. This association is a diision under the World Health Organization. 24 scientists from ten countries was given the task of investigating the carcinogenicity of shift work. Press release (læsoppe)…So from this date on, shift work was officially a known cause of cancer.
  • Shift work is placed in a group with agents that are well known to cause cancer. It is somewhat surprising that shift work is placed here among these well known carcinogens.
  • These are the most important hypothesized causes of cancer in night shift workers.Light at night leads to a number physiological changes. The SCN is a small cluster of cells that regulates our circadian phases
  • The mechanism through which light inhibits melatonin secretion.Light is caught by the eye, and the light signal travels via the retino hypothalamic tract to the suprachiasmatic nuclei (the master circadian clock).The suprachiasmatic nuclei then signal the pineal gland to suppress the secretion of melatonin.The opposite is true when darkness is caught by the eye. In darkness the suprachiasmatic nuclei orders the pineal gland to secrete melatonin.These are the mechanism for the regulation of melatonin.
  • Exposure to light at night:Light at night will be caugth by the eye, and from the eye the light signal is transmitted master circadian clock Suppresion of melatonin secretion:The master circadian then inhibits melatonin secretion in the pineal gland.Estrogen is a well known cause of breast cancer. So this is an very unfortunate aspect of shift work.Melatonin can decrease estrogen production and possibly block the estrogen receptor in the tissue.So if melatonin is not secreted it will not be able to perform these actions.The epithelium in female breasts are vulnerable to carciogenic agents
  • These studies formed the foundation of the report from the International Agency for Research on Cancer. The one mentioned on the first slide.Animals were exposed to many different light/dark regimes from 0.2 lux to 2500 lux. This was done in many different combinations for example continuous bright light at night, dim light at night, intermittent or pulsed light at night.Lesions of the SCN causes destroys the circadian control of body functions.This shows that time of exposure is important for tumour growth and incidence.Simulation of crossing different time zones. This is very important for humans, since crossing time zones is very common for travellers that travel across the pacific or the atlantic.Pinealectomy consists in the surgical removal of the pineal gland from the brain. It is the only way of eliminating the nocturnal melatonin secretion from the pineal gland. This can be done without affecting the suprachiasmatic nuclei. This procedure indirectly addresses whether the physiological nocturnal melatonin signal from the pineal gland is inhibitory to the process of tumorigenesis in experimental animal models. These studies have directly investigated the role of physiological, nocturnal concentrations of melatonin on experimental cancer growth. This was done “in vivo” which is when you use a whole living organism.
  • We have to acknowledge that there are differences in animal and human physiology.
  • On average2723 women were diagnosed with breast cancer every year from 2000 till 2009. There are no certain causes of why this disease develops, but are likely to be related to hormonal causes, inherited causes, socio-economical status, and even height and weight.On average 3575 men were diagnosed with prostate cancer every year from 2000 till 2009. In 2006 prostate cancer accounted for 27 procent of all new cancer causes, so this is one of the most commonly types of cancer. Norway is among the countries with highest occurrence and mortality from prostate cancer. But in relative terms, prostate cancer is not among the cancers with the highest relative mortality rate. Allmost 50 % of the prostate cancer incidences occurs in men obove 74 years of age. Age, heritage, hormonal changes, environment and lifestyle are probable risk factors.
