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The biological effects of different LED wavelengths in the health field. A review

Os efeitos biológicos de diferentes comprimentos de onda de LED na área da saúde. Uma revisão

Abstract

Introduction

the use of light emitting diodes (LED) in domestic and public vias have increased in the last 20 years. In addition, the LED light has been used as a light source for medical applications.

Objective

since humans are increasingly exposed to LEDs, there is an urgency to investigate the possible biological effects on tissues caused by this exposure. So, researchers have been focused their investigations in the application of this light in the health field.

Material and method

in this review, a search in important databases was performed on the biological effects caused after application of different LED light protocols in in vitro and in vivo studies.

Result

although most published papers have shown positive results, some of them reported negative biological effects of light LEDs technology on humans’ cells/tissues.

Conclusion

therefore, the comprehension of the biological effects caused by light LEDs will provide a better assessment of the risks involved using this technology.

Descriptors:
Phototherapy; light emitting diode; LED; light sources; LED biological effects

Resumo

Introdução

o uso de diodos emissores de luz (“LED”) em vias domésticas e públicas tem aumentado nos últimos 20 anos. Além disso, a luz LED tem sido usada para aplicações médicas.

Objetivo

pelo fato de seres humanos estarem cada vez mais expostos aos LEDs, há urgência em investigar os possíveis efeitos biológicos nos tecidos causados por esta exposição. Assim, pesquisadores têm focado suas investigações no uso desta luz na área da saúde.

Material e método

nesta revisão foi realizada uma pesquisa em bancos de dados conceituados sobre os efeitos biológicos causados após aplicação de diferentes protocolos de luz LED em estudos in vitro e in vivo.

Resultado

embora a maioria dos artigos publicados tenham mostrado resultados positivos, alguns deles relataram efeitos biológicos negativos da tecnologia de LEDs nas células/tecidos humanos.

Conclusão

portanto, a compreensão dos efeitos biológicos causados pela luz LED proporcionará uma melhor avaliação dos riscos envolvidos no uso desta tecnologia.

Descritores:
Fototerapia; diodo emissor de luz; LED; fontes de luz; efeitos biológicos do LED

INTRODUCTION

The search for safe and efficient energy devices has increased over the past 20 years, promoting major improvements in everyday use of equipment such as home appliances and electronics11 Chaves MEA, Araújo AR, Piancastelli ACC, Pinotti M. Effects of low-power light therapy on wound healing: LASER x LED. An Bras Dermatol. 2014 Jul-Aug;89(4):616-23. http://dx.doi.org/10.1590/abd1806-4841.20142519. PMid:25054749.
http://dx.doi.org/10.1590/abd1806-4841.2...
. The lamps are not the exception since the first incandescent lamps such as halogen and fluorescents had its energy efficacy improved11 Chaves MEA, Araújo AR, Piancastelli ACC, Pinotti M. Effects of low-power light therapy on wound healing: LASER x LED. An Bras Dermatol. 2014 Jul-Aug;89(4):616-23. http://dx.doi.org/10.1590/abd1806-4841.20142519. PMid:25054749.
http://dx.doi.org/10.1590/abd1806-4841.2...
. The light-emitting diode lamps (LED), have been commercialized with significant advantages over conventional devices, because of the internal energy-saving and lifetime that would compensate for the higher prices11 Chaves MEA, Araújo AR, Piancastelli ACC, Pinotti M. Effects of low-power light therapy on wound healing: LASER x LED. An Bras Dermatol. 2014 Jul-Aug;89(4):616-23. http://dx.doi.org/10.1590/abd1806-4841.20142519. PMid:25054749.
http://dx.doi.org/10.1590/abd1806-4841.2...
. Nowadays, the increasing public awareness of environmental concerns has pushed governments and supranational organizations to change the legislation, which regulates the electrical devices22 Behar-Cohen F, Martinsons C, Viénot F, Zissis G, Barlier-Salsi A, Cesarini JP, et al. Light-emitting diodes (LED) for domestic lighting: any risks for the eye? Prog Retin Eye Res. 2011 Jul;30(4):239-57. http://dx.doi.org/10.1016/j.preteyeres.2011.04.002. PMid:21600300.
http://dx.doi.org/10.1016/j.preteyeres.2...
. As an example, it was reported that in the European Union, it was imposed a gradual withdrawal of incandescent lamps from the market by replacing them with LEDs (Regulation (EC) n° 244/2009)22 Behar-Cohen F, Martinsons C, Viénot F, Zissis G, Barlier-Salsi A, Cesarini JP, et al. Light-emitting diodes (LED) for domestic lighting: any risks for the eye? Prog Retin Eye Res. 2011 Jul;30(4):239-57. http://dx.doi.org/10.1016/j.preteyeres.2011.04.002. PMid:21600300.
http://dx.doi.org/10.1016/j.preteyeres.2...
. In this context, in the future, people will become permanently exposed to LEDs, since these devices will illuminate their houses and the most public and private places. Soon, LED will comprehend at least 50% of the world lighting33 Xie C, Li X, Tong J, Gu Y, Shen Y. Effects of white light-emitting diode (LED) light exposure with different correlated color temperatures (CCTs) on human lens epithelial cells in culture. Photochem Photobiol. 2014 Jul-Aug;90(4):853-9. http://dx.doi.org/10.1111/php.12250. PMid:24483628.
http://dx.doi.org/10.1111/php.12250...
. Thus, although humans are increasingly exposed to LEDs, the scientific community has been worried about the possible biological effects on tissues caused by this exposure. However, the number of studies performed are scarce.

In the last 15 years, due to a better understanding of photobiology and increased demand for minimally invasive and effective treatments, LEDs have been used for dermatological treatments11 Chaves MEA, Araújo AR, Piancastelli ACC, Pinotti M. Effects of low-power light therapy on wound healing: LASER x LED. An Bras Dermatol. 2014 Jul-Aug;89(4):616-23. http://dx.doi.org/10.1590/abd1806-4841.20142519. PMid:25054749.
http://dx.doi.org/10.1590/abd1806-4841.2...
,44 Jagdeo J, Austin E, Mamalis A, Wong C, Ho D, Siegel DM. Light-emitting diodes in dermatology: a systematic review of randomized controlled trials. Lasers Surg Med. 2018 Jan;50(6):613-28. http://dx.doi.org/10.1002/lsm.22791. PMid:29356026.
http://dx.doi.org/10.1002/lsm.22791...
. In the early 1990s, when NASA developed a LED device that allowed its first clinical application55 Calderhead RG. The photobiological basics behind light-emitting diode (LED) phototherapy. Laser Ther. 2007 Jan;16(2):97-108. http://dx.doi.org/10.5978/islsm.16.97.
http://dx.doi.org/10.5978/islsm.16.97...
, the biological effects of LEDs started to be identified11 Chaves MEA, Araújo AR, Piancastelli ACC, Pinotti M. Effects of low-power light therapy on wound healing: LASER x LED. An Bras Dermatol. 2014 Jul-Aug;89(4):616-23. http://dx.doi.org/10.1590/abd1806-4841.20142519. PMid:25054749.
http://dx.doi.org/10.1590/abd1806-4841.2...
. Then, several improvements have been introduced to LED devices resulting in equipment with different wavelengths. These devices have been investigated for their effects on skin cells and, while some studies report an increase in cell proliferation of fibroblasts and keratinocytes, others report disagreeing results on the clinical benefits of using LED on skin wounds66 Opel DR, Hagstrom E, Pace AK, Sisto K, Hirano-Ali SA, Desai S, et al. Light-emitting diodes: a brief review and clinical experience. J Clin Aesthet Dermatol. 2015 Jun;8(6):36-44. PMid:26155326..

In a recent review, it was described that LED efficacy in photobiomodulation and others healthcare requests are well established and it may have therapeutic applications independent on the wavelength and protocol used77 Heiskanen V, Hamblin MR. Photobiomodulation: lasers vs. light emitting diodes? Photochem Photobiol Sci. 2018 Aug;17(8):1003-17. http://dx.doi.org/10.1039/c8pp00176f. PMid:30044464.
http://dx.doi.org/10.1039/c8pp00176f...
. In accordance with the ClinicalTrials.gov database, over 2800 scientific clinical investigations have been made focusing on the possible physiological effects of LED on the most varied parts of the human body, such as brain injury, skin healing, facial rejuvenation, lipolysis, periodontal diseases, temporomandibular disorders, healing of diabetic ulcers, photobiomodulation of Autism Spectrum Disorders (ASD), allergy, and sleeping bruxism88 ClinicalTrials.gov. FDAAA 801 and the final rule [Internet]. Bethesda: ClinicalTrials.gov; 2023 [cited 2023 Oct 26]. Available from: http://clinicaltrials.gov/ct2/manage-recs/fdaaa
http://clinicaltrials.gov/ct2/manage-rec...
.

