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BLUE LIGHT A review of the evidence on the potential benefits and harms of blue-filtering lenses • Thierry Villette PhD, Essilor International • Prof. John Lawrenson FCOptom, City U. London LECTURE. Monday 13 March. 11:30 am Blue-light – Part II AGENDA 01 BLUE-CUT TRADE-OFF 02 PHOTOBIOLOGY 03 LENS TECHNOLOGY & CRITERIA Blue-cut lenses: their promise Short-term benefits claimed: Long-term benefits claimed: reduces visual fatigue, digital eyestrain, glare better contrast, depth perception visual comfort, relaxed vision, ideally suited for digital world, for indoor activities … protects against harmful blue light, prevents retinal ageing, AMD, neurodegenerative process visual health, protects visual capital … Europe Amera US / CA … Latin America CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Blue-light – Part II AGENDA 01 BLUE-CUT TRADE-OFF 02 PHOTOBIOLOGY 03 LENS TECHNOLOGY & CRITERIA PHOTORECEPTION VISUAL VA, CS scotopic, color … NON VISUAL sleep, mood, alertness, cognition, pupil reflex … CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy PHOTOTOXICITY photochemical damage oxidative stress inflammation tissue dysfunction eye diseases Photoreception CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Photoreception – Light is essential for vision… CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Photoreception - … but also for non visual functions Light is the main synchronizer of our biological clock. New photoreceptor identified in 2002: ip-RGC (1 – 3% of RGCs) LOCOMOTOR ACTIVITY COGNITION MOOD PUPIL REFLEX SLEEP Blue-Turquoise 480 nm BODY TEMPERATURE ipRGC Melanopsin CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Without light, the biological clock drifts in phase Sleep hours Jours consécutifs dans le gouffre 1 Michel Siffre, 24 yo Summer 1962 62 days in French alps 10 20 30 40 33h shift 50 8 16 24 8 16 24 8 16 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Consequences of a poor light synchronization • Fatigue • Alertness disorders • Difficulties of concentrating • Memory disorders • Mood disorders • Sleepiness • Fragmented sleep • Poor sleep efficiency • Metabolic troubles • Muscular troubles • Digestive troubles • Cardiovascular troubles Nature reviews, Neurosciences CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Phototoxicity State of the art CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Light & the eye, multiple risk parameters Spectrum Eye absorption Radiance Genetics Orientation Ethnics Distance Time Light environment Individual risk profiling Patient Season Altitude Latitude Luminance ratios Age Gender Lifestyle (food, smoking…) Surface reflectances Protections CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Acute phototoxicity Rapid, bright light & short duration exposure 13 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Chronic / cumulative phototoxicity Long-term, moderate light & long duration exposure / repetitions / wavelength-dependent (photochemical reactions) 14 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Our light exposure behaviours are rapidly evolving 15 | CONFIDENTIAL | ESSILOR© and Paris Vision Institute –R&D Disruptive, Thierry Villette Artificial light sources vs Sunlight Daylight Halogen (sun) Incandescent Fluorescent Cold white LED Over 90% of light sources worldwide based on LEDs by 2020. 16 | CONFIDENTIAL | ESSILOR© and Paris Vision Institute –R&D Disruptive, Thierry Villette Fluorescent Photoreception VS Phototoxicity a threatened equilibrium PHOTORECEPTION PHOTOTOXICITY Vision / Well-being Pathology 17 | CONFIDENTIAL | ESSILOR© and Paris Vision Institute –R&D Disruptive, Thierry Villette Blue light, an identified risk factor for AMD • The Chesapeake Bay study, 1992 (Taylor et al., Arch Ophthalmol, 1992) • 838 watermen • Significant correlation (p=0.05) between blue light exposure during the previous 20 years and severe AMD. • Compared with age-matched controls, AMD patients were significantly higher exposed to blue light but equally exposed to UV. • The Beaver Dam Eye Study, 2004 • 5000 individuals, 43 – 84 yo • The amount of time spent outdoors between 13 and 19 and between 30 and 39 yo was significantly associated with development of both early and late AMD. • The EUREYE study, 2008 • Correlation between blue exposure and wet AMD for patients with lower antioxidant level • Sui et al., Br J Ophthalmol, 2012, Meta-analysis, 14 pooled studies. 