  • Start:When I investigated this area of research, I came across the same studies over and over again. So it seems as if there are very few studies in the area of research.This epidemiological evidence was based on cohort studies, and case control studies. Davis: Population based case control study. The subjects were women that were diagnosed with breast cancer. The study showed a positive effect of working the night shift and a positive effcts of number of years on the night shift. So the longer you work on the night shift, the more likely you are to get breast cancer.Hansen: Studied breast cancer risk among women working in manufacturing, transport services and catering services. This was a case control study, and it was showed that there were a positive trend towards breast cancer in the workers who had worked long durations on the night shift.Lie 1: Studied nurses and found that the odds ratio increased for breast cancer as the years with night work increased. It showed a two fold increase in breast cancer after 30 years working shifts. So again, the longer time on the shift, the larger the risk of getting breast cancer. Lie 2: Recent cohort study of nurses. Significant effect for breast cancer for those working more than 5 years on the night shift with 6 days in a row on the night shift. This is a very specific finding.O`Leary: Population based case control study of breast cancer. This study showed no effect of night shift work, only from evening work. Therefore this study showed no effect of working night shifts.Schernhammer 1: In this cohort study they studied nurses, and found that shift workers on the rotating shift working schedule showed an increased risk in comparison to those never working rotating night shifts.Schernhammer 2: This cohort study among nurses showed that the risk of breast cancer significantly increased as the number of years on the rotating shift increased. It also showed that those with more than 30 years on the night shift had an increased risk of getting breast cancer.Schwarzbaum: This study included the whole working force in Sweden, and had a follow up period from 1970-1989. This study did not find any increased risk of breast cancer in shift workers.Tynes: Case control study of radio and telegraph operators. This study showed that the odds ratio of breast cancer increased as the number of years on the shift increased. Pesch: Population based case control study. In this study they were not able to show any effects of shift work on breast cancer.Pronk: Cohort study of chinese women. This study did not show any association between night shift work and breast cancer. The study concludes that it is to early to consider shift work as an cause of breast cancer.There is evidence for an association between night shift work and breast cancer, it is unlikely to be a casual association.It is not certain that night work per se is the single risk factor, but rather the fact that night work brings along increased light exposure at night, sleep deprivation, diet, lifestyle etc.).It is however difficult to compared studies, due to the differences in protocol methodology, measured parameters, inaccurate exposure assesments and unknown risk factors. Frequency of breast cancer screeningThis is one of the reasons why the International Agency for Research on Cancer only gave shift work the Group 2A classification (probably carciogenic to humans), because it does not provide any final evidence or casual relations between shift work and breast cancer.
  • Kolstad made an in-depth analysis of 8 studies. Kolstad concluded that there is limited evidence for a casual association between breast cancer and night-shift work. Caused some scientific discussions in Denmark, because this study spoke against the advice from The Danish Cancer Society that regarded shift work as a well documented cause of cancer.It further caused discussion due to the fact that because the danish goverment has awarded compensation to cancer victims for thedisablement caused by night shift work. This study questioned that decision.Megdal made meta analysis of 13 studies, and concluded that shift work were likely to be the main cause of the 48 % increase in breast cancer.Wang made an in-depth review of several reviews and meta analysis, and concluded that there were some suggestive evidence for an association between breast cancer and night shift work.
  • Først:Some supportive evidence exist from female flight attendants.
  • The perspectives of studying prostate cancer is important, because this is the most frequently occurring in men. Further research is needed.The evidence in this area of research, is too limited and too inconsistent to make any firm conclusions.
  • Endometrium cancer: The fact that only obese women showed increases in endometrium cancer risk, might be due to the fact that obesity is a well known risk factor for endometrial cancer. So therefore shift work might not be the cause of the increased cancer risk. Non-Hodgkin lymphoma:
  • It is very difficult to make any solid and firm conclusions from these studies. This is due to the large inconsistencies between the studies.This is also pointed out by all meta analysis and the review articles that I obtained.So this is really the major concern of the presented epidemiological evidence, and this has profound impact on the conclusions of this presentation.This is basically why we cannot accept that there is a casual assiciation between shift work and cancer.
  • It might be that in 10 or 15 years there is a well documented association between night shift work and cancer. And indeed, shift work is still a burden for the worker, and it causes both fatigue and sleep deprivation. Therefore we should still give good advice to shift workers.No one should stay longer than 20 years working night shifts, since this has been somewhat associated with increased cancer risk. This was a trend in several of the articles on breast cancer.Estrogen is especially of concern, since this is elevated due to the suppression of melatonin.3. A fast adaptation to night shifts, will also stabilize the rhythm of melatonin faster. An advantage with regards to cancer. 4. Good sleep hygiene will give you a better sleep, and will optimize the secretion of melatonin which is important for the development of cancer.
  • There is considerable variation of the studies regarding design and measuring variables.The main strength of most of the studies are that they include many subjects from data collected in large cohorts. Many confounders were controlled for also.
  • Shift work and cancer. Public PhD. trial lecture for Jakob Hønborg Hansen.

    1. 1. Public trial lecture Jakob Hønborg Hansen Prescribed subject“Work at night and risk of cancer. The epidemiological evidence and options for prevention (if any).”