Taken together, it seems that the most of published papers demonstrated positive results in using different protocols and wavelengths of LED on cells or tissues, and the clinical trials that have been made using this device reinforce the idea that LED may be a promising alternative to treat human disorders in the future. Our counterword to this argument is that there are investigations in which protocol and wavelength of LED used were harmful to tissues. For this reason, this review examines the biological effects caused after the application of different LED protocols in the health field. A summary of protocols and wavelengths used is presented in Table 1.

Table 1
Summary finds of data extraction from included articles in the review

Red LED - 630-700 nm

In accordance with the literature, the red LEDs (630-700 nm) are known to permit the penetration of light deeper into tissues when compared to other LEDs with different wavelengths, so, they are used to reach adjacent skin structures and also the connective tissue4141 Simpson CR, Kohl M, Essenpreis M, Cope M. Near-infrared optical properties of ex vivo human skin and subcutaneous tissues measured using the Monte Carlo inversion technique. Phys Med Biol. 1998 Sep;43(9):2465-78. http://dx.doi.org/10.1088/0031-9155/43/9/003. PMid:9755939.
http://dx.doi.org/10.1088/0031-9155/43/9...
. For this reason, the search for protocols that allow the treatment of the most varied health problems has been the target of some investigations99 Barolet D, Duplay P, Jacomy H, Auclair M. Importance of pulsing illumination parameters in low-level-light therapy. J Biomed Opt. 2010 Jul-Aug;15(4):048005. http://dx.doi.org/10.1117/1.3477186. PMid:20799848.
http://dx.doi.org/10.1117/1.3477186...

10 Kim HK, Kim JH, Abbas AA, Kim DO, Park SJ, Chung JY, et al. Red light of 647 nm enhances osteogenic differentiation in mesenchymal stem cells. Lasers Med Sci. 2009 Mar;24(2):214-22. http://dx.doi.org/10.1007/s10103-008-0550-6. PMid:18386092.
http://dx.doi.org/10.1007/s10103-008-055...
-1111 Guo J, Wang Q, Wai D, Zhang QZ, Shi SH, Le AD, et al. Visible red and infrared light alters gene expression in human marrow stromal fibroblast cells. Orthod Craniofac Res. 2015 Apr;18(Suppl 1):50-61. http://dx.doi.org/10.1111/ocr.12081. PMid:25865533.
http://dx.doi.org/10.1111/ocr.12081...
. It has been reported that three applications of short and intermittent light delivery (red LED (630 nm) at a light dose of 8 J/cm2, seems to stimulate the human collagen production in vitro99 Barolet D, Duplay P, Jacomy H, Auclair M. Importance of pulsing illumination parameters in low-level-light therapy. J Biomed Opt. 2010 Jul-Aug;15(4):048005. http://dx.doi.org/10.1117/1.3477186. PMid:20799848.
http://dx.doi.org/10.1117/1.3477186...
. In another investigation, it has been reported that red light, when used at 647 nm wavelength, applied for 10 s, 30 s or 90 s at light doses of 0.093 J/cm2, 0.279 J/cm2 and 0.836 J/cm2, respectively, may promote the osteogenic differentiation in mesenchymal cells1010 Kim HK, Kim JH, Abbas AA, Kim DO, Park SJ, Chung JY, et al. Red light of 647 nm enhances osteogenic differentiation in mesenchymal stem cells. Lasers Med Sci. 2009 Mar;24(2):214-22. http://dx.doi.org/10.1007/s10103-008-0550-6. PMid:18386092.
http://dx.doi.org/10.1007/s10103-008-055...
. In addition, it has been reported that red LED (633 nm) altered the gene expression related to cell proliferation, osteogenic potential, adipogenesis, mRNA and protein content, in human marrow stromal fibroblast cells when irradiated at a light doses equivalent to 0.5, 1.0, 1.5 and 2.0 J/cm22 Behar-Cohen F, Martinsons C, Viénot F, Zissis G, Barlier-Salsi A, Cesarini JP, et al. Light-emitting diodes (LED) for domestic lighting: any risks for the eye? Prog Retin Eye Res. 2011 Jul;30(4):239-57. http://dx.doi.org/10.1016/j.preteyeres.2011.04.002. PMid:21600300.
http://dx.doi.org/10.1016/j.preteyeres.2...
,1111 Guo J, Wang Q, Wai D, Zhang QZ, Shi SH, Le AD, et al. Visible red and infrared light alters gene expression in human marrow stromal fibroblast cells. Orthod Craniofac Res. 2015 Apr;18(Suppl 1):50-61. http://dx.doi.org/10.1111/ocr.12081. PMid:25865533.
http://dx.doi.org/10.1111/ocr.12081...
.

In the clinical field, many protocols for using red LEDs devices have been studied including skin and mucosal wound healing, skin rejuvenation1212 Lee SY, Park KH, Choi JW, Kwon JK, Lee DR, Shin MS, et al. A prospective, randomized, placebo-controlled, double-blinded, and split-face clinical study on LED phototherapy for skin rejuvenation: clinical, profilometric, histologic, ultrastructural, and biochemical evaluations and comparison of three different treatment settings. J Photochem Photobiol B. 2007 Jul;88(1):51-67. http://dx.doi.org/10.1016/j.jphotobiol.2007.04.008. PMid:17566756.
http://dx.doi.org/10.1016/j.jphotobiol.2...
, treatment of precancerous lesions, warts, pain attenuation of oral mucositis1313 Whelan HT, Connelly JF, Hodgson BD, Barbeau L, Post AC, Bullard G, et al. NASA light-emitting diodes for the prevention of oral mucositis in pediatric bone marrow transplant patients. J Clin Laser Med Surg. 2002 Dec;20(6):319-24. http://dx.doi.org/10.1089/104454702320901107. PMid:12513918.
http://dx.doi.org/10.1089/10445470232090...
, postoperative pain and edema4242 Kim WS, Calderhead RG. Is light-emitting diode phototherapy (LED-LLLT) really effective? Laser Ther. 2011;20(3):205-15. http://dx.doi.org/10.5978/islsm.20.205. PMid:24155530.
http://dx.doi.org/10.5978/islsm.20.205...
. Corti et al.1414 Corti L, Chiarion-Sileni V, Aversa S, Ponzoni A, D’Arcais R, Pagnutti S, et al. Treatment of chemotherapy-induced oral mucositis with light-emitting diode. Photomed Laser Surg. 2006 Apr;24(2):207-13. http://dx.doi.org/10.1089/pho.2006.24.207. PMid:16706701.
http://dx.doi.org/10.1089/pho.2006.24.20...
, using a red LED device (645 nm) with an output delivery equivalent to 7.8 mW/cm2 and a dose of light of 0.99 J/cm2, three times a day for 1 week, observed a relief in the oral mucositis present in patients underwent to chemotherapy1414 Corti L, Chiarion-Sileni V, Aversa S, Ponzoni A, D’Arcais R, Pagnutti S, et al. Treatment of chemotherapy-induced oral mucositis with light-emitting diode. Photomed Laser Surg. 2006 Apr;24(2):207-13. http://dx.doi.org/10.1089/pho.2006.24.207. PMid:16706701.
http://dx.doi.org/10.1089/pho.2006.24.20...
. Another investigation reported the efficacy of phototherapy using red LED (660 mn) in the treatment of polymorphous light eruption (PLE). The patients presented a reduction in the skin erythema, after 5, 6 or 10 sessions of treatment during 1 to 3 weeks. It was used equipment with an output delivery of 60 mW/cm2 and a dose of light equivalent to 5 J/cm22 Behar-Cohen F, Martinsons C, Viénot F, Zissis G, Barlier-Salsi A, Cesarini JP, et al. Light-emitting diodes (LED) for domestic lighting: any risks for the eye? Prog Retin Eye Res. 2011 Jul;30(4):239-57. http://dx.doi.org/10.1016/j.preteyeres.2011.04.002. PMid:21600300.
http://dx.doi.org/10.1016/j.preteyeres.2...
,1515 Barolet D, Boucher A. LED photoprevention: reduced MED response following multiple LED exposures. Lasers Surg Med. 2008 Feb;40(2):106-12. http://dx.doi.org/10.1002/lsm.20615. PMid:18306161.
http://dx.doi.org/10.1002/lsm.20615...
. Barolet et al.1616 Barolet D, Roberge CJ, Auger FA, Boucher A, Germain L. Regulation of skin collagen metabolism in vitro using a pulsed 660 nm LED light source: clinical correlation with a single-blinded study. J Invest Dermatol. 2009 Dec;129(12):2751-9. http://dx.doi.org/10.1038/jid.2009.186. PMid:19587693.
http://dx.doi.org/10.1038/jid.2009.186...
demonstrated that the red LED at 660 mn can be a good choice to promote skin rejuvenation using in vitro and in vivo evaluation. In the in vitro assay, the authors used a Human Reconstructed Skin tissue (HRS) and applied 11 sequentially pulsed treatments of red LED for 4 weeks. For the in vivo study, patients received 12 applications of red LED being 3 treatments a week, for 4 weeks. Authors suggested that improvements in the skin of patients are justified by the upregulation of the collagen and downregulation of MMP-1, a gene encoding interstitial collagenase. However, details of the dose of light, time of application of each treatment and the output of the LED device were not mentioned1616 Barolet D, Roberge CJ, Auger FA, Boucher A, Germain L. Regulation of skin collagen metabolism in vitro using a pulsed 660 nm LED light source: clinical correlation with a single-blinded study. J Invest Dermatol. 2009 Dec;129(12):2751-9. http://dx.doi.org/10.1038/jid.2009.186. PMid:19587693.
http://dx.doi.org/10.1038/jid.2009.186...
. Recently, a clinical trial was performed for the treatment of wrinkles. The faces of 52 female patients, were irradiated daily, with 5.17 J/cm2 with red LED (660 nm) for 12 weeks and it was observed that red LED was the most successful protocol when compared to the LED wavelengths equivalent to 411 nm and 777 nm1717 Nam CH, Park BC, Kim MH, Choi EH, Hong SP. The efficacy and safety of 660 nm and 411 to 777 nm light-emitting devices for treating wrinkles. Dermatol Surg. 2017 Mar;43(3):371-80. http://dx.doi.org/10.1097/DSS.0000000000000981. PMid:28195844.
http://dx.doi.org/10.1097/DSS.0000000000...
. Additionally, it has been reported the capacity of red LED to induce angiogenesis on dorsal wounds after illumination, using a device with 15 mW and light dose of 10 J/cm2 in rats. The protocol was applied once a day for 7 days and it promoted a significant increase in angiogenesis1818 Sousa AP, Paraguassú GM, Silveira NT, Souza J, Cangussú MC, Santos JN, et al. Laser and LED phototherapies on angiogenesis. Lasers Med Sci. 2013 May;28(3):981-7. http://dx.doi.org/10.1007/s10103-012-1187-z. PMid:22923269.
http://dx.doi.org/10.1007/s10103-012-118...
.

