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Risk Factors of Blue and Bright Light Therapy

For the purposes of this discussion, blue light is defined as light within the wavelength range of 400-480 nm, because over 88% of the risk of photo-oxidative damage to the retina from fluorescent lamps (cool white or "broad spectrum") is due to light wavelengths in the range of 400-480nm. The blue light hazard peaks at 440 nm, and falls to 80% of peak at 460 and 415 nm. In contrast, green light of 500 nm is only one-tenth as hazardous to the retina than blue light with a wavelength of 440 nm.10 (The standards used in these measurements are from the International Commission on Non-Ionizing Radiation Protection.)

Photoretinitis, or light-induced photochemical damage to the eye, is related to the "blue light hazard", a term which suggests why the use of blue light therapy lamps, blue-enhanced light therapy lamps, or "bright light” therapy lamps substantially increases the risk of light-induced retinal damage1,2,3,4. In addition to the blue light from light emitting phosphors used in the fluorescent lamps of “bright light” therapy devices, these lamps contain mercury to bind the phosphors to the glass, and the mercury in a fluorescent lamp emits characteristic emission spikes at 436 nm and 406 nm on the blue light spectrum. For light therapy devices using white LEDs, the proportion of blue light emissions is even higher, which is why light therapy devices using white LEDs as light sources are often referred to as “blue-enhanced” light therapy lamps.

The following factors indicate why blue light therapy poses a significant, inestimable risk to the retina not accounted for by commercial assessments of blue light hazard:

1. The variability of individual susceptibility to AMD, as well as to the variability of the transmissibility of blue light through the eye to the retina:

The susceptibility for AMD varies greatly with the individual, and the conditions by which normal retinal deterioration from aging becomes the pathological deterioration known as AMD are not yet established. Contributing to the variability of susceptibility amongst individuals are genetic factors, macular pigment density, lifestyle factors such as the amount of fat, lutein, antioxidant vitamins and zinc in the diet, history of smoking, outdoor activity, and other environmental factors such as previous levels of light exposure.11,12,13

There is a problem determining the intensity of blue light needed for effective therapy. Recent studies have shown that monochromatic blue light (wavelengths 479 nm, or 460 nm) has no greater chronobiological effect than regular fluorescent white (polychromatic) light, even in young men.14, 14a Read more

Furthermore, the proportion of blue light reaching the eye that is transmitted to the retina is highly variable from one individual to another. Age-related yellowing of the lens and changes in the cornea and vitreous substantially decrease the amount of blue wavelengths reaching the retina by middle age. Therefore for middle-aged and older people the intensity of blue light (440-480 nm) needed for effective treatment would have to be substantially increased. The relationship of macular pigment density to age is contoversial and it may be that there is an age-related change in the density of the blue light absorbing macular pigment (peak absorption 460 nm). Macular pigment is considered to be protective of the small region of the retina involved in vision from photo-oxidative stress induced by blue light absorption. Macular pigment can prevent up to 95% of blue light from reaching the retina.15 Reduction in macular pigment (MP) density, which indicates the degree to which macular pigment absorbs blue light, is generally regarded as a risk factor for age-related macular degeneration.15a

MP density varies greatly from one individual to another.16 In addition to the age-related changes, MP density is related to genetic make-up, prior history of light exposure, and lifestyle factors. MP density is also substantially related to diet, and some studies indicate MP density can be variable from day to day in the same individual. 17 Since an impotant element by which macular pigment exerts its protective benefit appers to be screening blue light, increasing the intensity of blue light wavelengths to compensate for the age-related decrease in transmission through a yellowed lens might pose severe risk to people with lower levels of macular pigment.18

For all of these reasons, it would be impossible to calibrate a level of blue light that is both effective and safe for a wide range of individuals. Higher levels of exposure to blue light would be necessary to stimulate chronobiologically significant pathways in individuals in whom the ocular media prevents most blue light wavelengths from reaching the retina. But a blue light therapy device that provided sufficient intensity for effective stimulation of a middle-aged or older individual whose ocular media screens our most of the blue light could pose a significant risk of creating photo-oxidative damage in a person who has high transmissibility of blue light, such a younger adult or a person who has had cataract surgery, or a person is pre-disposed to retinal disease.

2. Risks of blue light therapy in the elderly, a target group for light therapy.

The geriatric population is one for whom the hazard from bright light or blue is especially concerning because the anti-oxidative mechanisms needed to protect the retina progressively deteriorate with age starting around age forty.19,20,21 Oxidative damage is of particular concern in the non-replicating photoreceptor cells because they are exceptionally rich in polyunsaturated fatty acids and lipoproteins that are highly susceptible to oxidative damage and exist in an environment that is very favorable to the generation of reactive oxygen species (ROS) from the high levels of oxygen and light energy.22,23 While there is a yellowing of the lens that helps screen out blue wavelengths, other age-related changes to the eye, including the reduction in effectiveness of anti-oxidative mechanisms that protect the retina which occurs with age, increase the susceptibility of the older retina to damage from incident blue light. The level of lipofuscin in the post- mitotic retinal pigment epithelium (RPE) cells adjacent to the photoreceptor cells, increases with age over a lifetime. Lipofuscin is largely made up of photooxidative debris that originates in photoreceptor cells and is phototoxic when it absorbs blue wavelengths of light. Thus exposure of the eye to blue light can lead to an increased level of ROS generation within RPE cells which impairs their functioning, causing the death of adjacent photoreceptor cells and promoting the development of AMD.24,25,26

