Author: james.runkle@drummondst.com

In the last two decades the role of antioxidants in skin care has radically changed. In the early 2000s, it was typical to find finished formulas on the shelf that contained butylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA), which were mostly added to enhance the shelf-life of the product. As time went on, formulas containing vitamin C and vitamin E (alpha-tocopherol) became more common since many studies carried out during that period demonstrated the invaluable benefits provided to the skin by these antioxidants.

As the personal care industry entered the end of the first decade in the new millennium, naturally derived ingredients started to become more and more common. Of course, most of these ingredients were based on botanical ingredients, which are chock-full of polyphenols and other ingredients with antioxidant properties. Antioxidants have also become key components of sunscreen formulas, as research demonstrated unique benefits from the addition of antioxidants in addition to any UV absorption properties. Further, a great deal of research has gone into delivery systems for antioxidants, which provide targeted delivery and stability for antioxidants. Nowadays, one can find antioxidants in just about every type of skin care product in the marketplace. In this article, we will review some of the latest advances in antioxidant technology in the skin care arena.

Skin Protection by Antioxidants from Natural Sources

Topical and oral administration of antioxidants for the skin is still a very active field of research [1]. In the personal care industry and academia, a great deal of understanding has been accomplished in the area of topical antioxidant treatments. There are a host of different molecules that have proven to be efficacious for the protection of skin. Some of the most commonly studied antioxidants for topical skin treatment consist of ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), and catechins from green tea. Some other popular ingredients include lycopene, carotene, genistein, rutin, and caffeine [2].

In recent years, most of the focus on new antioxidant product development has been in the botanical arena [1, 3, 4]. Phytochemicals are molecules that are produced by plants. Much effort has gone into understanding their antioxidant, anti-inflammatory, and anti-carcinogenic potential for skin care. There are several recent examples in the literature where the biological activity (antioxidant properties) of botanical ingredients applied to the skin or in cell culture is demonstrated (see Table 1).

Table 1. Examples of studies utilizing botanical ingredients for the treatment of skin.

In some cases, natural ingredients have a limited shelf life or are not stable in different formulation chassis. As such, synthetic ingredients are often inspired by nature. A recent example in the personal care industry is acetyl zingerone, which is structurally similar to zingerone found in the root of the ginger plant, Zingiber officinale [9]. Aguirre-Cruz et al. recently demonstrated the antioxidant potential of peptides, specifically hydrolyzed collagen, to protect the skin from environmental stress [10]. The precise mechanism in which peptides act as antioxidants is not known; however, proton (or electron) donation is suspected to play a role.

In the last decade a tremendous amount of research has been conducted to determine the benefits of molecules from cannabis—a genus of plants from the cannabaceae family. There are a number of phytocannabinoids that have been identified from the hemp plant; however, cannabidiol (CBD) is one of the most studied molecules. Baswan et al. provide a comprehensive review of work conducted in relation to the topical treatment of skin with CDB [11]. It was proposed that CDB has potential to treat eczema, psoriasis, pruritis, and inflammatory conditions.

In addition to topical application, antioxidants and other essential nutrients obtained through the diet (oral consumption) play an integral role in the health state of the skin. This is especially true in regard to moisturization, care of aging skin, and protection against the effects of UV radiation. Many of these key dietary components consist of: omega-3 and omega-6 fatty acids; vitamins A, C, and E; carotenoids; polyphenols; and selenium, zinc, and copper [12].

Antioxidant Delivery Systems

Some of the challenges with the conventional delivery of antioxidants stems from their poor solubility, limited shelf-life stability, compromised photostability, and low degree of skin permeability. Delivery systems enhance the ability of antioxidants to carry out their biological function. Various types of emulsion, vesicular, lipid particle, nanoparticle, and nanocarrier systems have been studied and developed in recent years to aid in the stabilization and delivery of antioxidants to the skin.