12 studies concluded to an increased risk of AMD with greater sunlight exposure (OD 1.379). 6 studies reported significant risks. • Higher prevalence of AMD after cataract surgery (loss of natural blue filtering) CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy YELLOW IOL’s & RETINAL PROTECTION Wang JJ, Klein R, Klein BE, Mitchell P et al. Increased risk (OR 5.7) for developing Ophthalmology 2003 late-stage ARM, particularly wet AMD, after 5-year of cataract surgery >6000 subjects; Pooled data from Beaver Dam Eye & Blue Mountains studies 110(10):1960-7 Nagai H et al. Henderson BA, Grimes KJ (2010) Survey Ophthalmol (55) 284-9 • Photoreception • • • • • • • • • Transmission Scotopic vision VA VA low contrast contrast sensitivity color vision Sleep/circadian Photoprotection good ++ • • • • • • • • Low • superior good good good good good good good • • • • • • • • typically similar to 53 y.o. may be altered in some subjects good good (save in low light) good (> in mesopic) good (except blue nuances) good (Mind the spectrum!) High CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy 25% blue-filtering IOLs (54% in the USA) TREND: Blue-light – Part II AGENDA 01 BLUE-CUT TRADE-OFF 02 PHOTOBIOLOGY 03 LENS TECHNOLOGY & CRITERIA CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Phototoxicity mechanism in outer retina - AMD Retinal Pigment Epithelium (RPE) cells ensure SURVIVAL, FUNCTIONING and RENEWAL of photoreceptor degenerate in maculopathies such as AMD CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Phototoxicity mechanism in outer retina - AMD (2/2) RPE RPE AND / OR AND / OR ATR hν O2 Reactive oxygen species hν Lipofuscin CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Lipofuscin: pathological photosensitizer in aging and AMD Delori et al., IOVS, 2012 Wing et al., IOVS; 1978 Fast lipofuscin accumulation in early age and after 45 yo CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Mains in vivo studies Increasing dose Blue light: lower thresholds for photochemical damages – Photoreceptor action spectra van Norren & Gorgels, PP, 2011 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Putting et al., IOVS, 1994 Model in vivo, rabbits Spectral band 12 nm-wide blue bands 408, 418, 439, 455 and 485 nm Exposure duration 1 to 6 h Light level 35 - 208 mW/cm² - high level Analysis Conclusion Fluorescein (permeability damage) 439 nm is the most toxic wavelength for permeability damage in rabbits. CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Sparrow et al., IOVS, 2000 Model in vitro, ARPE-19 cell line treated with A2E (100 µM) Spectral band 1/ Blue light ; 2/ Green light Exposure duration 60 s Light level 1/ 75 mW/mm² ; 2/ 200 mW/mm² - high level (acute) Analysis Conclusion No phototoxicity without photosensitizer. The higher the concentration in photosensitizers, the higher the phototoxicity. Blue light is 6.5 to 7.5 x more toxic than green light for RPE cells. CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Godley et al., JBC, 2005 Model in vitro, RPE cells treated with lipofuscin Spectral band Blue-green light [390 nm – 550 nm] Exposure duration 1 to 6 h Light level 2,8 mW/cm² - low level (chronic) Analysis v Conclusion Blue light at chronic light levels induces DNA lesions, espacially for RPE cells loaded with the age photosensitizer lipofuscin. CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Chamorro, Sanchez-Ramos et al., PP, 2013 Model in vitro, cell line RPE cells Spectral band LEDs - blue-468 nm, green-525 nm, red-616 nm and white light Exposure duration 3 light–darkness 12 h/12 h cycles Light level 5 mW/cm² Analysis Apoptosis Viability Conclusion LED radiations decrease 75–99% cellular viability, and increase 66–89% cellular apoptosis. Higher toxicity for cold-white and blue LEDs. CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Phototoxicity