The photobiomodulation therapy offers a non-invasive, safe, drug-free, and side-effect-free method for pain relief of both acute and chronic musculoskeletal conditions as well as fibromyalgia4343 Oliveira MF, Johnson DS, Demchak T, Tomazoni SS, Leal-Junior EC. Low-intensity LASER and LED (photobiomodulation therapy) for pain control of the most common musculoskeletal conditions. Eur J Phys Rehabil Med. 2022 Apr;58(2):282-9. http://dx.doi.org/10.23736/S1973-9087.21.07236-1. PMid:34913330.
http://dx.doi.org/10.23736/S1973-9087.21...
. When a super-pulsed laser (905 nm) combined with red (640 nm) and infrared (875 nm) light-emitting diodes, was used, it was observed that pain intensity decreased significantly, with a median decrease of 2.2 - 2.7 pain points on a 10-point scale and this decrease in pain was maintained for 48 h post treatment4444 Herpich CM, Leal-Junior ECP, Politti F, Gomes CAFP, Glória IPS, Amaral MFRS, et al. Intraoral photobiomodulation diminishes pain and improves functioning in women with temporomandibular disorder: a randomized, sham-controlled, double-blind clinical trial. Lasers Med Sci. 2020 Mar;35(2):439-45. http://dx.doi.org/10.1007/s10103-019-02841-1. PMid:31325122.
http://dx.doi.org/10.1007/s10103-019-028...
.

As can be seen, the protocols using red LED promoted a reduction of oral mucositis and skin lesions, increased angiogenesis and were efficient for skin rejuvenation. Besides, it has been reported an increase in cell proliferation of various cell types such as fibroblasts, endothelial cells, and keratinocytes. However, the biological mechanisms that justify the light actions of low intensity in tissues have not been elucidated.

Blue LED – 400-470 nm

It has been reported that the irradiation with blue LEDs (412, 419 and 426 nm) using a dose of light from 66 to 100 J/cm2 inhibited the proliferation of skin keratinocytes and altered cell differentiation1919 Liebmann J, Born M, Kolb-Bachofen V. Blue-light irradiation regulates proliferation and differentiation in human skin cells. J Invest Dermatol. 2010 Jan;130(1):259-69. http://dx.doi.org/10.1038/jid.2009.194. PMid:19675580.
http://dx.doi.org/10.1038/jid.2009.194...
. Likewise, in other investigations, dermal fibroblasts demonstrated reduced mitotic activity after exposure to blue LED (430-490 nm) for 20, 40, 80 and 120 seconds at a dose of light of 8, 14 and 15 J/cm2020 Malčić AI, Pavičić I, Trošić I, Simeon P, Katanec D, Krmek SJ. The effects of bluephase LED light on fibroblasts. Eur J Dent. 2012 Jul;6(3):311-7. http://dx.doi.org/10.1055/s-0039-1698966. PMid:22904660.
http://dx.doi.org/10.1055/s-0039-1698966...
,2121 Lev-Tov H, Mamalis A, Brody N, Siegel D, Jagdeo J. Inhibition of fibroblast proliferation in vitro using red light-emitting diodes. Dermatol Surg. 2013 Aug;39(8):1167-70. http://dx.doi.org/10.1111/dsu.12212. PMid:23590233.
http://dx.doi.org/10.1111/dsu.12212...
. Taflinski et al.2222 Taflinski L, Demir E, Kauczok J, Fuchs PC, Born M, Suschek CV, et al. Blue light inhibits transforming growth factor-β1-induced myofibroblast differentiation of human dermal fibroblasts. Exp Dermatol. 2014 Apr;23(4):240-6. http://dx.doi.org/10.1111/exd.12353. PMid:24533842.
http://dx.doi.org/10.1111/exd.12353...
, observed that human dermal fibroblasts exhibited a decrease in cell differentiation when irradiated with blue LED (420 nm), with an intensity of 50 mW/cm2 and a dose of light of 15 and 30 J/cm2. Human retinal cells have also been affected by blue LED irradiation2323 Knels L, Valtink M, Roehlecke C, Lupp A, de la Vega J, Mehner M, et al. Blue light stress in retinal neuronal (R28) cells is dependent on wavelength range and irradiance. Eur J Neurosci. 2011 Aug;34(4):548-58. http://dx.doi.org/10.1111/j.1460-9568.2011.07790.x. PMid:21781192.
http://dx.doi.org/10.1111/j.1460-9568.20...
. In an in vitro investigation, when human retinal cells were exposed to LED at 411 nm with an intensity of 0.6, 1.5 and 4.5 W/m2 and 470 nm with an intensity of 4.5 W/m2 was verified a cytotoxic effect of LED at 411 nm with the intensity of 4.5W/m2, which induced the retinal cells to apoptosis2323 Knels L, Valtink M, Roehlecke C, Lupp A, de la Vega J, Mehner M, et al. Blue light stress in retinal neuronal (R28) cells is dependent on wavelength range and irradiance. Eur J Neurosci. 2011 Aug;34(4):548-58. http://dx.doi.org/10.1111/j.1460-9568.2011.07790.x. PMid:21781192.
http://dx.doi.org/10.1111/j.1460-9568.20...
. In addition, it has been reported the anti-proliferative effect of blue LED in cancer cells of the human colon by induction of the extrinsic apoptotic pathway2424 Matsumoto N, Yoshikawa K, Shimada M, Kurita N, Sato H, Iwata T, et al. Effect of light irradiation by light emitting diode on colon cancer cells. Anticancer Res. 2014 Sep;34(9):4709-16. PMid:25202048.. Recently, another in vitro study reported that the blue LED (470 nm) used at doses of 72 J/cm2, 144 J/cm2, 216 J/cm2, and 288 J/cm2, reduced proliferation of human colorectal cancer cells2525 Yan G, Zhang L, Feng C, Gong R, Idiiatullina E, Huang Q, et al. Blue light emitting diodes irradiation causes cell death in colorectal cancer by inducing ROS production and DNA damage. Int J Biochem Cell Biol. 2018 Oct;103:81-8. http://dx.doi.org/10.1016/j.biocel.2018.08.006. PMid:30125666.
http://dx.doi.org/10.1016/j.biocel.2018....
.