Emulsions are dispersions of oil and water and can refer to microemulsions, nanoemulsions, and Pickering emulsions. Vesicular systems consist of liposomes, phytosomes, transferomes, ethosomes, and niosomes. Liposomes are the most popular vesicular system used in personal care applications and are composed of concentric layers of phospholipid bilayers spherically shaped with a hollow center for the active ingredient. Barba and coworkers developed nanoliposomes containing vitamin D3, vitamin K2, vitamin E, and curcumin for topical delivery [13]. On their own, these ingredients are unstable and do not penetrate into the skin very well.

Lipid particle systems consist of lipid microparticles and lipid nanoparticles. A recent study showed the utility of caffeic acid lipid nanoparticulate systems for applications in skin [14]. Nanoparticles and nanocarriers continue to be at the forefront of skin care research for their potential at stabilizing and delivering antioxidants to the skin. For example, gold nanoparticles are known for their anti-inflammatory, antiaging, and wound healing properties in skin care [15, 16]. Nanoencapsulation is another area that shows promise for the delivery of lipid soluble antioxidants to the skin [17].

Sunscreen Technologies Based on Antioxidants

Exposure of skin to UV radiation can cause direct damage to cellular DNA by crosslinking (UVB) or indirect DNA damage caused by photosensitization reactions (UVA). Photosensitization can occur due to the presence of endogenous (e.g., chromophores in proteins) or exogenous (e.g., UVA sunscreens) species in/on the skin. Almost twenty years ago, Hanson and Clegg demonstrated that sunscreen photoprotection could be enhanced if antioxidants were included in the formula [18]. This has become such an important area of research that the Journal of Photochemistry and Photobiology has recently announced that it will dedicate a special issue to the topic of endogenous photosensitizers and their roles in skin photodamage and photoprotection.

The majority of commercial sunscreen formulas contain antioxidants [1]. In part, this is due to the popularity of including botanical ingredients in skin care products. However, the presence of antioxidant species can ameliorate damage caused during and after sun exposure by reactive oxygen species. A recent review by Giacomoni presents this case in relation to the activity of molecules capable of impeding the damaging effects of superoxide anion and singlet oxygen [19].

Concluding Remarks

In the last several years, there has been significant progress in the scientific understanding of antioxidant treatment of the skin. Everly increasing numbers of studies of new ingredients continue to appear in the literature. Hopefully, in the years to come there will be some type of method harmonization across institutes and industry to more uniformly characterize antioxidant behavior from the vast array of botanical ingredients. Many antioxidants are unstable or not easily bioavailable after treatment. To circumvent these challenges, antioxidant delivery systems have been developed and show much promise in the future. Finally, antioxidants play an integral role in sun protection. They are incorporated into sunscreen formulas for their ability to ameliorate damage induced by reactive oxygen species resulting from exposure to UV radiation.