3. Additional blue light hazard due to the timing of light therapy

Light therapy is believed to be effective only during the subjective night, when melatonin levels are high. Studies show that the retina is much more sensitive to photic damage when serum melatonin levels are high.27  Furthermore, light therapy is often used upon awakening, when the eye is still dark-adapted. The dark-adapted eye is much more sensitive to photic damage than the eye that has previously been exposed to bright light for extended periods of time.28

4. Additional blue light hazard potentially contributed by other medical treatments

Some applications for which light therapy is used increase the risk of retinal damage. For example, some studies suggest that light therapy can enhance and hasten the response to antidepressant medication.29 However, antidepressants are photosensitizing,30,31 as are many other medications,32 including: 1) diuretics, a problem for treating geriatric chronobiological and sleep disorders33 2) some antibiotics, a problem for anyone who develops a bacterial infection while on light therapy 3) non-steroidal anti-inflammatory drugs (NSAIDs)34 4) some neuroleptics 35 5) heart medications and other commonly used medications and popular herbal treatments.36 There are additional medical factors that may increase risk of progressive ocular diseases such as AMD, including the removal of cataracts.37 (Read more on the effects of Blue Light on the Retina after Cataract Surgery)

5. Blue light therapy subverts protective mechanisms against the blue light hazard

In order to provide a sufficient intensity of light for effective treatment, light therapy device manufacturers generally instruct users to place the therapy lamp within the field of vision. In an attempt to reduce the risk of retinal damage from these devices, users are usually advised not to look directly at the light source. However, because of the structure of the eye, incoming light tends to be focused towards the macula, the small region of the retina where vision takes place, and where age-related macular degeneration occurs. Outdoors, in the natural environment, the light entering the eye is mostly light that has been reflected off the objects which are in the field of vision, which in nature are primarily brown or green. Blue light wavelengths therefore constitue only a small fraction of this indirect natural sunlight that enters the eye. A high intensity light source within the field of vision thus subverts a variety of defensive mechanisms that have evolved to protect the retina from the blue light hazard.

These defensive mechanisms include the anatomical positioning and structure of eye and its surrounding features, as well as human posture, which makes it awkward for humans to gaze upwards for long periods of time.38  When the sun is lower on the horizon, it passes through a thicker layer of air that filters out blue light wavelengths. Light that enters the eye generally is reflected off of the objects being viewed, which in most natural environments is typically made up of green, brown, yellow and red tones. Peoples who live in environments that expose the eye to high levels of blue light wavelengths typically develop protective accessories such as snow goggles and desert headdresses, indicating the inadequate adaptation of the human eye to exposure to blue light.39

Naturally protective responses against the "blue light hazard" are keyed to white light, rather than blue light, and thus the eye may be inefficient at protecting itself against a blue light therapy device.40 Numerous genes in retinal cells involved in protective mechanisms are activated or suppressed by exposure to bright light, and for many of these the spectral sensitivity of the stimulus that induces their activity is unknown.

Exposure of the eye to blue light wavelengths generates oxidative damage within photoreceptor cells which is then transferred to the RPE cells where it accumulates as phototoxic debris that contributes to the pathogenesis of AMD. This strongly implies that concern for an advanced onset of blindness from macular degeneration should extend to retinal stress from bright or blue light therapy even in young people without apparent retinal damage, as well as in older people and those with pre-existing retinal damage.41

Awareness is growing that "avoiding exposures to bright short-wavelength [blue] light is the simplest preventative measure against light damage"42. The extent of this concern about the link between blue light exposure and ARMD that exists around the world is attested to by the numerous research groups and the number of studies investigating the contribution of blue visible light to the development of AMD.

Some standards claim to assess the risk of short term damage to photoreceptor cells from high intensity white light sources for a "standard observer". However, individual susceptibility to blue light damage is so variable that these standards cannot presume to determine any individual's risk of acute damage from a blue light therapy device, let alone be used to determine the long term risk that repeated exposure may contribute towards the development of age-related macular degeneration (AMD), to which these standards do not apply.5,6,7  As well, the image of a light source emitting blue light wavelengths on a small area of the retina with the intensity necessary to be chronobiologically effective may damage the retina, even if the same number of photons diffused over a larger portion of the retina do not.8,9