In the dental field, the blue LED when applied with an intensity of 900 mW/cm2 and a dose of light equivalent to 162 J/cm2, inhibited the proliferation of gingival fibroblasts2626 Taoufik K, Mavrogonatou E, Eliades T, Papagiannoulis L, Eliades G, Kletsas D. Effect of blue light on the proliferation of human gingival fibroblasts. Dent Mater. 2008 Jul;24(7):895-900. http://dx.doi.org/10.1016/j.dental.2007.10.006. PMid:18164382.
http://dx.doi.org/10.1016/j.dental.2007....
. In another study, the blue LED was also applied to verify the viability and synthesis of dentin matrix proteins by odontoblast-like cells. The protocol used consisted in a single application using equipment with an intensity of 20 mW/cm and a dose of light equivalent to 0.5, 2, 4, 10, or 15 J/cm2 and it was observed that blue LED did not present bio stimulatory capacity on odontoblast-like cells4545 Alonso JR, Turrioni AP, Basso FG, Costa CAS, Hebling J. Synthesis of dental matrix proteins and viability of odontoblast-like cells irradiated with blue LED. Lasers Med Sci. 2016 Apr;31(3):523-30. http://dx.doi.org/10.1007/s10103-016-1889-8. PMid:26873499.
http://dx.doi.org/10.1007/s10103-016-188...
.

In an in vivo study it was demonstrated that the blue LED device induced intestine cells of neonatal rats to apoptosis when applied in an intensity of 55 mW/cm2 for 72 hours2727 Tanaka K, Hashimoto H, Tachibana T, Ishikawa H, Ohki T. Apoptosis in the small intestine of neonatal rat using blue light-emitting diode devices and conventional halogen-quartz devices in phototherapy. Pediatr Surg Int. 2008 Jul;24(7):837-42. http://dx.doi.org/10.1007/s00383-008-2170-4. PMid:18470518.
http://dx.doi.org/10.1007/s00383-008-217...
. Another in vivo investigation verified that the blue LED (460 nm) did not stimulate angiogenesis on dorsal cutaneous wounds. It was performed one application per day for 7 days using a device with an intensity of 22 mW and dose of light of 10 J/cm1818 Sousa AP, Paraguassú GM, Silveira NT, Souza J, Cangussú MC, Santos JN, et al. Laser and LED phototherapies on angiogenesis. Lasers Med Sci. 2013 May;28(3):981-7. http://dx.doi.org/10.1007/s10103-012-1187-z. PMid:22923269.
http://dx.doi.org/10.1007/s10103-012-118...
. Moreover, some in vivo investigations reported the genotoxicity of blue LED to mononuclear leukocytes and decreased the blood flow in blood vessels in jaundiced neonates2828 Benders MJ, Van Bel F, Van de Bor M. Cardiac output and ductal reopening during phototherapy in preterm infants. Acta Paediatr. 1999 Sep;88(9):1014-9. http://dx.doi.org/10.1111/j.1651-2227.1999.tb00199.x. PMid:10519346.
http://dx.doi.org/10.1111/j.1651-2227.19...
,2929 Aycicek A, Erel O. Total oxidant/antioxidant status in jaundiced newborns before and after phototherapy. J Pediatr. 2007 Jul-Aug;83(4):319-22. http://dx.doi.org/10.2223/JPED.1645. PMid:17625638.
http://dx.doi.org/10.2223/JPED.1645...
,4646 Kadalraja R, Patole SK, Muller R, Whitehall JS. Is mesenteric blood flow compromised during phototherapy in preterm neonates? Arch Dis Child Fetal Neonatal Ed. 2004 Nov;89(6):F564. http://dx.doi.org/10.1136/adc.2004.057646. PMid:15499160.
http://dx.doi.org/10.1136/adc.2004.05764...

47 Dennery PA, Lorch S. Neonatal blue-light phototherapy could increase the risk of dysplastic nevus development. Pediatrics. 2007;120(1):247-8. http://dx.doi.org/10.1542/peds.2007-0844. PMid:17606593.
http://dx.doi.org/10.1542/peds.2007-0844...

48 Furchgott RF. Endothelium-dependent relaxation, endothelium-derived relaxing factor and photorelaxation of blood vessels. Semin Perinatol. 1991 Feb;15(1):11-5. PMid:2063224.

49 Wu PY, Wong WH, Hodgman JE, Levan N. Changes in blood flow in the skin and muscle with phototherapy. Pediatr Res. 1974 Apr;8(4):257-62. http://dx.doi.org/10.1203/00006450-197404000-00007. PMid:4822668.
http://dx.doi.org/10.1203/00006450-19740...
-5050 Aycicek A, Kocyigit A, Erel O, Senturk H. Phototherapy causes DNA damage in peripheral mononuclear leukocytes in term infants. J Pediatr. 2008;84(2):141-6. http://dx.doi.org/10.2223/JPED.1765. PMid:18350230.
http://dx.doi.org/10.2223/JPED.1765...
.

Similarly, to other areas, the investigations about the effects of blue LED in the ophthalmology field have increased3030 Ortín-Martínez A, Valiente-Soriano FJ, García-Ayuso D, Alarcón-Martínez L, Jiménez-López M, Bernal-Garro JM, et al. A novel in vivo model of focal light emitting diode-induced cone-photoreceptor phototoxicity: neuroprotection afforded by brimonidine, BDNF, PEDF or bFGF. PLoS One. 2014 Dec;9(12):e113798. http://dx.doi.org/10.1371/journal.pone.0113798. PMid:25464513.
http://dx.doi.org/10.1371/journal.pone.0...
,3131 Krigel A, Berdugo M, Picard E, Levy-Boukris R, Jaadane I, Jonet L, et al. Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity. Neuroscience. 2016 Dec;339:296-307. http://dx.doi.org/10.1016/j.neuroscience.2016.10.015. PMid:27751961.
http://dx.doi.org/10.1016/j.neuroscience...
. An in vivo investigation reported the phototoxicity effect of blue LED (400 nm) on retinal cells of rats, using an intensity equivalent to 200 Lux for 10 seconds3030 Ortín-Martínez A, Valiente-Soriano FJ, García-Ayuso D, Alarcón-Martínez L, Jiménez-López M, Bernal-Garro JM, et al. A novel in vivo model of focal light emitting diode-induced cone-photoreceptor phototoxicity: neuroprotection afforded by brimonidine, BDNF, PEDF or bFGF. PLoS One. 2014 Dec;9(12):e113798. http://dx.doi.org/10.1371/journal.pone.0113798. PMid:25464513.
http://dx.doi.org/10.1371/journal.pone.0...
. In another investigation, it was observed that the blue LED (455-465 nm) may cause retinal toxicity in rats, after illumination of 500 Lux, which is the domestic classic light intensity3131 Krigel A, Berdugo M, Picard E, Levy-Boukris R, Jaadane I, Jonet L, et al. Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity. Neuroscience. 2016 Dec;339:296-307. http://dx.doi.org/10.1016/j.neuroscience.2016.10.015. PMid:27751961.
http://dx.doi.org/10.1016/j.neuroscience...
. An in vivo study revealed that blue LED at 460 nm, was toxic for retinal pigment epithelial cells3232 Lin CH, Wu MR, Huang WJ, Chow DS, Hsiao G, Cheng YW. Low-luminance blue light-enhanced phototoxicity in A2E-Laden RPE cell cultures and rats. Int J Mol Sci. 2019 Apr;20(7):1799. http://dx.doi.org/10.3390/ijms20071799. PMid:30979028.
http://dx.doi.org/10.3390/ijms20071799...
. The authors illuminated rats with an intensity of 150 Lux for 3 h per day for 21 days and verified that the light caused fundus damage, decreased total retinal thickness, and caused neuron transduction injury in the retina3232 Lin CH, Wu MR, Huang WJ, Chow DS, Hsiao G, Cheng YW. Low-luminance blue light-enhanced phototoxicity in A2E-Laden RPE cell cultures and rats. Int J Mol Sci. 2019 Apr;20(7):1799. http://dx.doi.org/10.3390/ijms20071799. PMid:30979028.
http://dx.doi.org/10.3390/ijms20071799...
. It has also been documented that the degeneration of the pigment epithelium under blue light is promoted by the accumulation of A2E (bis-retinoid N-retinyl-N-retinylidene ethanolamine), but this effect does not show significant disturbances5151 Alaimo A, Liñares GG, Bujjamer JM, Gorojod RM, Alcon SP, Martínez JH, et al. Toxicity of blue led light and A2E is associated to mitochondrial dynamics impairment in ARPE-19 cells: implications for age-related macular degeneration. Arch Toxicol. 2019 May;93(5):1401-15. http://dx.doi.org/10.1007/s00204-019-02409-6. PMid:30778631.
http://dx.doi.org/10.1007/s00204-019-024...
.