References

1. McMullen, R., Antioxidants and the Skin. 2nd ed. 2019, Boca Raton, FL: CRC Press.
2. Azevedo Martins, T.E., C.A. Sales de Oliveira Pinto, A. Costa de Oliveira, M.V. Robles Velasco, A.R. Gorriti Guitiérrez, M.F. Cosquillo Rafael, J.P.H. Tarazona, and M.G. Retuerto-Figueroa, Contribution of topical antioxidants to maintain healthy skin—A review. Scientia Pharmaceutica, 2020. 88(2): p. 27.
3. Herranz-López, M. and E. Barrajón-Catalán, Antioxidants and skin protection. Antioxidants, 2020. 9: p. 704.
4. Petruk, G., R. Del Giudice, M.M. Rigano, and D.M. Monti, Antioxidants from plants protect against skin photoaging. Oxid. Med. Cell. Longev., 2018. 2018: p. 1454936.
5. Athikomkulchai, S., P. Tunit, S. Tadtong, P. Jantrawut, S. Sommano, and C. Chittasupho, Moringa oleifera seed oil formulation physical stability and chemical constituents for enhancing skin hydration and antioxidant activity. Antioxidants, 2021. 8(1): p. 2.
6. Ahn, J., D. Kim, C. Park, B. Kim, H. Sim, H. Kim, T.-K. Lee, J.-C. Lee, G. Yang, Y. Her, J. Park, T. Sim, H. Lee, and M.-H. Won, Laminarin attenuates ultraviolet-induced skin damage by reducing superoxide anion levels and increasing endogenous antioxidants in the dorsal skin of mice. Mar. Drugs, 2020. 18: p. 345.
7. Karunarathne, W., I. Molagoda, K. Lee, Y. Choi, S.-M. Yu, C.-H. Kang, and G.-Y. Kim, Protective effect of anthocyanin-enriched polyphenols from Hibiscus syriacus L. (Malvaceae) against ultraviolet B-induced damage. Antioxidants, 2021. 10: p. 584.
8. H, P., S. JW, L. TK, K. JH, K. JE, L. TG, P. JHY, H. CS, Y. H, and L. KW, Ethanol extract of yak-kong fermented by lactic acid bacteria from a Korean infant markedly reduces matrix metallopreteinase-1 expression induced by solar ultraviolet irradiation in human keratinocytes and a 3D skin model. Antioxidants, 2021. 10(2): p. 291.
9. Chaudhuri, R., T. Meyer, S. Premi, and D. Brash, Omni antioxidant: Acetyl zingerone scavenges/quenches reactive species, selectively chelates iron. Int. J. Cosmet. Sci., 2020. 42: p. 36-45.
10. Aguirre-Cruz, G., A. León-López, V. Cruz-Gómez, R. Jiménez-Alvarado, and G. Aguirre-Álvarez, Collagen hydrolysates for skin protection: Oral administration and topical formulation. Antioxidants, 2020. 9(2): p. 181.
11. Baswan, S., A. Klosner, K. Glynn, A. Rajgopal, K. Malik, S. Yim, and N. Stern, Therapeutic potential of cannabidiol (CBD) for skin health and disorders. Clin. Cosmet. Investig. Dermatol., 2020. 13: p. 927-942.
12. Michalak, M., M. Pierzak, B. Kręcisz, and E. Suliga, Bioactive compounds for skin health: A review. Nutrients, 2021. 13: p. 203.
13. Bochicchio, S., A. Dalmoro, V. De Simone, P. Bertoncin, G. Lamberti, and A.A. Barba, Simil-microfluidic nanotechnology in manufacturing of liposomes as hydrophobic antioxidants skin release systems. Cosmetics, 2020. 7(2): p. 22.
14. Hallan, S., M. Sguizzato, M. Drechsler, P. Mariani, L. Montesi, R. Cortesi, S. Björklund, T. Ruzgas, and E. Esposito, The potential of caffeic acid lipid nanoparticulate systems for skin application: In vitro assays to assess delivery and antioxidant effect. Nanomaterials, 2021. 11(1): p. 171.
15. Ben Haddada, M., E. Gerometta, R. Chawech, J. Sorres, A. Bialecki, S. Pesnel, J. Spadavecchia, and A.-L. Morel, Assessment of antioxidant and dermoprotective activities of gold nanoparticles as safe cosmetic ingredient. Colloid. Surface. B, 2020. 189: p. 110855.
16. Gubitosa, J., V. Rizzi, P. Fini, R. Del Sole, A. Lopedota, V. Laquintana, N. Denora, A. Agostiano, and P. Cosma, Multifunctional green synthetized gold nanoparticles/chitosan/ellagic acid self-assembly: Antioxidant, sun filter and tyrosinase-inhibitor properties. Mater. Sci. Eng. C, 2020. 106: p. 110170.
17. Davies, S., R.V. Contri, S.S. Guterres, A.R. Pohlmann, and I.C.K. Guerreiro, Simultaneous nanoencapsulation of lipoic acid and resveratrol with improved antioxidant properties for the skin. Colloid. Surface. B, 2020. 192: p. 111023.
18. Hanson, K. and R. Clegg, Bioconvertible vitamin antioxidants improve sunscreen photoprotection against UV-induced reactive oxygen species. J. Cosmet. Sci., 2003. 54(6): p. 589-598.
19. Giacomoni, P., Appropriate technologies to accompany sunscreens in the battle against ultraviolet, superoxide, and singlet oxygen. Antioxidants, 2020. 9: p. 1091.