An independent study by the Canadian Defense Department and the U.S. Air Force has now confirmed that blue light wavelengths are not needed for visible light to effectively influence the non-visual physiological pathway from the retina to the brain. The Department of Sleep Medicine at Harvard University has concurred with this finding. The Sunnex Biotechnologies Lo-LIGHT, which filters out blue light wavelengths shorter than 480 nm, was found to be much more efficient than light therapy devices such as the Litebook which usse LED's that emit light with a high proportion of wavelengths from the blue portion of the visible light spectrum, as well being superior to lamps manufactured by Philips with higher emissions of blue light than common white light lamps normally used for indoor lighting. Read more. There is compelling and growing evidence that repeatedly viewing a light source that emits high levels of blue light will substantially advance the development of age-related macular degeneration (AMD). With the confirmation that hazardous blue light wavelengths are not necessary or beneficial for effective light therapy, some experts in retinal damage and some researchers in Light Therapy have recommended that visible blue light wavelengths should be screened out of "bright" light therapy units.43, 44

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REFERENCES

1 "modern light sources operate at high colour temperatures and emit substantial radiant energy at short wavelengths in the visible spectrum, which are known to be more hazardous for retinal tissue than other wavelengths in the visible spectrum. This is the so-called blue light hazard." Cole BL. When is artificial light hazardous? Clin Exp Optom. 2005 Jul; 88(4):195-6.

2 "In conclusion, the current study delineates the vulnerability of the photoreceptor to blue light, providing a mechanistic explanation for blue light hazard in the retina It supports the suggestion that lifetime exposure of the retina to light affects its rate of ageing, in turn contributing to the pathogeneses of age-related macular degeneration."   Blue light induced retinal damage. Wu, Jiangmei   Doktorsavhandling vid Karolinska Institutet October 8, 2004

3 "Visible, non-coherent blue light has a high damage potential. Green light, insharp contrast, does not induce any lesions ... Because sunlight and many high-intensity artificial light sources contain relatively high proportions of blue, and the retina as well as pigment epithelium contain several types of blue-absorbing molecules, the short-wavelength band of the visible spectrum may contribute to the pathogenesis of age-related macular degeneration and amplify some forms of inherited retinal degeneration." Reme CE, Wenzel A, Grimm G, Iseli HP. Mechanisms of Blue Light-Induced Retinal Degeneration and the Potential Relevance for Age-Related Macular Degeneration and Inherited Retinal Diseases. SLTBR Annual Meeting Abstracts 2003; Abstract 3.5 Chronobiology International 2003;20(6):1186-7.

4 "Measurements of the spectrum and energy indicated that the ICNIRP safety guidelines for photochemical retinal damage are exceeded within 1 minute for nine out of 10 combinations [commercial light sources with recommended filters used for endoillumination in ocular surgery]. With an additional 475 nm long pass filter, light levels below 10 mW, and a distance from light probe to retina of at least 10 mm, the allowable exposure time can be increased up to 13 minutes." {This demonstrates the extent to which blue light wavelengths in the region of 400-475 nm contribute to retinal damage from a white light source - our comment} Van den Biesen PR, Berenschot T, Verdaasdonk RM, van Weelden H, van Norren D. Endoillumination during vitrectomy and phototoxicity thresholds. J Ophthalmol. 2000 Dec;84(12):1372-5.

5 "The principal retinal hazard resulting from viewing bright light sources is photoretinitis... Only in recent years it has become clear that photoretinitis results from a photochemical injury mechanism following exposure of the retina to shorter wavelengths in the visible spectrum, i.e., violet and blue light... it has been shown that an intense exposure to short-wavelength light (frequently referred to as "blue light") can cause retinal injury... By filtering out short-wavelengths [blue light] from a white-light arc lamp, Ham et al. showed that the risk of photochemical injury to the retina could be enormously reduced." Guidelines on Limits of Exposure to Broad-Band Incoherent Optical Radiation (0.38 to 3 micro m), The International Commission on Non-Ionizing Radiation Protection. Health Physics 1997; 73(3):539-554.

6 ".. it is clear that blue light damage, with its long accumulation time, is always a threat" Retinal Damage by Optical Radiation. An alternative to Current, ACGIH-inspired Guidelines.  Vos JJ, van Norren D. Clin Exp Optom. 2005 Jul;88(4):200-11

7 "As photochemical reactions depend on the energy of the photons and the rate of reaction depends on the number of photons incident per unit time, there is no "threshold" for a photochemical reaction. It simply happens faster or slower depending on the irradiance." Light Effects on the Retina John Mellerio Principles and Practice Of Ophthalmology Chapter 116 Eds. D M Albert, F A Jakobiec.  W B SAUNDERS Philadelphia, 1994

8 "The assessment of lighting conditions in workplaces has traditionally focused on the measurement of illuminance. ... Illuminance was found to be inadequate to evaluate the effects of natural and artificial environmental light in the workplace. This is due to the fact that the luxmeter is designed to integrate the light detected over a large angle, whereas in near work the operator's retina is mainly stimulated by light originating from objects/images placed in the occupational visual field." B. Piccoli, G. Soci, P. L. Zambelli and D. Pisanello. Photometry in the Workplace: The Rationale for a New Method. Ann. Occup.Hyg., Vol. 48, No. 1, pp. 29-38, 2004