In general, while only one investigation reported the benefits of using blue LEDs, in the inhibition of mitotic activity of cancer cells of the human colon2424 Matsumoto N, Yoshikawa K, Shimada M, Kurita N, Sato H, Iwata T, et al. Effect of light irradiation by light emitting diode on colon cancer cells. Anticancer Res. 2014 Sep;34(9):4709-16. PMid:25202048., other investigations observed that different protocols using this LED may cause apoptosis in intestine cells of rats2727 Tanaka K, Hashimoto H, Tachibana T, Ishikawa H, Ohki T. Apoptosis in the small intestine of neonatal rat using blue light-emitting diode devices and conventional halogen-quartz devices in phototherapy. Pediatr Surg Int. 2008 Jul;24(7):837-42. http://dx.doi.org/10.1007/s00383-008-2170-4. PMid:18470518.
http://dx.doi.org/10.1007/s00383-008-217...
and human retinal cells3030 Ortín-Martínez A, Valiente-Soriano FJ, García-Ayuso D, Alarcón-Martínez L, Jiménez-López M, Bernal-Garro JM, et al. A novel in vivo model of focal light emitting diode-induced cone-photoreceptor phototoxicity: neuroprotection afforded by brimonidine, BDNF, PEDF or bFGF. PLoS One. 2014 Dec;9(12):e113798. http://dx.doi.org/10.1371/journal.pone.0113798. PMid:25464513.
http://dx.doi.org/10.1371/journal.pone.0...

31 Krigel A, Berdugo M, Picard E, Levy-Boukris R, Jaadane I, Jonet L, et al. Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity. Neuroscience. 2016 Dec;339:296-307. http://dx.doi.org/10.1016/j.neuroscience.2016.10.015. PMid:27751961.
http://dx.doi.org/10.1016/j.neuroscience...
-3232 Lin CH, Wu MR, Huang WJ, Chow DS, Hsiao G, Cheng YW. Low-luminance blue light-enhanced phototoxicity in A2E-Laden RPE cell cultures and rats. Int J Mol Sci. 2019 Apr;20(7):1799. http://dx.doi.org/10.3390/ijms20071799. PMid:30979028.
http://dx.doi.org/10.3390/ijms20071799...
. Regarding the retinal cells, it was demonstrated that independently on the protocol of illumination used, the association between blue light and chronic retinal degeneration was verified3333 Tosini G, Ferguson I, Tsubota K. Effects of blue light on the circadian system and eye physiology. Mol Vis. 2016 Jan;22:61-72. PMid:26900325.. Short-wavelength blue light (455 nm to 495 nm) is characterized as high-energy radiation in the visible spectrum and is easily transmitted to the lens, directly causing damage to the retina3333 Tosini G, Ferguson I, Tsubota K. Effects of blue light on the circadian system and eye physiology. Mol Vis. 2016 Jan;22:61-72. PMid:26900325.. In addition, it was also reported that blue light inhibited the activity of superoxide dismutase and catalase3434 Tokarz P, Kaarniranta K, Blasiak J. Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD). Biogerontology. 2013 Oct;14(5):461-82. http://dx.doi.org/10.1007/s10522-013-9463-2. PMid:24057278.
http://dx.doi.org/10.1007/s10522-013-946...
and induced the retinal pigment epithelium cells to death3434 Tokarz P, Kaarniranta K, Blasiak J. Role of antioxidant enzymes and small molecular weight antioxidants in the pathogenesis of age-related macular degeneration (AMD). Biogerontology. 2013 Oct;14(5):461-82. http://dx.doi.org/10.1007/s10522-013-9463-2. PMid:24057278.
http://dx.doi.org/10.1007/s10522-013-946...
. Exposure to artificial light at night is a new source of pollution, because it affects the circadian clock and consequently, the secretion of melatonin and estrogen5252 Touitou Y, Point S. Effects and mechanisms of action of light-emitting diodes on the human retina and internal clock. Environ Res. 2020 Nov;190:109942. http://dx.doi.org/10.1016/j.envres.2020.109942. PMid:32758719.
http://dx.doi.org/10.1016/j.envres.2020....
. This topic is an important issue and needs to be emphasized since people are daily exposed to this type of light in their electronic products such as smartphones, tablets, and computers5252 Touitou Y, Point S. Effects and mechanisms of action of light-emitting diodes on the human retina and internal clock. Environ Res. 2020 Nov;190:109942. http://dx.doi.org/10.1016/j.envres.2020.109942. PMid:32758719.
http://dx.doi.org/10.1016/j.envres.2020....
,5353 O’Hagan JB, Khazova M, Price LL. Low-energy light bulbs, computers, tablets and the blue light hazard. Eye. 2016 Feb;30(2):230-3. http://dx.doi.org/10.1038/eye.2015.261. PMid:26768920.
http://dx.doi.org/10.1038/eye.2015.261...
.

