Licht und Gesundheit: Neue Perspektiven

Transcription

1 Licht und Gesundheit: Neue Perspektiven Univ. Prof. DDr. Eva Schernhammer Medical University of Vienna and Harvard Medical School Jahrestagung der Österreichischen Gesellschaft für Arbeitsmedizin Villach, 22. September

2 Disclosures None

3 Halloween,

4 1880: Thomas Alva Edison invents the incandescent light bulb Howard Lewis Latimer improves the filaments Tim O'Brien Faculty, Cover of "Time" magazine: June 5,

5 Carl Auer von Welsbach 1898 first metal filament light bulbs Thomas Alva Edison & Lewis Howard Latimer 1880 first commercially available light bulb First public application of Edison light bulb in the Mahen Deutschen Stadttheater in Brno 1882 Empires of Light: The Race to Electrify the World Titel der Präsentation ODER des Vortragenden Organisationseinheit 5

6 Today, cities are usually fully lit at night

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8 Fotocredit: buzzfeed Light Pollution changes our wildlife and ecosystems

9 Light affects not only flora and fauna, but also us human beings 9

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11 Geographic variation of cancer rates Age-standardized Annual Cancer Mortality Rates per 100,000, 1997 (WHO Cancer Mortality Bank)

12 Biological clock in hypothalamus controls biological rhythms

13 Biological 24-hour rhythms direct our lives Sleep Wake Rest Activity Body temperatur Blood pressure Drug metabolism Secretion of hormones Kidney function Gene expression Drinking rhythmus Immun system

14 Why is night work a particularly relevant model to study the impact of light at night on health in humans? - Night workers are chronically exposed to light at night - They have their eyes open, allowing light to directly stimulate their retinal receptors (as opposed to individuals who sleep at night, with their eye lids closed) - They usually cannot change their exposure (unlike e.g., adolescents who stay up late, or individuals who voluntarily expose themselves to social jetlag ) 14

15 External Zeitgeber impact the biological clock

16 Overview: Desynchronization of the biological clock primarily via light and metabolism Nat Reviews Rheumatologie

17 Central molecular pathways regulating circadian rhythms Bass, Nature 2012

18 Human circadian rhythms Autonomic Processes

19 Human circadian rhythms Autonomic Processes Hormone Production

20 Human circadian rhythms Autonomic Processes Hormone Production Gene Expression

21 Melatonin Most important oncostatic mechanisms: Antimitotic, antioxidant, suppression of tumorlinoleic acid uptake, circulating estrogen Production almost exclusively at night Will be suppressed by light at night

22 Testing the Melatonin Hypothesis Mechanisms by which the circadian system regulates breast cancer risk Downregulation of the neuroendocrinen axis Reduction of estrogen receptor expression Blocking the binding of the estrogen receptor complex to estrogen response elements (ERE) in the DNA Cos S et al, Cancer Detection Prev 2006

23 The Nurses Health Studies - The Beginnings DR. SPEIZER DR. WILLETT DR. COLDITZ DR. HANKINSON

24 NHS NH2 NHS3 Began 1976 Began1989 Began registered US nurses, years old registered US nurses, years old Enrollment ongoing Biannual questionnaires Biannual questionnaires Online questionnaires Blood and urine specimen collected Blood and urine specimen collected Currently > enrolled

25 Individuals Shift work distribution in NHS Never 1-2 years 3-5 years 6-9 years years years years 30+ years % 40.5% 24.0% 16.8% 6.8% 4.6% 2.8% 2.8% 1.8% N Shift work In addition to shift work, a wide range of potential disease risk factors, confounders, effect modifiers, and mediators, including e.g., medication use, diet, lifestyle, and multiple socioeconomic determinants, have been validated and repeatedly assessed since baseline in all three NHS cohorts

26 Night work and breast cancer risk Schernhammer et al, J Natl Cancer Inst 2001, 2003

27 Night work also associated with risk of other cancers? Type of cancer Extended periods of rotating night shift work Breast cancer (NHS) Breast cancer (NHS2) Colorectal cancer Cervical cancer Ovarian cancer Lung cancer 36% risk increase 79% risk increase 35% risk increase 43% risk increase no association 28% risk increase e.g., Schernhammer et al, J Natl Cancer Inst 2001, 2003, Epidemiol 2006, Cancer Res 2007, CEBP 2011, Am J Epidemiol 2013

28 Night work increases breast cancer risk by ~50% Megdal, Schernhammer, Europ J Cancer 2005

29 Night work and prostate cancer risk First study to explore associations in men: Kubo et al (AJE) Conlon et al. (2007): Canadian population-based case-control study 14,052 working Japanese men, 31 cases of prostate cancer Ever worked full-time rotating night shifts 20% risk increase 3-fold increased prostate cancer risk among rotating shift workers Men who began shift work in their mid- 20s 40% risk increase Adjusted for perceived job stress