9 "Young adult rhesus monkeys were anesthetized, and received blue [460 nm] LED exposure from a modified slit-lamp. A 3 mm beam of 0.85 mW was imaged onto the retina through a lens positioned before the cornea and exposure damage was determined at time intervals for 12 to 90 min... Two days after 40 min exposure, there was a grey, discolored region, which was over-fluorescent in FAG, and an increase in HRT and S-ERG corresponding to the site which was exposed to LED light. In histological examination at 30 days, the LED had caused produced a marked disruption of the disks of photoreceptor cells, damaged retinal pigment epithelium (RPE) apical villi, and a loss of RPE melanin after 90 min exposure. CONCLUSION: A threshold level was found around 40 min. This morphological damage may impair function and continuous exposure to blue light is potentially dangerous to vision." Koide R, Ueda TN, Dawson WW, Hope GM, Ellis A, Somuelson D, Ueda T, Iwabuchi S, Fukuda S, Matsuishi M, Yasuhara H, Ozawa T, Armstrong D.Nippon. Retinal hazard from blue light emitting diode. Ganka Gakkai Zasshi. 2001 Oct;105(10):687-95.

10 Table 1.  Spectral hazard weighting functions. Guidelines on Limits of Exposure to Broad-Band Incoherent Optical Radiation (0.38 to 3 micro m). The International Commission on Non-Ionizing Radiation Protection. Health Physics Vol. 73, No 3, pp 539-554, 1997.

11 "Age-related macular degeneration (AMD) is thought to be the result of a lifetime of oxidative insult that results in photoreceptor death within the macula. Increased risk of AMD may result from low levels of lutein and zeaxanthin (macular pigment) in the diet, serum or retina, and excessive exposure to blue light. Through its light-screening capacity and antioxidant activity, macular pigment may reduce photooxidation in the central retina." Bone RA, Landrum JT, Guerra LH, Ruiz CA. Lutein and Zeaxanthin Dietary Supplements Raise Macular Pigment Density and Serum Concentrations of these Carotenoids in Humans. Journal of Nutrition 2003 Apr;133(4):992

12 "Late-onset macular degeneration (i.e., AMD) is usually defined as either "dry" or "wet" and is a slow, progressive disease with genetic influences as well as environmental risk factors such as cigarette smoking and perhaps diet and lifetime light exposure" Drusen Proteome Analysis: An Approach to the Etiology of Age-Related Macular Degeneration. Crabb JW, et al. Proceedings of the National Academy of Sciences 2002; 99(23):14682-7

13 "The etiology of age-related macular degeneration (ARMD) is multifactorial, but visible light may play a role in the pathogenesis of this potentially devastating disease. In the Maryland watermen study, advanced ARMD was more common in men exposed to increased levels of blue light (400-500 nm), but not in those with increased levels of ultraviolet exposure. Similarly, the Beaver Dam Eye Study found that exposure to visible light was associated with ARMD in men....Visible light has also been responsible for acute photic retinopathy caused by the operating room microscope." Stenson SM, West CE. Refraction, Spectacles, Contact Lenses, and Visual Rehabilitation. American Academy of Ophthalmologists LEO Clinical Topic Update; April 2003

14 "monochromatic blue light (lamda max 479 nm) was matched with polychromatic white light for total melanopsin-stimulating photons at three light intensities. The ability of these light conditions to suppress nocturnal melatonin production was assessed....A within-subject crossover design was used to investigate the suppressive effect of nocturnal light on melatonin production in a group of diurnally active young male subjects aged 18-35 yrs. A 30 min light pulse, individually timed to occur on the rising phase of the melatonin rhythm, was administered between 23:30 and 01:30 h... Polychromatic [White] light was more effective at suppressing nocturnal melatonin than monochromatic blue light matched for melanopsin stimulation." Light-induced melatonin suppression in humans with polychromatic and monochromatic light. Revell VL and Skene DJ. Chronobiol Int. 2007;24(6):1125-37.

14a See Link in Text Spectral Responses of the Human Circadian System Depend on the Irradiance and Duration of Exposure to Light. JJ Gooley, SMW Rajaratnam, GC Brainard, RE Kronauer, CA Czeisler and SW Lockley. Sci Transl Med 12 May 2010: 2(31) p. 31ra33.

15 "The [macular] pigments absorb a full third of the visible spectrum and it is not uncommon to find peak absorbance as high as 1.3 optical density units (meaning only about 5% of the "blue" or short-wave light is transmitted on to the photoreceptors)." Journal of Food Science Jan/Feb 2010; 75(1): R24-R29, The Influence of Dietary Lutein and Zeaxanthin on Visual Performance. JM Stringham, ER Bovier, JC Wong, BR Hammond, Jr.