refined spectral data CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Collaborative research program since 2009 Custom-made cell illumination systems in vitro models of eye diseases Biomarker analysis 30 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy in vitro photoprotection Cell model of retinal photoageing and AMD A2E A2E Primary RPE cell cultures Major component of lipofuscin 31 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Tight junctions Nucleus photometry & illumination model LED-based fibered system, 14 narrow illumination bands (10 nm) from 390 to 520 nm + 630 nm, adjustable irradiances Moderate irradiances normalized to retinal sunlight irradiances 18h light exposure, n≥ 6 E e,retina (λ ) = A pupil u '² ×L e , source (λ ) × τ (λ ) Calculated irradiances reaching the A2E-loaded RPE cells (mW/cm²) UNIT 2 1,42 1,35 1,40 1,30 1,42 1,36 1,60 1,40 1,47 1,50 1,23 1,09 1,20 1,00 0,82 0,80 0,59 0,60 0,35 0,40 0,20 0,11 0,04 0,00 380 UNIT 1 430 480 530 Wavelength (nm) 56 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy 580 630 680 The phototoxicity action spectrum on RPE cells (outer retina): 415-455nm * * * 8 1,8 * * * 7 * * * 1,6 * * * 1,4 6 1,2 5 1,0 4 0,8 3 0,6 2 0,4 1 0,2 0 0,0 Dark 390 410 430 450 470 Eclairements (mW/cm²) Mort cellulaire – apoptose 40 µM A2E 9 490 510 630 Longueur d’onde (nm) • Toxicity not strictly correlated to irradiances • Toxicity not strictly correlated to the photon energy • Very significant increase of cell death 415 – 455 nm 33 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy PLOS ONE paper. August 2013 PLoS ONE (www.plosone.org). August 2013. 8(8). e71398 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy ↑ SOD clustering activity but ⇊ functioning ⇈ peri-nuclear for nucleus protection + ⇈ ROS (reactive ⇈ ROS (reactive globular shape oxygen species) oxygen species) **** **** ⇊ catalase activity and functioning **** 0 0 3 6 0 4 8 4 0 4 0 rk a D **** **** 4 * ** * ** * BV light induces… **** * *** * *** * *** * *** **** ** *** **** *** **** 0 0 63 0 48 44 40 D ar k 0 * BV light at 430 nm Darkness /Red light 02.⇈ cell death GPX 1,6 1,4 0,2 0 0,0 D CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy 0 1 ↑ glutathione activity but ⇊ functioning 3 0,4 0 2 6 0,6 8 3 0 0,8 4 4 **** H20 + 02 4 1,0 0 5 4 1,2 a 6 0 7 H 20 + 02 1,8 4 8 ** * ** * ** * * * * CAT H 2 02 rk 9 SOD Conclusion - Blue-light induced retinal damage • Blue-violet toxicity action spectrum on RPE cells confirmed with oxidative stress biomarkers (415 – 455 nm). • Blue-violet light induces high ROS production (H2O2, O2.-). • Blue-violet light acts as a strong inhibitor of antioxidant mechanisms (glutathione, SOD, catalase). • Blue-violet light directly impacts mitochondria: peri-nuclear clustering, globular shape, decreased respiration rate. • Low-irradiance blue-violet light induces apoptotic cell death. • … Accelerated retinal photo-ageing and AMD. 36 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy BLUE LIGHT HAZARD FUNCTION should be revised to a B2(λ) curve for cumulative hazard B (λ) = [Ham et al’s 1976] acute action spectrum on monkey eyes (acute) X spectral transmittance of the human crystalline lens Blue hzard function - relative spectral effectiveness weighting function B (normalized to 1) 1 1997 0.9 0.8 0.7 0.6 0.5 B1 0.4 B2 0.3 0.2 0.1 0 380 400 420 440 460 480 500 Wavelength (nm) Ham W.T., Mueller H.A. and Sliney D.H. (1976) Retinal sensitivity to damage from short wavelength light. Nature. 260(5547):153-5 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Photoprotection potency in vitro CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Photoprotection benefits A complete protection on front AND back sides 1 A 20% cut of noxious Blue-Violet light in vitro quantification of protective effect Decrease of 25% in average of the target retinal cell death over [400 nm ; 455 nm] compared to the naked eye Apoptose 40 µM A2E 6,00 5,00 Crizal Prevencia 4,00 Naked eye 3,00 Crizal Prevencia 2,00 Naked eye 1,00 0,00 Noir 400 410 420 430 440 450 460 480 490 500 Longueur d’onde (nm) The UV protection on back side 2 A 25x higher protection compared