30 Validation of melatonin as biomarker of the circadian system to be used in large-scale prospective studies Melatonin changes very little over time (here measured repeatedly over 3 years) Melatonin secretion remains stable if urine samples are deep-frozen within hours of collection ICC over 3 years: 0.72 (95% CI: ) Schernhammer et al, Cancer Epidemiol Biomarker Prev 2004

31 Checking biological mechanisms: are higher melatonin levels associated with lower breast cancer risk? e.g., Schernhammer et al, J Natl Cancer Inst 2005, 2008, CEBP 2009, 2010

32 Shiftwork that involves circadian disruption is probably carcinogenic to humans (Group 2A) Based on limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals

33 What new evidence has accumulated since 2007?

34 Travis et al J Natl Cancer Inst: largest study to date Study populations: Million Women Study ( ) EPIC Oxford ( ) UK Biobank (~ ) Shift work definition: Ever worked nightshifts in their lives Current night work only assessed in UK Biobank

35 Overview of Travis et al. study Cohort Follow-up and avg. age at start of follow-up Def. of night work Total cases and cases among night workers Million Women Study (2.6yrs) Age: ~68.5 Ever/never night work? Duration info collected 4, EPIC Oxford (3.1yrs) Age: ~57 Ever/never night work? Duration collected, but only 1 case UK Biobank (3.8yrs) Age: ~55 Current job involves night shifts? No duration info 2, Travis et al. J Natl Cancer Inst 2016

36 Conclusion by Travis et al.: The totality of the prospective evidence shows that night shift work, including long-term shift work, has little or no effect on breast cancer risk Classification of night shift work as probable carcinogen is no longer justified

37 Limitations/Problems Older women, close to or after retirement (effects of night work likely to wane over time once exposure ceases) Short follow-up (max. 3 years), left-truncation bias due to continued follow-up after exposure cessation Low case numbers, prohibits duration analyses in EPIC Oxford, and no duration info collected at all, in UK Biobank Conclusion that extrapolates from breast cancer to all cancers is not supported by data

38 Many more studies accrued since 2007, particularly for breast cancer (risk increase by 20-32%) Comparison casecontrol studies (Group A) and cohort and nested case-control studies (Group B) Jia et al, CEBP 2013

39 Current status regarding night work and female cancers To date, over 60 studies (including Travis et al.) have now examined the association between night work and various female cancers, 2/3 of which focused on breast cancer Cancers that were studied include breast, colorectal, ovarian, endometrial, lung, NHL, melanoma, thyroid Duration of night work remains associated with female cancer in the majority of these studies

40 Current status regarding night work and male cancers To date, over 20 studies (14 cohort, 5 caco, 2 nested caco studies) have examined the association between night work and various cancers in men, including 6 common cancers Cancers that were studied include prostate, digestive system, and lung Risks were significantly associated with each of these cancers by between 25 and 80% Dose-response relationship significant (for every 5 years, risk increased by ~24%)

41 Association between night work and prostate cancer risk Rao et al, OncoTargets and Therapy 2015

42 Night work and colon cancer meta-analysis Wang et al, Oncotarget 2015

43 Two additional recent studies of relevance: 1) Night work and breast cancer risk: additional follow-up 2) Higher levels of light at night associated with breast cancer risk?

44 1) Night work and breast cancer risk: additional follow-up Initial Publication Updated Analysis NHS (2001, 2017) 10 years fu ( ) 24 years of fu ( ) 2,441 cases 5,971 cases RR for 30+ years: 1.36 ( ) RR for 30+ years: 0.95 ( ) NHS2 (2006, 2017) 12 years of fu ( ) 24 years of fu ( ) 1,352 cases 3,570 cases RR for 20+ years: 1.79 ( ) Schernhammer et al., RR for 20+ years: 2.15 ( ) Wegrzyn et al. AJE 2017

45 Baseline characteristics by categories of rotating nightshift work duration NHS: 1988, n=78,516 NHS2: 1989, n=114,559 Wegrzyn et al. Am J Epidemiol 2017

46 Associations of duration of nightshift work and invasive breast cancer risk, 24 years fu Wegrzyn et al. Am J Epidemiol 2017

47 Stratified by follow-up period, adding post-retirement years in NHS Wegrzyn et al. Am J Epidemiol 2017

48 Other findings from this updated analysis No heterogeneity by tumor receptor status, though risk appeared slightly stronger for ER/PR positive tumors, but weak power for other categories or HR status Shift work duration accrued pre- versus postmenopausally, or before versus after first pregnancy not differentially associated with breast cancer risk

49 Two additional recent studies of relevance: 1) Night work and breast cancer risk: additional follow-up 2) Higher levels of light at night associated with breast cancer risk?