15a"Age-related changes in lens density are known to reduce the transmission of short wavelength light, which has been shown to be most effective in suppressing nocturnal melatonin. The aim of the study therefore was to investigate age-related changes in melatonin suppression in response to short and medium wavelength light. ... Melatonin suppression was compared across light treatments and between age groups. Significantly reduced melatonin suppression was noted in the elderly [age 47 +/- 5 years] subjects following exposure to short wavelength (456 nm) light compared to the young subjects. These results are likely to reflect age-related changes in lens density." Light-Induced Melatonin Suppression: Age-Related Reduction in Response to Short Wavelength Light. Herljevic M, Middleton B, Thapan K, Skene DJ.   Exp Gerontol. 2005 Mar;40(3):237-42.
"Macular pigment (MP) is composed of the two dietary carotenoids lutein (L) and zeaxanthin (Z), and is believed to protect against age-related maculopathy (ARM)....We report a statistically significant age-related decline in MP optical density. ... In the absence of retinal pathology, and in advance of disease onset, the relative lack of MP seen in association with increasing age, tobacco use and family history of ARM supports the hypothesis that the enhanced risk that these variables represent for ARM may be attributable, at least in part, to a parallel deficiency of macular carotenoids.
The optical density of the MP in 800 healthy subjects had a mean value of .299 and a range of 0 to 0.868. ... In conclusion, there is a relative lack of MP in association with the most important and established risk factors for ARM (age, cigarette smoking and family history of ARM), several decades before the onset of disease. The importance of this finding rests on the fact that any protective effect of MP depends on its ability to defend against chronic and cumulative retinal oxidative damage, whether induced by blue light (photochemical) or as a result of high oxygen metabolism and will have to be exerted in young to middle age." Risk Factors for Age-Related Maculopathy are Associated with a Relative Lack of Macular Pigment. Experimental Eye Research, Jan, 2007; 84(1): 61-74. J. Nolan, J. Stack, O. O' Donovan, E. Loane, S. Beatty

16 "Macular pigment (MP) filters short-wavelength light before it reaches the visual pigments. At peak absorbance (460 nm), transmission of light through MP can range from almost 100% transmission to as little as 3%." Compensation for Light Loss Resulting from Filtering by Macular Pigment: Relation to the S-cone pathway. Stringham et al. Optom Vis Sci. 2006 Dec;83(12):887-94.
"Individual differences in macular pigmentation are large: in studies using more than 10 subjects, macular pigment density has been found to vary from 0.0. to 1.2 log units at 460 nm." CVRL Color Vision database at the Institute of Ophthalmology in London. Updated: November 20th, 2003.

17 "As in previous studies, however, a significant day-to-day difference in [macular pigment optical density] was observed for both subjects." Wenzel AJ, Fuld K, Stringham JM. Light exposure and macular pigment optical density. Invest Ophthalmol Vis Sci. 2003 Jan;44(1):306-9.

18 "Conclusions:The high amounts of macular pigment in the foveal inner retina are most likely functioning as light filters since they are not in close proximity to the RPE where the bulk of singlet oxygen is generated." B.Li, P.S. Bernstein. The Singlet Oxygen Scavenging Mechanism of Human Macular Pigment. ARVO Annual Meeting, May 2007 (submitted) Poster 2140/B749

19 "Excessive light exposure in the elderly may be particularly risky, since the biological repair processes at the cellular level are generally considered to be less effective as one ages." D.H. Sliney. Ocular Injury Due to Light Toxicity. International Ophthalmology Clinics 1988;28(3):246-250.

20 "Damage to the young and adult eye by intense ambient light is avoided because the eye is protected by a very efficient antioxidant system... After middle age there is a decrease in the production of antioxidants and antioxidant enzymes. At the same time, the protective pigments are chemically modified (lenticular 3-hydroxy kynurenine pigment is enzymatically converted into the phototoxic chromophore xanthurenic acid; melanin is altered from an antioxidant to pro-oxidant) and fluorescent chromophores (lipofuscin) accumulate to concentrations high enough to produce reactive oxygen species. We have known for some time that exposure to intense artificial light and sunlight either causes or exacerbates age-related ocular diseases... Unfortunately, most of these protective enzymes decrease beginning at 40 years of age." Roberts JE. Ocular Phototoxicity. J Photochem Photobiol B. 2001 Nov 15;64(2-3):136-43.

21 "The antioxidants [in the RPE] may be insufficient to detoxify all the radicals and there may be an insidious buildup of oxidative damage throughout life that only manifests itself in the aged." Winkler BS, Boulton ME, Gottsch JD, Sternberg P. Oxidative damage and age-related macular degeneration. Mol Vis. 1999 Nov 3;5:32

22 "Photoreceptor outer segments live in a potentially toxic environment that includes high oxygen and high photon flux. These conditions are conducive to photooxidative damage, and the production of byproducts of lipid peroxidation such as malondialdehyde, which can cross link proteins." Bok D. New Insights and New Approaches Towards the Study of Age-Related Macular Degeneration (AMD). Proceedings of the National Academy of Sciences 2002; 99(23):14619

23 "Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates (ROI), has been implicated in many disease processes, especially age-related disorders. ROIs include free radicals, hydrogen peroxide, and singlet oxygen, and they are often the byproducts of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light." Beatty S. et al. The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration. Surv Ophthalmol. 2000 Sep-Oct;45(2):115-34.

