Public trial lectureJakob Hønborg Hansen

Prescribed subject

“Work at night and risk of cancer. The epidemiological evidence and options

for prevention (if any).”

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

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

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.

Mechanism of melatonin secretion

Buijs RM & Kalsbeekk, 2001

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.

Darkness from 00:00-08:00

Darkness from 18:00-08:00

Constant light

From Wehr, 1991

”The melatonin hypothesis”

Exposure to light at night

Suppression of melatonin secretion

Increased estrogen production

Risk factor for breast cancer

Schernhammer et al., 2004

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

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

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

Human studies

• Many studies concerns nurses, flight attendants, factoryworkers, radio operators.

• Cancers studied:– Breast cancer (women)

– Prostate cancer (men)

– Colon cancer

– Endometrium cancer

– Lymphomas

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.

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.

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.

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

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

Prostata cancer – HumansLimited 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.

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.

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 measuresKolstad, 2008; Wang et al., 2010

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.

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

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

Thanks

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)