50 2) Higher levels of light at night associated with breast cancer risk? Nurses Health Study 2 - Biennial addresses geocoded from Analyses restricted to those with a geocoded home address at the street segment level Location of NHS2 residential addresses over follow-up

51 Deriving Light at night (LAN) Satellite imagery data from the US Defense Meteorological Satellite Program s Operational Linescan System Annual composite of lights from cities, towns, and other sites with persistent lighting, representing the relative levels of nighttime illumination to 1 km 2 scale Assign nighttime radiance value for each geocoded address at each year from ww.nasa.gov

52 Cumulative average outdoor LAN and breast cancer risk , NHS2 James, Schernhammer et al, Env Health Persp 2017

53 Cumulative average LAN and breast cancer risk stratified by menopausal status at time of exposure James, Schernhammer et al, Env Health Persp 2017

54 Cumulative average LAN and breast cancer risk stratified by ER/PR status James, Schernhammer et al, Env Health Persp 2017

55 Summary Association between LAN and breast cancer risk more pronounced among premenopausal women, and most strongly linked to ER positive tumor types While further work is required, these findings suggest that outdoor LAN, or its correlates, may contribute to breast cancer risk

56 Summary night work cancer evidence today Since 2007, a large number of new studies on shift work and cancer risk has been published The totality of this evidence continues to support carcinogenic effect of night shift work Subgroup phenotyping will help delineate night workers at highest risk (age, geography, genetic make up, chronotype, etc.)

57 Importance of genetics in these associations Of 15 selected circadian genes, one in particular (Neuronal PAS domaine protein 2, NPAS2) was associated with breast cancer risk Women who were homocygouse for the minor allele AA, experienced a 2.83-times higher risk of breast cancer after as little as 2, or more, years of night shift work NPAS2 <2 years nightwork 2+ years nightwork Ala/Ala Ala/Thr Thr/Thr NPAS2 <2 years nightwork 2+ years nightwork Ala/Ala Ala/Thr Thr/Thr Monsees, Schernhammer et al, Int J Cancer 2012

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59 Night work and other chronic diseases / conditions High blood pressure Cardiovascular disease Diabetes Overweight / Obesity Mental health

60 Nightwork increases risk of developing high blood pressure Effect modification by ethnicity (P int =0.01): Black women White women Never nightwork Lieu, Schernhammer et al, J Hypertens 2012 Ever nightwork ( ) ( ) Individuals with higher melatonin levels experienced lower risk of developing hypertension Age-adjusted RR (95% CI) MV RR (95% CI) Lowest Melatonin Quartile Forman, Curhan, Schernhammer, J Hypertens 2010 Highest Melatonin Quartile ( ) ( ) P Trend <0.001 <0.001

61 Night work and cardiovascular disease risk: a dynamic association Risk significantly increases with each year of night work But also declines once night work ceases Vetter, Schernhammer et al, JAMA 2016 Tuniv.-Prof. DDr. Eva Schernhammer

62 Lower melatonin levels associated with higher diabetes risk Women with the highest melatonin levels had an estimated incidence rate of 427 diabetes cases per personyears, compared to 927 diabetes cases per personyears among women with the lowest melatonin levels. Highest Melatonin Tertile Middle Melatonin Tertile Lowest Melatonin Tertile >49 ng/mg ng/mg 26 ng/mg ( ) McMullan, Schernhammer et al, JAMA ( )

63 Type of shift work and type 2 diabetes risk Vetter, Schernhammer et al. Diabetes Care 2018

64 Average number of night shifts per month predicts type 2 diabetes risk: Vetter, Schernhammer et al. Diabetes Care 2018

65 Night work increases risk of developing type 2 diabetes, - chronotype modifies this association In mega-study, clear association demonstrated Significant interaction between chronotype and night work Per 5 years of night work, the risk of developing type 2 diabetes went up by 11% Weight gain of 0.45 kg per each 5 years of nightwork Pan, Schernhammer et al, Plos Med 2011 Odds Ratio (95% Confidence Intervals) None Significant interaction p=0.004 Intermediate 1-10 yrs 10+ yrs None Early 1-10 yrs 10+ yrs * None * 1-10 yrs Late 10+ yrs Exposure to Night Shift Work Vetter, Schernhammer et al, Diabetes Care 2015

66 Does light at night affect everyone equally?

67 Clock <24 hrs Clock >24 hrs

68 Chronotypes in the population early larks early risers perform mentally and physically at their best in the morning go to bed early in the evening Roenneberg et al 2003 night owls stay up late at night rise at a later time perform best mentally and physically in the late afternoon or evening