24 "The observed photoreactivity of human RPE cells is, to a significant extent, determined by their lipofuscin content... [B]lue light seems to be the most efficient radiation under physiologically relevant conditions. This is because ultraviolet radiation is completely filtered out by the cornea and lens of the adult human eye and, as a result, virtually no light below 400 nm is transmitted to the retina. ... RPE lipofuscin becomes apparent only during the second decade of life and accumulates with age."Rozanowska M. et al. Blue light-induced reactivity of retinal age pigment. In vitro generation of oxygen-reactive species. J Biol Chem. 1995 Aug 11; 270(32): 18825-30

25 "Accumulation of lipofuscin (LF) is a prominent feature of aging in the human retinal pigment epithelium (RPE) cells. This age pigment exhibits substantial photoreactivity, which may increase the risk of retinal photodamage and contribute to age-related maculopathy. In a previous study, we detected singlet oxygen generation by lipofuscin granules excited with blue light. ... The action spectrum of singlet oxygen formation indicated that this process was strongly wavelength-dependent and its efficiency decreased with increasing wavelength by a factor of ten, comparing 420 nm and 520 nm." Rozanowska et al Blue light-induced singlet oxygen generation by retinal lipofuscin in non-polar media. Free Radic Biol Med. 1998 May;24(7-8):1107-12.

26 "[Lipofuscin] action spectra: ... The onset of photoinduced oxygen uptake occurs at 490 nm and then increases with decreasing wavelength. ... Only light of wavelengths longer than 400 nm reaches the adult retina, thus the initial absorbing species relevant to retinal toxicity in vivo must be blue absorbing." Pawlak et al. Action spectra for the photoconsumption of oxygen by human ocular lipofuscin and lipofuscin extracts. Arch Biochem Biophys. 2002 Jul 1;403(1):59-62.

27 "Melatonin treatment increases the susceptibility of retinal photoreceptors to light-induced cell death... Chronic exposure to natural or artificial light and simultaneous intake of melatonin may potentially contribute to a significant loss of photoreceptor cells in the aging retina. ...The illuminances and exposure times were chosen to mimic the conditions of the human eye in the presence of high and low dosages of melatonin and exposed to intermittent bright sunlight. The low concentrations of melatonin were used to mimic normal dosages for taken as a sleep aid.
In light of the evidence presented in this study, we suggest that it would be prudent for individuals to avoid chronic self-administration of melatonin in the presence of high levels of environmental illumination." Influence of dietary melatonin on photoreceptor survival in the rat retina: An ocular toxicity study. Exp Eye Res. 2008 Feb;86(2):241-50 Wiechmann AF, Chignell CF, Roberts JE.

28 "In all animals, retinal light damage was the most severe when intense light exposure began during the dark period. However, this severe damage was significantly reduced by pretreatment with the antioxidant. ... Our data supportthe notion of a circadian rhythm of light damage susceptibility that peaks in the dark period and yet can be modulated by the exogenous administration of an antioxidant." Evidence for a circadian rhythm of susceptibility to retinal light damage. Photochem Photobiol. 2002, May;75(5): 547-53 Vaughan DK, Nemke JL, Fliesler SJ, Darrow RM, Organisciak DT.

29 "CONCLUSION: The combination of citalopram and light treatment was more effective than citalopram and placebo in the treatment of major depression. With an optimized timing of administration, low-intensity light treatment significantly hastened and potentiated the effect of citalopram, thus providing the clinical psychiatrists with an augmenting strategy that was found effective and devoid of side effects. The lighting device (Sunnex Biotechnologies, Winnipeg, Manitoba, Canada) provided 400 lux green light, with a spectrum ranging from 485 to 515 nm and peak at 500-505 nm." Morning Light Treatment Hastens the Antidepressant Effect of Citalopram: A Placebo-Controlled Trial. Benedetti F, Colombo C, Pontiggia A, Bernasconi A, Florita M, Smeraldi E. The Journal of Clinical Psychiatry. June 2003; 64(6):648-53>

30 "We examined the potential photoxicity of six common antidepressant and neuroleptic drugs (Amitrityline (AM), Chlorpromazine (CPZ), Imipramine (IM), Iprindol (IP), Prozac (PR), and Thioridazine (TH). We found that the potential of phototoxicity of the six drugs tested was CP=IP > TH > IM > AM=PR." R.H. Wang, C.E. Reme, R. Whitt, J. Dillon, and J.E. Roberts. Potential Ocular Phototoxicity of Antidepressant Drugs with Light Therapy of Winter Depressives. Photodermatology Photoimmunology & Photomedicine 1991;8(1):49.