Yellow LED 570-590 nm

Beyond the red and blue LEDs, previous investigations have reported the photobiomodulation caused by Yellow LED (570 - 590 nm)3535 McDaniel DH, Weiss RA, Geronemus R, Ginn L, Newman J. Light–tissue interactions I: photothermolysis versus photomodulation laboratory findings. Lasers Surg Med. 2002 Jan;14:25.,3636 Weiss RA, McDaniel DH, Geronemus RG, Weiss MA. Clinical trial of a novel non-thermal LED array for reversal of photoaging: clinical, histologic, and surface profilometric results. Lasers Surg Med. 2005 Feb;36(2):85-91. http://dx.doi.org/10.1002/lsm.20107. PMid:15654716.
http://dx.doi.org/10.1002/lsm.20107...
. In these investigations, several protocols were developed, and the authors verified that the collagen synthesis was related to the clinical alterations found in human skin, including a lower production of some metalloproteinases3535 McDaniel DH, Weiss RA, Geronemus R, Ginn L, Newman J. Light–tissue interactions I: photothermolysis versus photomodulation laboratory findings. Lasers Surg Med. 2002 Jan;14:25.. Based on the results, one protocol was defined (irradiations of 250 milliseconds with a dose of light of 0.1 J/cm2 and the output delivery of 4.0 mW/cm2) and used for 4, 8, 12, 18 weeks and 6 and 12 months. The authors observed the improvement of the skin texture of 90 patients treated with yellow LED3636 Weiss RA, McDaniel DH, Geronemus RG, Weiss MA. Clinical trial of a novel non-thermal LED array for reversal of photoaging: clinical, histologic, and surface profilometric results. Lasers Surg Med. 2005 Feb;36(2):85-91. http://dx.doi.org/10.1002/lsm.20107. PMid:15654716.
http://dx.doi.org/10.1002/lsm.20107...
. In another study, it was observed that the photobiomodulation caused by yellow LED was efficient to decrease the incidence of dermatitis in patients with breast cancer3737 DeLand MM, Weiss RA, McDaniel DH, Geronemus RG. Treatment of radiation-induced dermatitis with light-emitting diode (LED) photomodulation. Lasers Surg Med. 2007 Feb;39(2):164-8. http://dx.doi.org/10.1002/lsm.20455. PMid:17311276.
http://dx.doi.org/10.1002/lsm.20455...
. The patients were treated by application of 100 pulses, 250 milliseconds per pulse at a dose of light of 0.15 J/cm22 Behar-Cohen F, Martinsons C, Viénot F, Zissis G, Barlier-Salsi A, Cesarini JP, et al. Light-emitting diodes (LED) for domestic lighting: any risks for the eye? Prog Retin Eye Res. 2011 Jul;30(4):239-57. http://dx.doi.org/10.1016/j.preteyeres.2011.04.002. PMid:21600300.
http://dx.doi.org/10.1016/j.preteyeres.2...
,3737 DeLand MM, Weiss RA, McDaniel DH, Geronemus RG. Treatment of radiation-induced dermatitis with light-emitting diode (LED) photomodulation. Lasers Surg Med. 2007 Feb;39(2):164-8. http://dx.doi.org/10.1002/lsm.20455. PMid:17311276.
http://dx.doi.org/10.1002/lsm.20455...
. McDaniel et al.3838 McDaniel DH, Weiss RA, Geronemus RG, Mazur C, Wilson S, Weiss MA. Varying ratios of wavelengths in dual wavelength LED photomodulation alters gene expression profiles in human skin fibroblasts. Lasers Surg Med. 2010 Aug;42(6):540-5. http://dx.doi.org/10.1002/lsm.20947. PMid:20662030.
http://dx.doi.org/10.1002/lsm.20947...
, to upgrade the achieved clinical results, conducted an in vitro investigation combining the yellow LED with infra-red LED (590/870 nm). The output delivery used was equivalent to 4.0 mW/cm2 and the dose of light was equivalent to 0.1 J/cm 2. Authors observed a significant increase in collagen I and decrease in collagenase3838 McDaniel DH, Weiss RA, Geronemus RG, Mazur C, Wilson S, Weiss MA. Varying ratios of wavelengths in dual wavelength LED photomodulation alters gene expression profiles in human skin fibroblasts. Lasers Surg Med. 2010 Aug;42(6):540-5. http://dx.doi.org/10.1002/lsm.20947. PMid:20662030.
http://dx.doi.org/10.1002/lsm.20947...
. When the LED (590 nm) was evaluated in cells, it inhibited human microvascular endothelial cells migration, vascular endothelial growth factor and stem cell factor, being a novel therapeutic option for treat melasma5454 Dai X, Jin S, Xuan Y, Yang Y, Lu X, Wang C, et al. 590 nm LED irradiation improved erythema through inhibiting angiogenesis of human microvascular endothelial cells and ameliorated pigmentation in melasma. Cells. 2022 Dec;11(24):3949. http://dx.doi.org/10.3390/cells11243949. PMid:36552713.
http://dx.doi.org/10.3390/cells11243949...
. It is important to notice that, since this type of light has photobiomodulation activity on human tissues, the number of investigations that used the yellow LED is scarce. Therefore, since these treatments yielded relevant results, further studies are necessary to clarify the effect of yellow LED on biological tissues.

White LED 411-777 nm

The photobiological effects of white LED on human cells were also evaluated33 Xie C, Li X, Tong J, Gu Y, Shen Y. Effects of white light-emitting diode (LED) light exposure with different correlated color temperatures (CCTs) on human lens epithelial cells in culture. Photochem Photobiol. 2014 Jul-Aug;90(4):853-9. http://dx.doi.org/10.1111/php.12250. PMid:24483628.
http://dx.doi.org/10.1111/php.12250...
and considering the optical characteristics, white LEDs may be quite diverse due to the different manufacturing techniques of the equipment. As a better description of the spectral characteristics of the white LED, the photobiological effects of the correlated color temperature (CCT) of white LED on cultured human corneal epithelial cells has been evaluated. Cells were irradiated with white LED with CCTs equivalent to 2954, 5624, and 7378 K. The irradiation was performed for 8 h/16 h, to mimic our daily routine. The results showed that LEDs increased the production of intracellular ROS and were genotoxic, both in a dose-dependent manner. Thus, white LED toxicity for lens epithelial cells was also directly dependent CCT33 Xie C, Li X, Tong J, Gu Y, Shen Y. Effects of white light-emitting diode (LED) light exposure with different correlated color temperatures (CCTs) on human lens epithelial cells in culture. Photochem Photobiol. 2014 Jul-Aug;90(4):853-9. http://dx.doi.org/10.1111/php.12250. PMid:24483628.
http://dx.doi.org/10.1111/php.12250...
. In another investigation, commercially available white LEDs and four different blue LEDs (507, 473, 467, and 449 nm) were used for exposure of retinal cells of rats. Animals were exposed to constant light for 6, 12, 18, 24, 48, and 72 h, and it was verified a loss of photoreceptors and the activation of caspase-independent apoptosis, necroptosis, and necrosis3939 Jaadane I, Boulenguez P, Chahory S, Carré S, Savoldelli M, Jonet L, et al. Retinal damage induced by commercial light emitting diodes (LEDs). Free Radic Biol Med. 2015 Jul;84:373-84. http://dx.doi.org/10.1016/j.freeradbiomed.2015.03.034. PMid:25863264.
http://dx.doi.org/10.1016/j.freeradbiome...
. A recent report demonstrated that the blue component of white-LED caused retinal toxicity in albino rats4040 Nam CH, Park BC, Kim MH, Choi EH, Hong SP. The efficacy and safety of 660 nm and 411 to 777 nm light-emitting devices for treating wrinkles. Dermatol Surg. 2017 Mar;43(3):371-80. http://dx.doi.org/10.1097/DSS.0000000000000981. PMid:28195844.
http://dx.doi.org/10.1097/DSS.0000000000...
. These results were observed after 24 hours of exposure at different light intensities (6000 lux, 1500, 1000 and 500 lux)3131 Krigel A, Berdugo M, Picard E, Levy-Boukris R, Jaadane I, Jonet L, et al. Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity. Neuroscience. 2016 Dec;339:296-307. http://dx.doi.org/10.1016/j.neuroscience.2016.10.015. PMid:27751961.
http://dx.doi.org/10.1016/j.neuroscience...
. In contrast, white LED (411-777 nm) when applied at a dose of light of 5.17 J/cm2 was able to improve the periocular wrinkles of female patients4040 Nam CH, Park BC, Kim MH, Choi EH, Hong SP. The efficacy and safety of 660 nm and 411 to 777 nm light-emitting devices for treating wrinkles. Dermatol Surg. 2017 Mar;43(3):371-80. http://dx.doi.org/10.1097/DSS.0000000000000981. PMid:28195844.
http://dx.doi.org/10.1097/DSS.0000000000...
. The oxidative stress activates multiple signaling pathways including mitogen-activated protein kinase cascades that are responsible to causes retinal pigment epithelium damage5555 Chamorro E, Bonnin-Arias C, Pérez-Carrasco MJ, Muñoz de Luna J, Vázquez D, Sánchez-Ramos C. Effects of light-emitting diode radiations on human retinal pigment epithelial cells in vitro. Photochem Photobiol. 2013 Mar-Apr;89(2):468-73. http://dx.doi.org/10.1111/j.1751-1097.2012.01237.x. PMid:22989198.
http://dx.doi.org/10.1111/j.1751-1097.20...
.

As commented previously, the blue component of white light seems to be the main responsible for its toxicity. Taking into consideration that white LED is the most used light in domestic lighting, public and private roads, their widespread use needs to be reassessed.