    2. 2. Shift work – Report• International Agency of Research on Cancer (IARC).• IARC is an agency of the World Health Organization.• Press release 5. December 2007: “Shiftwork that involves circadian disruption is probably carcinogenic to humans (Group 2A)”.• Group 2A: “There is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals”. IARC Monographs, 2008
    3. 3. Group 2A• Shift work is placed in the same group as: – Diesel exhaust fumes. – Anabolic steroids. – Frying. Emissions from high temperature frying. – Lead compounds. – And many others. IARC Monographs, 2008
    4. 4. Causes of cancer in night shift workers (hypothesized) • Light at night – Disruption of the master circadian clock (SCN). – Disruption of endocrine function. – Suppression of melatonin secretion. • Sleep deprivation – Alterations in immune function. May permit establishment or growth of malignant cells. Costa, 2010, Turek & Zee, 1999.
    5. 5. Mechanism of melatonin secretion Buijs RM & Kalsbeekk, 2001
    6. 6. Properties of melatonin• Circadian phase shifting properties.• Strong antioxidant.• Protect cells from DNA damage.• Oncostatic actions: • Counteracts cancer cell proliferation and cancer invasiveness. Wang et al., 2011; Turek & Zee, 1999; Costa, 2010.
    7. 7. Darkness from 00:00-08:00Darkness from 18:00-08:00Constant light From Wehr, 1991
    8. 8. ”The melatonin hypothesis” Exposure to light at nightSuppression of melatonin secretion Increased estrogen production Risk factor for breast cancer Schernhammer et al., 2004
    9. 9. Simple solution...• Expose night workers to complete darkness!!!• Why this is a bad idea: – Impaired cognitive performance. – Increased sleepiness. – Risk of accidents. Boivin et al., 2007, Folkard & Tucker, 2003
    10. 10. Animal studies• Alterations in light exposures. – 18 of 20 studies were positive for cancer incidence and growth.• Lesions of the SCN – 1 of 1 studies were positive for cancer incidence and growth.• Circadian timing of carcinogen administration – 4 of 4 studies were positive for cancer incidence and growth.• Effects of experimental jetlag. – 2 of 2 studies were positive for cancer incidence and growth.• Effects of pinealectomi (gland removal). – 13 of 21 studies were positive for cancer incidence and growth.• Direct effect of nocturnal melatonin secretion on tumorigenesis. – 5 of 5 studies were positive for the inhibition of various tumor growth factors. IARC Monographs, 2008
    11. 11. The relevance of animal models to human health • Differences between species. • Animal disease do not adequately reflect disease in humans. • Differences in study design. – Rarely blinded – Rarely randomized • Thus, we should be careful in making any direct comparisons between species. Perel et al., 2006; Hackam et al., 2006
    12. 12. Human studies• Many studies concerns nurses, flight attendants, factoryworkers, radio operators.• Cancers studied: – Breast cancer (women) – Prostate cancer (men) – Colon cancer – Endometrium cancer – Lymphomas
    13. 13. Breast cancer and prostate cancer• Breast cancer is the most common type of cancer in women in Norway and in Western Europe.• Prostate cancer is the most common type of cancer in menn in Norway and in Western Europe. Cancer Registry of Norway report, 2009.
    14. 14. Breast cancer – Humans• Epidemiological evidence: – Davis et al., 2001 (Case control: Cases=767, Controls=743)  – Hansen, 2001 (Case control: Cases=6281, Controls=6024)  – Lie et al., 2006 (Case control: Cases=537, Controls=2143)  – Lie et al., 2011 (Cohort study: 49402)  – O`Leary et al., 2006 (Case control: Cases=487, Controls=509)  – Schernhammer et al., 2001 (Cohort study N=78562)  – Schernhammer et al., 2006 (Cohort study N=115022)  – Schwartzbaum et al., 2007 (Cohort study N=72816)  – Tynes et al., 1996 (Cohort study N=2619 (and case control))  – Pesch et al., 2010 (Case control: Cases=857, Controls=892)  – Pronk et al.,2010 (Cohort study N=73049) • 7 of 11 studies showed an increased risk of breast cancer in women from working night shifts.• Long term night shift work (20-30 years) seems to increase the risk.
    15. 15. Breast cancer – Humans• Meta analysis and In-Depth reviews – Kolstad, 2008 • Limited evidence for a casual association between night shift work and breast cancer. – Megdal et al. ,2005 • 48 % increase in the risk of breast cancer from shift work. – Wang et al., 2011 • Suggestive evidence for an association between breast cancer and night shift work. Not a casual association.