Roger L. McMullen, Ph.D.

Dr. Roger McMullen has over 20 years of experience in the personal care industry with specialties in optics, imaging, and spectroscopy of hair and skin. Currently, he is a Principal Scientist at Ashland Specialty Ingredients G.P. and leads the Material Science team in the Measurement Science department. Roger has over 30 publications in peer-reviewed journals and textbooks. He is also the author of Antioxidants and the Skin, 2^nd edition and founded the online news magazine The Cosmetic Chemist. Roger received a B.S. in Chemistry from Saint Vincent College and completed his Ph.D. in Biophysical Chemistry at Seton Hall University.

Roger actively engages and participates in educational activities in the personal care industry. He frequently teaches continuing education courses for the SCC and TRI-Princeton. In addition, Roger is an Adjunct Professor at Fairleigh Dickinson University and teaches Biochemistry to students pursuing M.S. degrees in Cosmetic Science and Pharmaceutical Chemistry. Prior to pursuing a career in science, Roger served in the U.S. Navy for four years on board the USS YORKTOWN (CG 48). He is fluent in Spanish and Catalan and currently is learning to play the classical guitar.

What is the Exposome?  According to the CDC/NIOSH[1] website, the exposome can be defined as: “the measure of all the exposures of an individual in a lifetime and how those exposures relate to health.  An individual’s exposure begins before birth and includes insults from environmental and occupational sources.  Understanding how exposures from our environment, diet, lifestyle, etc. interact with our own unique characteristics such as genetics, physiology, and epigenetics impact our health is how the exposome will be articulated.” [2]  In other words, the exposome is the analysis of risk factors encompassing environmental exposures (chemicals, diet, stress, and physical factors), behaviors and genetic variations with overall corresponding biological responses.  This relatively new concept and approach in epidemiological and biomedical research has stirred up some excitement among scientists, with many calling for more efforts to map the human exposome,[3] in order to safeguard future generations from the increasing number of chemical pollutants in our environment.  In this blog, we discuss the main factors comprising the skin aging exposome and how they impact our personal care and skin health.

The Skin Aging Exposome

Skin aging is caused by a combination of two cumulative processes: (1) intrinsic aging and (2) extrinsic aging.  The former is the normal genetic process that occurs over time, including body’s internal oxidation due to metabolic activities and oxygen consumption;[4] while the latter, or accelerated aging, is resulted from exposure to skin exposome factors (Figure 1).  Extrinsic environmental factors, such as sunlight, pollution, and climate, can trigger biological processes that participate and accelerate skin aging.  Self-induced factors, such as smoking, and lifestyle choices also play a role in potentiating skin aging.

Specifically, Krutmann et al.[5] have proposed the following environmental factors as part of the skin aging exposome: (1) solar radiation: ultraviolet radiation, visible light and infrared radiation, (2) air pollution (ozone and diesel exhaust), (3) tobacco smoke, (4) nutrition, (5) other miscellaneous factors, including lifestyle choices and use of cosmetic products.  In fact, it is estimated as high as 80% of skin aging signs are caused by the exposome.[6]^, [7]  It is important to note that skin exposome factors often act synergistically to accelerate the aging process.  For instance, “photo-pollution”[8] is the exposome resulted from the synergistic combination of sunlight and pollution.  In the following, we will briefly describe each skin aging exposome factor.

1. Solar Radiation

Since ancient times, humans have tried various methods to shield the harmful solar radiation and protect skin against the adverse effects of the sun.  In modern times, more sophisticated photoprotection products, i.e., sunscreen and/or daily skin care products, have been developed for the prevention of acute (e.g., sunburn) and chronic (e.g., skin cancer and photoaging) skin damage that may result from exposure to ultraviolet rays (UVB and UVA).