The Action of LEDs on Cells

In general, it has been suggested that the cytotoxicity of LEDs is related to the increase of cell apoptosis, production of reactive oxygen species (ROS), lipid peroxidation and DNA damage33 Xie C, Li X, Tong J, Gu Y, Shen Y. Effects of white light-emitting diode (LED) light exposure with different correlated color temperatures (CCTs) on human lens epithelial cells in culture. Photochem Photobiol. 2014 Jul-Aug;90(4):853-9. http://dx.doi.org/10.1111/php.12250. PMid:24483628.
http://dx.doi.org/10.1111/php.12250...
,5555 Chamorro E, Bonnin-Arias C, Pérez-Carrasco MJ, Muñoz de Luna J, Vázquez D, Sánchez-Ramos C. Effects of light-emitting diode radiations on human retinal pigment epithelial cells in vitro. Photochem Photobiol. 2013 Mar-Apr;89(2):468-73. http://dx.doi.org/10.1111/j.1751-1097.2012.01237.x. PMid:22989198.
http://dx.doi.org/10.1111/j.1751-1097.20...
. Mitochondria have also been identified as a target for the toxicity of LED illumination1515 Barolet D, Boucher A. LED photoprevention: reduced MED response following multiple LED exposures. Lasers Surg Med. 2008 Feb;40(2):106-12. http://dx.doi.org/10.1002/lsm.20615. PMid:18306161.
http://dx.doi.org/10.1002/lsm.20615...
,2323 Knels L, Valtink M, Roehlecke C, Lupp A, de la Vega J, Mehner M, et al. Blue light stress in retinal neuronal (R28) cells is dependent on wavelength range and irradiance. Eur J Neurosci. 2011 Aug;34(4):548-58. http://dx.doi.org/10.1111/j.1460-9568.2011.07790.x. PMid:21781192.
http://dx.doi.org/10.1111/j.1460-9568.20...
,5656 Yoshida A, Yoshino F, Makita T, Maehata Y, Higashi K, Miyamoto C, et al. Reactive oxygen species production in mitochondria of human gingival fibroblast induced by blue light irradiation. J Photochem Photobiol B. 2013 Dec;129:1-5. http://dx.doi.org/10.1016/j.jphotobiol.2013.09.003. PMid:24141287.
http://dx.doi.org/10.1016/j.jphotobiol.2...
,5757 Buravlev EA, Zhidkova TV, Osipov AN, Vladimirov YA. Are the mitochondrial respiratory complexes blocked by NO the targets for the laser and LED therapy? Lasers Med Sci. 2015 Jan;30(1):173-80. http://dx.doi.org/10.1007/s10103-014-1639-8. PMid:25118663.
http://dx.doi.org/10.1007/s10103-014-163...
, which could be related to the induction of apoptosis. It is known that the mitochondria, a fundamental organelle for maintaining vital cellular functions, also plays a key role in cell death through the regulation of cytochromes5858 Lev-Tov H, Mamalis A, Brody N, Siegel D, Jagdeo J. Inhibition of fibroblast proliferation in vitro using red light-emitting diodes. Dermatol Surg. 2013 Aug;39(8):1167-70. http://dx.doi.org/10.1111/dsu.12212. PMid:23590233.
http://dx.doi.org/10.1111/dsu.12212...
,5959 Rimessi A, Giorgi C, Pinton P, Rizzuto R. The versatility of mitochondrial calcium signals: from stimulation of cell metabolism to induction of cell death. Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):808-16. http://dx.doi.org/10.1016/j.bbabio.2008.05.449. PMid:18573473.
http://dx.doi.org/10.1016/j.bbabio.2008....
, intracellular Ca2+ concentration5959 Rimessi A, Giorgi C, Pinton P, Rizzuto R. The versatility of mitochondrial calcium signals: from stimulation of cell metabolism to induction of cell death. Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):808-16. http://dx.doi.org/10.1016/j.bbabio.2008.05.449. PMid:18573473.
http://dx.doi.org/10.1016/j.bbabio.2008....
, reactive oxygen species (ROS)6060 Huang L, Wu S, Xing D. High fluence low-power laser irradiation induces apoptosis via inactivation of Akt/GSK3β signaling pathway. J Cell Physiol. 2011 Mar;226(3):588-601. http://dx.doi.org/10.1002/jcp.22367. PMid:20683916.
http://dx.doi.org/10.1002/jcp.22367...

61 Sun X, Wu S, Xing D. The reactive oxygen species-Src-Stat3 pathway provokes negative feedback inhibition of apoptosis induced by high-fluence low-power laser irradiation. FEBS J. 2010 Nov;277(22):4789-802. http://dx.doi.org/10.1111/j.1742-4658.2010.07884.x. PMid:20977672.
http://dx.doi.org/10.1111/j.1742-4658.20...
-6262 Wu S, Xing D, Gao X, Chen WR. High fluence low-power laser irradiation induces mitochondrial permeability transition mediated by reactive oxygen species. J Cell Physiol. 2009 Mar;218(3):603-11. http://dx.doi.org/10.1002/jcp.21636. PMid:19006121.
http://dx.doi.org/10.1002/jcp.21636...
, transmembrane mitochondrial potential6363 Koutná M, Janisch R, Veselská R. Effects of low-power laser irradiation on cell proliferation. Scr Med (Brno). 2003 Jun;76(3):163-72., mitochondrial transition pores by caspases or ATP depletion6262 Wu S, Xing D, Gao X, Chen WR. High fluence low-power laser irradiation induces mitochondrial permeability transition mediated by reactive oxygen species. J Cell Physiol. 2009 Mar;218(3):603-11. http://dx.doi.org/10.1002/jcp.21636. PMid:19006121.
http://dx.doi.org/10.1002/jcp.21636...
, changes in the redox state metabolism6464 Belletti S, Uggeri J, Mergoni G, Vescovi P, Merigo E, Fornaini C, et al. Effects of 915 nm GaAs diode laser on mitochondria of human dermal fibroblasts: analysis with confocal microscopy. Lasers Med Sci. 2015 Jan;30(1):375-81. http://dx.doi.org/10.1007/s10103-014-1651-z. PMid:25351448.
http://dx.doi.org/10.1007/s10103-014-165...
and cyclosporine A-sensitive mitochondrial permeability transition6262 Wu S, Xing D, Gao X, Chen WR. High fluence low-power laser irradiation induces mitochondrial permeability transition mediated by reactive oxygen species. J Cell Physiol. 2009 Mar;218(3):603-11. http://dx.doi.org/10.1002/jcp.21636. PMid:19006121.
http://dx.doi.org/10.1002/jcp.21636...
. The irradiation by LED is absorbed by mitochondrial chromophores, including cytochrome c oxidase11 Chaves MEA, Araújo AR, Piancastelli ACC, Pinotti M. Effects of low-power light therapy on wound healing: LASER x LED. An Bras Dermatol. 2014 Jul-Aug;89(4):616-23. http://dx.doi.org/10.1590/abd1806-4841.20142519. PMid:25054749.
http://dx.doi.org/10.1590/abd1806-4841.2...
. Irradiation affects the mitochondrial respiratory chain by changing the electrical power of cellular membranes and, consequently, the selective permeability of sodium, potassium, and calcium ions or through increased activity of enzymes, such as cytochrome c oxidase and ATP synthase6363 Koutná M, Janisch R, Veselská R. Effects of low-power laser irradiation on cell proliferation. Scr Med (Brno). 2003 Jun;76(3):163-72.,6565 Magrini TD, Santos NV, Milazzotto MP, Cerchiaro G, Martinho HS. Low-level laser therapy on MCF-7 cells: a micro-Fourier transform infrared spectroscopy study. J Biomed Opt. 2012 Oct;17(10):101516. http://dx.doi.org/10.1117/1.JBO.17.10.101516. PMid:23223992.
http://dx.doi.org/10.1117/1.JBO.17.10.10...
. In addition, it has been reported an increase in the mitochondrial respiration in the respiratory control state of rat liver cells, after irradiation with LED at 650 nm in a dose of 3 J/cm2 or higher6666 Buravlev EA, Zhidkova TV, Vladimirov YA, Osipov AN. Effects of laser and LED radiation on mitochondrial respiration in experimental endotoxic shock. Lasers Med Sci. 2013 May;28(3):785-90. http://dx.doi.org/10.1007/s10103-012-1155-7. PMid:22797824.
http://dx.doi.org/10.1007/s10103-012-115...
. On the other hand, the same research group found a decrease of mitochondrial respiration of rat liver cells, in the phosphorylating state, after irradiation using the same red LED and doses of light. They demonstrated that the cytochrome c oxidase is important in the photoreactivation of mitochondrial activity blocked by nitric oxide5757 Buravlev EA, Zhidkova TV, Osipov AN, Vladimirov YA. Are the mitochondrial respiratory complexes blocked by NO the targets for the laser and LED therapy? Lasers Med Sci. 2015 Jan;30(1):173-80. http://dx.doi.org/10.1007/s10103-014-1639-8. PMid:25118663.
http://dx.doi.org/10.1007/s10103-014-163...
. Therefore, according to the results of these studies the alteration caused by LED on the mitochondrial level is still controversial.