    16. 16. Breast cancer – Humans Supportive evidence• Female flight attendants: – 6 of 7 studies showed an increased risk of breast cancer.• This was compared to the general population.• Studies did not address shift work specifically. Megdal et al., 2005
    17. 17. Prostate cancer - Humans• There are many epidemiological studies of prostate cancer. Very few adressed the issue of shift work• All population based studies• Epidemiological evidence: – Conlon et al., 2007 (Case-control:760 cases, 1632 controls)  – Kubo et al., 2006 (Cohort: N=14052)  – Schwarzbaum et al., 2007 (Cohort: N=3250787) • 2 of 3 studies showed an increased risk of night shift work
    18. 18. Prostata cancer – Humans Limited supported evidence• Costa et al., 2010 (In-depth review) – 11 studies of prostate cancer – Commercial airline pilots, military pilots, civilian pilots and crew members. – No general increased risk of prostate cancer. – In fact, some studies showed they had less prostate cancer than the general population.
    19. 19. Other cancers - Humans• Colon cancer. – Tynes et al., 1996 (Cohort study N=2619 (and case control)  – Schernhammer et al., 2003 (Cohort study N=78586)  – Schwarzbaum et al.,2007 (Cohort study N=72816)  – 3 of 3 studies showed no effect of shift work on colon cancer incidence.• Endometrium cancer. – Visnawanathan et al., 2007 (Cohort study N=121701)  – 1 study showed that obese women on night shifts, showed a 2-fold increase in endometrial cancer risk.• Ovarian cancer. – Poole et al., 2011 (Cohort N=181548)  – 1 study showed that night shift work is not associated with ovarian cancer.• Non-Hodgkin`s lymphoma. – Lahti et al., 2008 (Cohort study N=1669272)  – 1 study showed that night shift workers were prone to cancer.
    20. 20. Methodological issues• Few studies• Very difficult to compare across studies• Different shift work exposures between studies – Shift pattern – Shift frequency – Duration of shifts• Endless list of confounders – Smoking, alcohol consumption, obesity, lifestyle, menopause, socioeconomic status, electro magnetic radiation etc.• To few objective measures• Imprecise objective measures Kolstad, 2008; Wang et al., 2010
    21. 21. In summary• There is still much to be learned about shift work and the development of cancer.• Breast cancer: – There are some indications of an association between night shift work and breast cancer in women. – Years on the night shift seems to be an important factor. – There is limited evidence for a casual association.• Prostate cancer, colon cancer, endometrial cancer, Non-Hodgkin`s lymphoma: – There is insufficient evidence of an association between these cancer types and night shift work. – No evidence of a casual association.
    22. 22. Options for prevention• Reduce number of years on the night shift. – 20-30 years working night shifts possibly increases cancer risk.• Shift work should be reduced to a minimum for women during their reproductive years. – The epithelium in the female breast is sensitive to carcinogenic agents during this period.• A fast adaptation should be promoted for those on long duty cycles.• Promote good sleep hygiene after a night shift. – Sleep should be in dark, cold and noise free conditions. Wang et al., 2011; Turek & Zee, 1999; Costa, 2010; Kolstad, 2008; Reiter et al., 2007
    23. 23. Future studies should include:• Studies vary significantly. Difficult to compare across studies.• Future studies should include: • Rotating,fixed or permanent shifts. • Speed of rotation. • Forward/backward rotating shifts. • Start of shifts and end of shifts. • Duration of work i.e. years employed. • Sleep, naps, quality of sleep. • Specific work tasks. • Light exposure at work place and at home. • Natural or artificial light exposure. • Person characteristics (evening type, morning type etc.). • More objective measures. Stevens et al. 2011, Costa et al. 2010
    24. 24. Thanks
