The Risks and Benefits of Cutaneous Sunlight Exposure A thesis submitted to The University of Manchester for the degree of Doctor of Medicine in the Faculty of Biology, Medicine and Health 2016 Sarah Jane Felton School of Biological Sciences Division of Musculoskeletal & Dermatological Sciences 2 CONTENTS List of contents......................................................................................................................................... 3 List of figures ............................................................................................................................................ 8 List of tables ............................................................................................................................................10 List of abbreviations ............................................................................................................................11 Abstract ....................................................................................................................................................15 Declaration ..............................................................................................................................................16 Copyright statement ...........................................................................................................................17 Acknowledgements .............................................................................................................................18 CHAPTER 1: INTRODUCTION 1.1 Electromagnetic Radiation ....................................................................................................19 1.1.1 The electromagnetic spectrum ............................................................................19 1.1.2 Ultraviolet radiation .................................................................................................21 1.1.3 Ultraviolet radiation reaching the Earth’s surface.......................................22 1.2 Vitamin D .......................................................................................................................................23 1.2.1 Sources of vitamin D .................................................................................................23 1.2.1.1 Dietary .........................................................................................................23 1.2.1.2 Cutaneous synthesis ..............................................................................24 1.2.2 Vitamin D metabolism .............................................................................................25 1.2.2.1 Control of vitamin D synthesis ..........................................................26 1.2.3 Functions of vitamin D ............................................................................................26 1.2.3.1 Musculoskeletal health .........................................................................27 1.2.3.2 Systemic diseases and malignancies................................................28 1.2.4 Vitamin D supplementation ..................................................................................29 1.2.5 Age and vitamin D production .............................................................................30 3 1.3 Skin pigmentation, delayed tanning and phototype ...................................................31 1.3.1 Constitutive pigmentation .....................................................................................31 1.3.2 Facultative pigmentation and epidermal thickening ..................................32 1.3.3 Skin phototype.............................................................................................................33 1.3.4 Minimal erythemal dose ..........................................................................................33 1.4 Skin cancer ...................................................................................................................................34 1.4.1 Incidence .......................................................................................................................34 1.4.2 Risk factors ...................................................................................................................35 1.5 Cutaneous Deoxyribonucleic acid (DNA) ........................................................................36 1.5.1 Structure: Base pairing ............................................................................................36 1.5.2 Direct DNA damage ...................................................................................................37 1.5.2.1 Cyclobutane pyrimidine dimers (CPD) ..........................................37 1.5.2.2 Pyrimidine-6-4-pyrimidone photoproducts (6-4 PP)..............38 1.5.2.3 Oxidative DNA damage: 8-Oxo-2'-deoxyguanosine .................38 1.5.3 Estimation of DNA damage by urinary excretion .........................................40 1.5.3.1 Urinary 8-oxodG ......................................................................................40 1.5.3.2 Urinary CPD ...............................................................................................43 1.5.4 DNA damage and repair ..........................................................................................45 1.6 UVR-induced erythema ...........................................................................................................48 1.7 Photoageing .................................................................................................................................50 1.8 UVR effects on immunity.........................................................................................................51 1.8.1 Photo-immunosuppression ...................................................................................51 1.8.2 Antimicrobial peptides.............................................................................................52 1.9 Endocannabinoid system .......................................................................................................54 1.9.1 Anandamide and 2-arachidonyl glycerol .........................................................54 1.9.2 The cutaneous endocannabinoid system ........................................................54 4 1.9.3 Involvement in skin disease...................................................................................55 1.9.4 Response to UVR.........................................................................................................56 1.9.5 Involvement in mood ................................................................................................57 1.10 Psychological effects of sunlight exposure .....................................................................58 1.10.1 Seasonal affective disorder..................................................................................59 1.10.2 Dependency on suntanning ................................................................................59 1.10.3 Opioids and suntanning .......................................................................................60 1.11 Artificial sunlight ........................................................................................................................62 1.11.1 Sunbeds .......................................................................................................................62 1.11.2 Psoriasis and phototherapy ................................................................................63 1.12 Guidance on sunlight exposure ............................................................................................64 1.12.1 National campaigns ................................................................................................64 1.12.2 Apparent discordance between national guidance and health benefits ......................................................................................................................................65 1.13 Aims of this thesis .....................................................................................................................66 Contribution of the author and her co-authors ......................................................................68 Rationale for submitting in alternative format .......................................................................69 CHAPTER 2: METHODOLOGY ......................................................................................................71 2.1 Intervention study ....................................................................................................................71 2.1.1 Study design and approval .....................................................................................71 2.1.2 Subjects ..........................................................................................................................71 2.1.3 Protocol overview .....................................................................................................72 2.1.4 Baseline MED assessment ......................................................................................74 2.1.4.1 Waldmann UV6 lamp .............................................................................74 2.1.4.2 UVR output measurements .................................................................74 5 2.1.4.3 MED testing procedure .........................................................................74 2.1.5 Simulated summer sunlight