Concerning the DNA damage, it is important to note that DNA damage would be expected as a consequence of mitochondrial impairment and ROS production caused by LED irradiation independently of the wavelength used2525 Yan G, Zhang L, Feng C, Gong R, Idiiatullina E, Huang Q, et al. Blue light emitting diodes irradiation causes cell death in colorectal cancer by inducing ROS production and DNA damage. Int J Biochem Cell Biol. 2018 Oct;103:81-8. http://dx.doi.org/10.1016/j.biocel.2018.08.006. PMid:30125666.
http://dx.doi.org/10.1016/j.biocel.2018....
. However, reports on genotoxicity are scarce and sometimes contradictory2525 Yan G, Zhang L, Feng C, Gong R, Idiiatullina E, Huang Q, et al. Blue light emitting diodes irradiation causes cell death in colorectal cancer by inducing ROS production and DNA damage. Int J Biochem Cell Biol. 2018 Oct;103:81-8. http://dx.doi.org/10.1016/j.biocel.2018.08.006. PMid:30125666.
http://dx.doi.org/10.1016/j.biocel.2018....
,5555 Chamorro E, Bonnin-Arias C, Pérez-Carrasco MJ, Muñoz de Luna J, Vázquez D, Sánchez-Ramos C. Effects of light-emitting diode radiations on human retinal pigment epithelial cells in vitro. Photochem Photobiol. 2013 Mar-Apr;89(2):468-73. http://dx.doi.org/10.1111/j.1751-1097.2012.01237.x. PMid:22989198.
http://dx.doi.org/10.1111/j.1751-1097.20...
,6767 Karadag A, Yesilyurt A, Unal S, Keskin I, Demirin H, Uras N, et al. A chromosomal-effect study of intensive phototherapy versus conventional phototherapy in newborns with jaundice. Mutat Res. 2009 May;676(1-2):17-20. http://dx.doi.org/10.1016/j.mrgentox.2009.03.008. PMid:19376266.
http://dx.doi.org/10.1016/j.mrgentox.200...
. Considering that these radiations may promote DNA modifications, they can become potentially mutagenic and cause malignancy in human cells, so, this aspect should be explored in the future. Moreover, the effects that LED may cause human cells is dependent on the wavelength, the intensity of the LED device, the distance between the equipment and the cells irradiated, energy delivered per surface area and the exposure time employed for each protocol used. Each color of light or wavelength presents different penetration depths on biological tissues, beyond each biological effect related to differences in chromophore targets44 Jagdeo J, Austin E, Mamalis A, Wong C, Ho D, Siegel DM. Light-emitting diodes in dermatology: a systematic review of randomized controlled trials. Lasers Surg Med. 2018 Jan;50(6):613-28. http://dx.doi.org/10.1002/lsm.22791. PMid:29356026.
http://dx.doi.org/10.1002/lsm.22791...
,6868 Freitas LF, Hamblin MR. Proposed mechanisms of photobiomodulation or low-level light therapy. IEEE J Sel Top Quantum Electron. 2016 May-Jun;22(3):7000417. http://dx.doi.org/10.1109/JSTQE.2016.2561201. PMid:28070154.
http://dx.doi.org/10.1109/JSTQE.2016.256...
.

Relevant Considerations

In the present review, it is important to mention the ICNIRP Guideline, 2013 (International Commission on non‐ionizing radiation protection), which describes the principles of protection against laser radiation hazards, in parallel to the exposure to non-laser optical radiation6969 International Commission on Non-Ionizing Radiation Protection – ICNIRP. ICNIRP Guidelines on Limits of Exposure to Laser Radiation of Wavelengths between 180 nm and 1,000 μm. Health Phys. 2013 Sep;105(3):271-95. http://dx.doi.org/10.1097/HP.0b013e3182983fd4. PMid:30522251.
http://dx.doi.org/10.1097/HP.0b013e31829...
. In accordance with ICNIRP, shorter-wavelength visible radiation in the region from 400 nm to 550 nm (blue light region), has been suggested to damage the retina, for lasers and non-laser radiation7070 Marshall J. Radiation and the ageing eye. Ophthalmic Physiol Opt. 1985;5(3):241-63. PMid:3900875.

71 Young RW. Solar radiation and age-related macular degeneration. Surv Ophthalmol. 1988 Jan-Feb;32(4):252-69. http://dx.doi.org/10.1016/0039-6257(88)90174-9. PMid:3279560.
http://dx.doi.org/10.1016/0039-6257(88)9...
-7272 Remé CE. The dark side of light: rhodopsin and the silent death of vision the proctor lecture. Invest Ophthalmol Vis Sci. 2005 Aug;46(8):2672-82. http://dx.doi.org/10.1167/iovs.04-1095. PMid:16043837.
http://dx.doi.org/10.1167/iovs.04-1095...
. Thus, based in these observations one can assume that the harmful effects caused by LED radiation would be reproduced by laser radiation, just using the same power and wavelength of light. However, the guideline suggests that the safety limits of exposure for laser and non-laser sources, such as the sun, tungsten filaments xenon lamps, and LEDs, may be different6969 International Commission on Non-Ionizing Radiation Protection – ICNIRP. ICNIRP Guidelines on Limits of Exposure to Laser Radiation of Wavelengths between 180 nm and 1,000 μm. Health Phys. 2013 Sep;105(3):271-95. http://dx.doi.org/10.1097/HP.0b013e3182983fd4. PMid:30522251.
http://dx.doi.org/10.1097/HP.0b013e31829...
. These differences might be related to the nature of each radiation, for instance, the controlled or non-controlled emission of photons and also the type of beam produced by the light source such as the case of the laser beam, which is well collimated, while LED beam is not collimated6969 International Commission on Non-Ionizing Radiation Protection – ICNIRP. ICNIRP Guidelines on Limits of Exposure to Laser Radiation of Wavelengths between 180 nm and 1,000 μm. Health Phys. 2013 Sep;105(3):271-95. http://dx.doi.org/10.1097/HP.0b013e3182983fd4. PMid:30522251.
http://dx.doi.org/10.1097/HP.0b013e31829...
. As the exposure limits also depend on the irradiance diameter (spot size), a collimated beam is more conservative than the non-collimated counterpart, in the context of light safety exposure.

As for the emission spectrum, it has been reported that LED devices is constituted of blue radiations or blue components, known to be potentially dangerous to the retina. It was verified that the blue components cause retinal toxicity at occupational domestic illuminance and not only under experimental conditions3131 Krigel A, Berdugo M, Picard E, Levy-Boukris R, Jaadane I, Jonet L, et al. Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity. Neuroscience. 2016 Dec;339:296-307. http://dx.doi.org/10.1016/j.neuroscience.2016.10.015. PMid:27751961.
http://dx.doi.org/10.1016/j.neuroscience...
. So, the biological effects reported here, allow us to question the safeness of the LED radiation. It is possible to suggest that the effects produced by the LED devices, are related not only to the power or wavelength of LED device but also to the nature of the light radiation. Taking together, these arguments reinforce the idea that the nature of light can be another factor to cause adverse effects on biological tissues.

CONCLUSION

In summary, the phototherapy seems to be a promising alternative to treat a varied range of diseases. However, the results described in the literature are inconsistent, mainly due to the lack of methodological standardization of the studies. It is important to state that most investigations were performed based on acute light exposure and do not take into account the effects of prolonged exposures on timescales of weeks, months, and years to mimic human daily routine3131 Krigel A, Berdugo M, Picard E, Levy-Boukris R, Jaadane I, Jonet L, et al. Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity. Neuroscience. 2016 Dec;339:296-307. http://dx.doi.org/10.1016/j.neuroscience.2016.10.015. PMid:27751961.
http://dx.doi.org/10.1016/j.neuroscience...
,6969 International Commission on Non-Ionizing Radiation Protection – ICNIRP. ICNIRP Guidelines on Limits of Exposure to Laser Radiation of Wavelengths between 180 nm and 1,000 μm. Health Phys. 2013 Sep;105(3):271-95. http://dx.doi.org/10.1097/HP.0b013e3182983fd4. PMid:30522251.
http://dx.doi.org/10.1097/HP.0b013e31829...
. Therefore, the comprehension of biological effects caused by repeated exposure of LEDs will provide a better assessment of risks involved using this technology. These data would be of extreme importance to manufacturers of light devices to improve the safeness and eliminate the harmful effects of LED irradiation.

ACKNOWLEDGMENTS

This work was supported by São Paulo Research Foundation (FAPESP), Brazil (grants numbers #2013/07276-1, #2016/13868-7 and # 2017/02559-6).

  • How to cite: Carmello JC, Barbugli PA, Jordão CC, Oliveira R, Pavarina AC. The biological effects of different LED wavelengths in the health field. A review. Rev Odontol UNESP. 2023;52:e20230028. https://doi.org/10.1590/1807-2577.02823

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Publication Dates

  • Publication in this collection
    27 Nov 2023
  • Date of issue
    2023

History

  • Received
    25 Oct 2023
  • Accepted
    26 Oct 2023
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