    25. 25. References[1] IARC. Shift Work (IARC) Report. 2008.[2] Costa G, Haus E, Stevens R. Scandinavian journal of work, environment & health 2010;36:163-79.[3] Turek FW, Zee PC. Regulation of Sleep and Circadian Rhythms. New York: Marcel Dekker Inc., 1999.[4] Wang X-S, Armstrong MEG, Cairns BJ, Key TJ, Travis RC. Occupational medicine (oxford, england) 2011;61:78-89.[5] Schernhammer ES, Rosner B, Willett WC, Laden F, Colditz GA, Hankinson SE. Cancer epidemiology, biomarkers & prevention  a publication of the : american association for cancer research, cosponsored by the american society of preventive oncology 2004;13:936-43.[6] Wehr TA. The journal of clinical endocrinology and metabolism 1991;73:1276-80.[7] Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS. Bmj (clinical research ed.) 2007;334:197.[8] Hackam DG, Redelmeier DA. Jama  the journal of the american medical association 2006;296:1731-2. :[9] Boivin DB, Tremblay GM, James FO. Sleep med 2007;8:578-89.[10] Folkard S, Tucker P. Occup med (lond) 2003;53:95-101.[11] Norwegian. Cancer in Norway 2009. Oslo: Norwegian Cancer Registry, 2009.[12] Hansen J. Epidemiology (cambridge, mass.) 2001;12:74-7.[13] Davis S, Mirick DK, Stevens RG. Journal of the national cancer institute 2001;93:1557-62.[14] Lie J-AS, Kjuus H, Zienolddiny S, Haugen A, Stevens RG, Kjærheim K. American journal of epidemiology 2011;173:1272-9.[15] Lie J-AS, Roessink J, Kjaerheim K. Cancer causes & control  ccc 2006;17:39-44. :[16] O’Leary ES, Schoenfeld ER, Stevens RG, Kabat GC, Henderson K, Grimson R, Gammon MD, Leske MC. American journal of epidemiology 2006;164:358- 66.[17] Schernhammer ES, Laden F, Speizer FE, Willett WC, Hunter DJ, Kawachi I, Colditz GA. J natl cancer inst 2001;93:1563-1568.[18] Schernhammer ES, Kroenke CH, Laden F, Hankinson SE. Epidemiology (cambridge, mass.) 2006;17:108-11.[19] Schwartzbaum J, Ahlbom A, Feychting M. Scandinavian journal of work, environment & health 2007;33:336-43.[20] Tynes T, Hannevik M, Andersen A, Vistnes AI, Haldorsen T. Cancer causes & control  ccc 1996;7:197-204. :[21] Pesch B, Harth V, Rabstein S, Baisch C, Schiffermann M, Pallapies D, Bonberg N, Heinze E, Spickenheuer A, Justenhoven C, Brauch H, Hamann U, Ko Y, Straif K, Brüning T. Scandinavianjournal of work, environment & health 2010;36:134-41.[22] Pronk A, Ji B-T, Shu X-O, Xue S, Yang G, Li H-L, Rothman N, Gao Y-T, Zheng W, Chow W-H. American journal of epidemiology 2010;171:953-9.[23] Megdal SP, Kroenke CH, Laden F, Pukkala E, Schernhammer ES. European journal of cancer (oxford, england  1990) 2005;41:2023-32. :[24] Kolstad HA. Scandinavian journal of work, environment & health 2008;34:5–22.[25] Conlon M, Lightfoot N, Kreiger N. Epidemiology (cambridge, mass.) 2007;18:182-3.[26] Kubo T, Ozasa K, Mikami K, Wakai K, Fujino Y, Watanabe Y, Miki T, Nakao M, Hayashi K, Suzuki K, Mori M, Washio M, Sakauchi F, Ito Y, Yoshimura T, Tamakoshi A. American journal of epidemiology 2006;164:549-55.[27] Viswanathan AN, Hankinson SE, Schernhammer ES. Cancer research 2007;67:10618-22.[28] Poole EM, Schernhammer ES, Tworoger SS. Cancer epidemiology, biomarkers & prevention  a publication of the american association for cancer : research, cosponsored by the american society of preventive oncology 2011;20:934-8.[29] Lahti T a, Partonen T, Kyyrönen P, Kauppinen T, Pukkala E. International journal of cancer. journal international du cancer 2008;123:2148-51.[30] Reiter RJ, Tan DX, Korkmaz A, Erren TC, Piekarski C, Tamura H, Manchester LC, others. Crit rev oncog 2007;13:303–28.[31] Stevens RG, Hansen J, Costa G, Haus E, Kauppinen T, Aronson KJ, Castaño-Vinyals G, Davis S, Frings-Dresen MHW, Fritschi L, Kogevinas M, Kogi K, Lie J- A, Lowden A, Peplonska B, Pesch B, Pukkala E, Schernhammer E, Travis RC, Vermeulen R, Zheng T, Cogliano V, Straif K. Occupational and environmental medicine 2011;68:154-62.[32] Buijs RM & Kalsbeek A. Hypothalamic integration of central and peripheral clocks. Nature Reviews Neuroscience 2, 521-526 (July 2001)

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