to the naked eye CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy in vitro photoprotective potency (% decrease in cell death) in vitro photoprotection potency model 100% y = 6.5008x3 - 6.3084x2 + 2.3115x R² = 0.9196 80% 60% 40% 20% 0% 0% 20% 40% 60% 80% BVC (%) The first biological quantification of the effect of blue-cut optical filters in vitro CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy 100% Blue-light – Part II AGENDA 01 BLUE-CUT TRADE-OFF 02 PHOTOBIOLOGY 03 LENS TECHNOLOGY & CRITERIA CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy LENS TECHNOLOGIES for BLUE-VIOLET FILTERING interferential vs absorption … or combined Antireflective coating HMC system HC system Absorber in coating Additional layer Nanostructure technologies Absorber in MASS Substrate interferential Filtering % (efficacy) Narrow band (selectivity) low w. thin films absorption high ++ -- CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Spectral selectivity narrow-band ‘gutter profile’ SELECTIVITY of a BLUE-CUT LENS Blue cut filter concepts Target λ selectivity cut the bad, leave the good 100 90 Transmission (%) 80 70 60 50 40 30 retina cell protection 20 chronobiology light 10 0 400 410 420 430 440 450 460 470 480 490 500 Wavelenghts (nm) 1. The selectivity of the filter for the Blue-Violet light cut [415-455] nm 2. The selectivity of the filter for the chronobiological light [465-495]nm CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy Product performances: toward next generations of blue-cut lenses AR efficacy 0.6 (Rv >2,5= not AR) 1 T blue-turquoise% Visible transmission [465-495]nm 100% 100% (Tv% <80%=Class 1) 92% 92% >2,5 80% + Yellow index (b*) 80% 20% + lens aesthetics Product A 25 Product B Product C 40% Blue-violet cut [400-455]nm 50% 50 ESPF: UV protection + in vitro photoprotection potency 44 | CONFIDENTIAL | ESSILOR© and Paris Vision Institute –R&D – AprilDisruptive, 2013 - R&D Thierry Disruptive Villette Coralie Barrau, Thierry Villette CONCLUSIONS • Blue-violet light 380-455nm is a recognized risk factor in retinal ageing and maculopathies • Opportunity and filtering level of blue-cut lenses to be discussed with ophthalmologists and optometrists: advice vs individual risk and environmental exposure level trade-off photoprotection vs photoreception • Adopting relevant criteria for a blue-filtering lens: 45 blue-violet light filtering: T% in [380-455nm], T% in [415-455nm] in vitro photoprotection potency (RPE cell model of AMD) – biology QC chronobiology blue T% [465-495nm] Tv(%), yellow index (b*), aesthetics CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy FUTURE RESEARCH NEEDED • Prospective and controled clinical studies to assess the benefit of blue-cut lenses to slow down retinal ageing and AMD target population / filtering level / endpoint / follow-up 3+ years • To what extent does blue-violet light contribute to pathogenesis? to disease progression? • Blue-cut lenses and immediate benefits what spectral determinant / what filtering dose-effect on eye fatigue, digital eye strain, glare, photosensitivity … 46 CONFIDENTIAL © 2016 ESSILOR - All rights reserved – Do not copy A review of the evidence on the potential benefits and harms of blue-filtering lenses Professor John Lawrenson City University London Declarations of Interest • John Lawrenson has no prorietary interests in the development or marketing of any product mentioned in this lecture ASA Ruling ‘Boots did not provide evidence that a modest 20% reduction in the amount of harmful blue light entering the eye would lead to a significant reduction in the amount of retinal damage caused by exposure, as implied by the ad. In the context of an ad which purported that harmful blue light was damaging to retinal cells and implied that the majority, if not all, harmful blue light was filtered out by Boots’ lens coating before it reached the retina, we did not consider the evidence was adequate to support the implied claim made. We therefore concluded the ad was misleading.’ https://www.asa.org.uk/Rulings/Adjudications/2015/10/Boots-Professional-ServicesLtd/SHP_ADJ_293200.aspx#.Vt62ueaHuFt Questions for the Optometrist • Should we worry about exposure to blue light in our natural visual environment? • Do computers, tablets and smartphones pose a serious risk to ocular health ? • Is there a case for photo-protection and if so how can this be achieved? Is blue light harmful? Radiance Radiant power emitted into a solid angle Wm− 2 sr − 1 Luminance Luminous power as perceived by a human standard observer cd m-2 http://www.icnirp.org/cms/upload/publications/ICNIRPVisible_Infrared2013.pdf Is blue light harmful? http://www.crizalusa.com/content/dam/crizal/us/en/pdf/bl ue-light/Blue-Light-Roundtable_White-Paper.pdf Is blue light harmful? Is blue light harmful? http://www.icnirp.org/cms/upload/publications/ICNIRPVisible_Infrared2013.pdf Role of the Pupil http://www.icnirp.org/cms/upload/publications/ICNIRPVisible_Infrared2013.pdf Natural protective filter Lens transmission aged 5, 50, 80 years http://www.ncbi.nlm.nih.gov/pubmed/16445433 Natural protective filter http://www.sciencedirect.com/science/article/pii/S1350946 215000865 Sunlight and AMD Sunlight and AMD http://bjo.bmj.com/content/97/4/389.abstract Sunlight and AMD In the low exposure group 20 people out of 1000 developed late AMD over 75 years, compared to 27 (95% CI 22 to 34) out of 1000 for the high exposure group Sunlight and AMD The number needed to harm (NNH) indicates how many patients on average need to be exposed to a risk-factor over a specific period to cause harm in a patient who would otherwise not have been harmed. NNH=135 In the low exposure group 20 people out of 1000 developed late AMD over 75 years, compared to 27 (95% CI 22 to 34) out of 1000 for the high exposure group Cataract Extraction and AMD http://www.ncbi.nlm.nih.gov/pubmed/16445433 Cataract Extraction and AMD Relative Risk =3.05; CI 2.05 - 4.55 http://www.ncbi.nlm.nih.gov/pubmed/21144031 Cataract Extraction and AMD Benefits versus side effects of blue-filtering IOLs http://www.ncbi.nlm.nih.gov/pubmed/16445433 Benefits of Blue Light http://www.abbottmedicaloptics.com/products/cataract/m onofocal-iols/tecnis-1-piece-iol Based on the evidence the authors of this perspective disagreed on the IOL they would choose should they need cataract surgery in the future! • MAM opted for a UV-only blocking IOL to provide maximal UV protection and to wear sunglasses in bright environments, which can be removed for optimal vision in dim environments • JRS opted for a UV+ blue blocking IOL to provide the same protection against phototoxicity and scotopic sensitivity as a 50 year old crystalline lens and to wear sunglasses in bright environments , which can be removed for optimal vision in dim environments Dr John O’Hagan Group Leader, Laser and Optical Radiation Dosimetry Group Public Health England http://www.ncbi.nlm.nih.gov/pubmed/26768920 The International Commission on Non-Ionizing Radiation Protection (ICNIRP) ‘rule of thumb’ is that detailed risk assessments within spectral range 380-780 are not required for luminance values <104 cd m-2 The ICNIRP blue light weighted radiance exposure limit for long-term viewing in range 300-700nm is 100Wm− 2 sr − 1 http://www.ncbi.nlm.nih.gov/pubmed/26768920 Blue light weighted spectral radiance: • clear day in June = 10.4 Wm−2 sr −1 • cloudy day in December = 3.4 Wm− 2 sr − 1 These exposures represent 10.4% and 3.4% of the exposure limit. http://www.ncbi.nlm.nih.gov/pubmed/26768920 Filtering the Blue Blue light hazard peaks at 440nm 10% 40% 5 yr old versus 50 yr old lens https://www.2020mag.com/ce/TTViewTest.aspx?LessonId=10865 4 http://www.ncbi.nlm.nih.gov/pubmed/10701805 Filtering the Blue 50% UV versus blue filtering IOL http://www.ncbi.nlm.nih.gov/pubmed/10701805 Filtering the Blue 50% Filtering the Blue http://www.ncbi.nlm.nih.gov/pubmed/10701805 Summary • Blue light has the potential to cause retinal phototoxicity although blue light also plays a role in scotoptic sensitivity and circadian entrainment • Blue light sources encountered indoors are unlikely to approach exposure limits, even for extended viewing times • The eye possesses natural defences to mitigate blue light damage • Photoprotection could be considered in ‘at risk’ individuals