31 "To report a unique case of a woman who developed simultaneous bilateral maculopathy presumed to result from intake of sertraline hydrochloride, a serotonin reuptake inhibitor...during twenty months of follow-up her visual acuity and abnormalities in other psychophysical tests did not improve. CONCLUSION: Patients started on sertraline should be informed of the potential risk of developing maculopathy, and they should be examined regularly to detect possible early alterations." Presumed Sertraline Maculopathy. Sener EC, Kiratli H. Acta Ophthalmol Scand 2001; 79(4):428-30

32 "Despite the presence of such a multitude of antioxidative mechanisms, defence against phototoxicity can still be overwhelmed, even with seemingly non-harmful ambient light when the retina is presented with exogenous photosensitizing agents. This class of drugs and chemicals, when excited by appropriate wavelengths of light, undergo photosensitized oxidative reactions leading to free radical and singlet oxygen formation."
"There is a vast number of potential photosensitizing drugs in clinical use ...from antibiotics, psychoactive drugs, antiarrhythmic drugs and diuretics ... have been implicated in causing drug-induced RPE disturbances, impaired visual acuity and defective visual fields highlighting the importance of eliciting a thorough drug history before subjecting patients to unprotected light exposure. This is of particular relevance in intraocular surgery where prolonged and direct illumination of the retina with strong light source may be used, and in light therapy for Seasonal Affective Disorder [SAD] for which neuroleptics and antidepressants are often concomitantly prescribed." TL Siu, JW Morley and MT Coroneo. Toxicology of the Retina: Advances in Understanding the Defence Mechanisms and Pathogenesis of Drug- and Light-Induced Retinopathy. Clinical and Experimental Ophthalmology 2008; 36:176-185.

"[P]hotosensitizing drugs can potentiate the damaging effects of ultraviolet and visible radiation on the eye. We recommend the following precautions: a washout period for potentially dangerous drugs before extended exposure to bright lights." J.E. Roberts, C.E. Reme, J. Dillon, and M. Terman. Exposure to Bright Light and the Concurrent Use of Photosensitizing Drugs. New England Journal of Medicine. 1992; 326(22): 1500-01

33 "[N]eovascular AMD was positively associated with thiazide diuretics (p<0.001) Conclusions: These findings suggest that severe neovascular AMD are associated with thiazide diuretics long-lasting treatment." E. de la Marnierre, M. Quaranta, M. Mauget-Faysse. Drugs-Induced Phototoxicity as a Risk for Age-Related Macular Degeneration. ARVO 2001: 4296.

34 "Some commonly used drugs, such as certain antibiotics, nonsteroidal anti‑inflammatory drugs (NSAIDs), and psychotherapeutic agents, as well as some popular herbal medicines, can produce ocular phototoxicity." Glickman RD. Phototoxicity to the retina: mechanisms of damage. Int J Toxicol. 2002 Nov‑Dec;21 (6):473-90.

35 "Vigabatrin (VGA, SabrilTM), a structural analog of gamma-aminobutyric acid, is an irreversible inhibitor of gamma-aminobutyric acid transaminase. Because of its effects on GABA accumulation in the extracellular space, VGA is being developed as an antiepileptic agent for drug-resistant seizures. Oculotoxicity of VGA was first characterized as visual field defects. VGA may also induce optic nerve atrophy and it has recently been shown that VGA induces apoptosis in photoreceptors...These observations indicate that VGA's oculotoxicity is acute when the retina is exposed to light." Izumi Y, Ishikawa M, Benz AM, M.Izumi, Zorumski CF, Phototoxic Effects of Vigabatrin (SabrilTM) in the Acute Rat Retinal Preparation. ARVO 2003: 2850/B689

36 "St. John's Wort (SJW), an over-the-counter antidepressant, contains hypericin, which absorbs light in the UV and visible ranges... There have been reports of the use of hypericin in conjunction with light therapy for treatment of depression...Because the level of hypericin reaching the RPE cells may be as high as 10 - 20 micro M, these treatments may lead to oxidative damage in the eye which could lead to transient or permanent blindness." Phototoxicity in Human Retinal Epithelial Cells Promoted by Hypericin, a Component of St. John's Wort. Wielgus et al. Photochem Photobiol. 2007 May-Jun;83(3):706-13.
"BACKGROUND: to report on the possible correlation between incident retinal phototoxicity and the use of photosensitizing drugs... The common finding in these four patients was the fact that they were all taking one or more photosensitizing drugs (hydrochlorothiazide, furosemide, allopurinol, and benzodiazepines). CONCLUSION: phototoxicity following incidental light exposure may occur in patients taking drugs of photosensitizing potential. Therefore, the thorough history of systemic drug ingestion should be obtained if patients have exposure to strong light sources."Mauget-Faysse M, Quaranta M, Francoz N, BenEzra D. Incidental Retinal Phototoxicity Associated with Ingestion of Photosensitizing Drugs. Graefes Arch Clin Exp Ophthalmol 2001; 239(7):501-8.