69 Chronotype assessed via MEQ Morning-Eveningness Horne and Ostberg chronotype questionnaire (MEQ) 19 multiple choice questions each answer assigned a value from 0 to 6 score ranging from 16 to 86, with lower values corresponding to evening types. 19. One hears about "morning" and "evening" types of people. Which ONE of these types do you consider yourself to be? Definitely a "morning" type Rather more a "morning" than an "evening" type Rather more an "evening" than a "morning" type Definitely an "evening" type R > 90% Q19 with Questionnaire s Score

70 Evening types are more prevalent among night workers in NHS2 Chronotype N Day-shift N Rotating OR 95% CI 1 (Def. AM) 10 (22%) 18 (22%) Referent 2 (AM>PM) 22 (48%) 30 (36%) (PM>AM) 9 (20%) 20 (24%) (Def. PM) 5 (10%) 15 (18%)

71 Circadian light meter Develop an instrument that will: Accurately measure retinal light exposure from daylight and electric light as it impacts visual system and nonvisual biological responses Measure activity Measure temporal characteristics Instrument s characteristics Lightweight Portable, headset Inconspicuous Photo: Dennis Guyon Slide Courtesy LRC/M. Figueiro

72 Shift schedules effect on circadian rhythm

73 Chronotype s effect on circadian rhythm Among day workers only Morning type Intermediate Evening type

74 Effect of night work depends on degree of mismatch between chronotype and work hours: = 3 day shifts = 3 night shifts morning types intermediate types _._ evening types

75 A mismatch between internal and external clock: Chronotype and working times interact in their association with type 2 diabetes How does a mismatch between chronotype and working hours affect other diseases, e.g. cancer risk?

76 Interaction between shift schedules and chronotype cancer risk? Only few studies, to date, have used a more refined assessment of circadian disruption, taking chronotype into account: Hansen et al., OEM 2012 Ramin et al., Chronobiol Intl 2013 Papantoniou et al., Int J Cancer 2014

77 Women with morning preference who work night shifts have a higher risk of breast cancer than evening types: Hansen & Lassen, OEM 2012

78 Prostate cancer risk Papantoniou et al. (2014): Spanish population-based case-control study (1,095 cases and 1,388 controls) Elevated risk, particularly for high-risk tumors and with longer duration of shift work: 28+ years, 63% risk increase, p-trend = Chronotype influences risks

79 Suggestive for a role of chronotype in the association between night work and prostate cancer risk: Papantoniou et al., Int J Cancer 2014

80 Offspring depression risk higher if mother worked shifts that were mismatched with her internal clock History of rotating night shift work Never <3 yrs 3-5 yrs 6+ yrs P trend Ever worked rotating night shifts Self-reported physician diagnosed depression Definite morning types OR (95 %CI) Cases/participants 20/542 35/528 30/391 13/182 78/1, MV model 1 (ref) ( ) ( ) ( ) 0.03 ( ) Intermediate and definite evening types OR (95 %CI) Cases/participants 70/1,138 64/973 48/740 10/ /2, MV model 1 (ref) ( ) ( ) ( ) 0.13 ( ) Strohmaier, Schernhammer, work in progress P interaction =0.03

81 Currently ongoing work in NHS3 Development and validation of circadian strain metrics (i.e. work and sleep hours mismatch score) Based on both MEQ as well as midpoint of sleep on work free days Proof of principle with BMI as first endpoint to associate with this derivation of circadian strain

82 How to make sense of all of this Univ.-Prof. DDr. Eva Schernhammer Light up my Life 82

83 Preventive measures Reduce light at night? Rube Goldberg

84 We are moving towards precision prevention Association between night work and risk of cancer as well as several other chronic diseases appears sufficiently demonstrated Risk appears to be stronger among certain individuals Individual health risk when working night shifts (or otherwise chronically exposed to light at night) is influenced by several components: Genetic phenotype Chronotype und mismatch between chronotype and work hours Particularly sensitive age groups Baseline melatonin levels as sign of health circadian system (rigid vs. flexible) Preventive strategies likely also ought to focus on a handful of important lifestyle choices Univ.-Prof. DDr. Eva Schernhammer Light up my Life 84

85 Funding National Institutes of Health: Research NIH/CDC grants: R01 OH R01 OH R21MH R01 CA50385 R21 OH Infrastructure of the NHS cohorts UM1 CA UM1 CA R01 CA49449 P01 CA87969 R01 CA67262

86 Terminankündigung Manolis Kogevinas ISGlobal Barcelona (previously CREAL) 13. März 2019 in Wien, Zentrum für Public Health, Meduni Wien Gleichzeitig 5-Jahres Feier ÖGEpi (Österreichische Gesellschaft für Epidemiologie)

87 Vielen Dank für Ihre Aufmerksamkeit! CélineVetter Lani Wegrzyn Jen Massa Eric Zhou Claudia TrudelFitzgerald Elizabeth Devore Univ.-Prof. DDr. Eva Schernhammer