37 "A history of cataract surgery was associated with an increased prevalence of late AMD in all three data sets after adjusting for age, race, sex, and smoking... A history of cataract surgery may be associated with an increased prevalence of late AMD. However, having a severe cataract in the eye may also be associated with a higher prevalence of late AMD. Additional research is needed to investigate whether a causal relationship exists between cataract surgery and AMD or whether this relationship is due to residual confounding or bias." Freeman EE, Munoz B, West SK, Tielsch JM, Schein OD. Is there an association between cataract surgery and age-related macular degeneration? Data from three population-based studies. Am J Ophthalmol. 2003 Jun;135(6):849-56

38 "When considering how much radiation reaches the retina a number of obvious but often overlooked factors must not be forgotten. These include the direction of gaze, whether the pupil is obscured by the lids, the pupil diameter, and whether the subject has "screwed up" the eyes or responded with an aversion reflex. Any or all of these factors may have to be included in an exposure calculation. The effects of retinal exposure also depend on the optical properties of the preceding media and how they transmit radiation as well as on the chromophores in the retina itself. The situation is, in fact, a complex one." Mellerio J. Light Effects on the Retina Principles and Practice Of Ophthalmology Chapter 116 Eds.Albert D M, Jakobiek FA, Saunders WB. Philadelphia, 1994.

39 "For currently available visible LED sources, only aspect (c) [photochemical damage] is of concern;...It should be recognized that the eye is well adapted for protection against the harmful full-spectrum optical radiation from environmental sunlight encountered in all but the most extreme natural environment. Humans have learned to use protective measures, such as hats and eye-protectors to shield against the harmful effects upon the eye from very intense UV present in sunlight over snow or sand. Bright light sources such as the sun, arc lamps, and welding arcs produce a natural aversion response by the eye. This response limits the duration of exposure to a fraction of a second (less than 0.25 s)." ICNIRP Statement on light-emitting diodes (LEDS) and laser diodes: Implications for Hazard Assessment (2000). International Commission on Non-Ionizing Radiation Protection.

40 "To better understand the mechanism of light-induced retinal damage and to identify the early events leading to photoreceptor cell death, the gene expression profile immediately after exposure to constant bright light was studied in rat retina... Out of 8800 genes in the probe array... the expression of 15-21 % genes were changed (> 2 fold) in light damaged retinas compared to controls: 8.7-12.2 % were increased and 6.2-9.2 % were decreased. Among the genes showing highly significant changes (> 4 fold), we identified transcription of 35 genes was turned on and 40 other genes was enhanced in response to damaging light. On the other hand transcription of 30 genes was turned off and repressed significantly for an additional 38 genes. The biological processes they are associated with include oxidative stress response, cellular defense response, stimulation for DNA damage and cell death, neuronal cell function, carbohydrate and lipid metabolism, and cytoskeleton generation." M.A. Mandal, R.A. Bush, P.A. Sieving, R.Ayyagari. Early response of retina to damaging light - a microarray analysis. ARVO 2004 684/B6578

41 "AMD is a disease of the elderly, but it develops progressively over many years before diagnosis. We suggest that photooxidation events initiated in RPE lipofuscin and continuing over time contribute to the inflammatory processes underlying the disease processes."
"These findings link four factors that have been posited as being associated with AMD: inflammation, oxidative damage, drusen, and RPE lipofuscin." Complement Activation by Photooxidation Products of A2E, a Lipofuscin Constituent of the Retinal Pigment Epithelium. Zhou J, Jang YP, Kim SR, and Sparrow JR. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16182-7.

42 "elevated chronic exposure to light has been identified as a risk factor for development of ARMD. ...avoiding exposures to bright short-wavelength [blue] light is the simplest preventative measure against light damage." Rozanowska M. Sarna T. Light-Induced Damage to the Retina: Role of Rhodopsin Chromophore Revisited. Photochem Photobiol. 2005 Nov-Dec;81(6):1305-30. Review

43 "Recent studies have suggested a maximal chronobiotic effect for wavelengths in the range of 420 to 530 nm (deep blue to blue-green; Brainard et al., 2001; Wright & Lack, 2001; Wright et al., 2004). But ironically there is also concern about the so-called "blue light hazard" with a potentially peak damaging effect in the range 420 to 480 nm (Okuno, Saito, & Ojima, 2002). It should be noted that broad-spectrum white light, traditionally used for bright light therapy, also contains blue light of potential concern particularly for very high intensity, long- duration exposure. Clearly, the safety of bright light therapy for people needs investigating. In the meantime it would be suggested that light in the 500 to 530 nm wavelength range (blue-green) should still be effective while avoiding the putative blue hazard." L.C. Lack. and H.R. Wright Clinical Management of Delayed Sleep Phase Disorder. Behavioral Sleep Medicine 2007, 5(1):57-76

44 "The main finding of this experiment is that blue light reduces photoreceptor responses after only a single administration. This brings important concerns with regard to blue-enriched light therapy lamps used to treat SAD symptoms and other disorders." Gagné AM, Lévesque F, Gagné P, Hébert M. Impact of Blue vs Red Light on Retinal Response of Patients with Seasonal Affective Disorder and Healthy Controls. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Nov 20. [Epub ahead of print}

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