However, with recent advances in skin care research, we have learned that wavelengths beyond the ultraviolet spectrum (UVB, 290–320 nm, and UVA, 320–400 nm), visible light (400–770 nm) and infrared (IR) radiation (770 nm–1 mm), contribute to skin damage in general and photoaging including pigmentary problems of human skin (Figure 2).[9]  Consequently, attempts have been made to develop sunscreen and skin care products that not only protect against UVB or UVA radiation but also provide photoprotection against visible light and infrared radiations.[10]

1.1 Ultraviolet (UV) Radiation

The role of UV radiation in skin aging is well established and the term “photoaging” is coined to emphasize this cause-and-effect relationship.  This is the most studied exposome factor in skin aging for the past several decades.  Herein we will summarize a few key points from review articles on the role of UV radiations in skin aging:[11]^,[12]^,[13]^,[14]

• • Exposure to UV radiation is the primary factor of extrinsic skin aging. It affects all three layers of the skin, e., the epidermis, dermis and hypodermis.  This is the primary cause of early, premature wrinkles, sagging skin and pigmentation.
  • All UV wavelengths (UVB, UVA2 and UVA1) rays contribute to photoaging of human skin.
  • Susceptibility is strongly influenced by endogenous protection systems in human skin, such as skin pigmentation, DNA repair, antioxidant defense, etc.
  • Acute stress responses and chronic damage responses drive the skin aging process.
  • Photoaging mainly results from daily exposure to non-extreme, low doses radiation. UVA rays, in particularly long wavelength UVA1 is a major contributor.
  • Lastly and most importantly, it is highly probable that the regular use of sunscreens can help delay the photoaging process of human skin.

1.2 Visible Light (VL)

Of even lesser energy, visible light (400–700 nm) accounts for approximately 50% of the total solar spectrum.  It penetrates deeply into biological tissues and about 20% reaches the hypodermis.  Evidence suggests that VL plays a fundamental role in hyperpigmentation, particularly in individuals with deeper skin phototypes (Fitzpatrick skin type III-VI) where persistent pigment darkening has been observed following VL exposure.[15]^, [16]  It is demonstrated that the lower wavelength, higher energy portion of visible light (blue-violet light from 400 to 500 nm) is responsible for the highest pigmentation induced by VL.  Even the green part of VL accounts for more than 30% of skin pigmentation.[17]  Studies have shown that physiological doses comparable to 90 – 150 min of midday summer sun exposure can induce lasting pigmentation.¹⁶ Recently, a unique mechanism involving activation of melanogenesis via the opsin 3 photoreceptor has been described.[18]

1.3 Infrared (IR) Radiation

IR rays accounts for approximately 45% of the total solar energy received.  Only the shortest wavelengths, IR-A (770-1400 nm) have sufficient energy for skin penetration to cause significant damage.  IR radiation is known to upregulate the production of matrix metalloproteinases (MMPs), enzymes that facilitate the degradation of extracellular matrix proteins.[19]  The earliest biological event that occurs after IR-A radiation in human fibroblasts is an increase in the intra-mitochondrial production of reactive oxygen species (ROS).  There is a shift in the glutathione equilibrium to its oxidized state.  The discovery of this mitochondrial signaling response caused by IR-A has a direct clinical impact as it indicates that the use of antioxidants may be an effective strategy to help protect the skin against effects from IR-A.

2. Air Pollution and Tobacco Smoking

Exposures to pollutants, exhaust, smog-derived ozone and cigarette smoke have been associated with accelerated skin ageing (pigmentation, loss of elasticity and wrinkles) and increased cancer risks.[20]  Airborne particles (particulate matters, PM), rich in polycyclic aromatic hydrocarbons (PAHs), can exert detrimental effects on human skin and contribute to facial lentigines formation.[21]  In general, topical exposure to pollutants harms the skin by increasing oxidative stress that modifies lipid DNA and protein function.[22]^, [23]^, [24]  Soeur and coworkers at L’Oréal demonstrated the effect of “photo-pollution”, where with exposure to UVA1 irradiation (i.e., long UVA, 350-400 nm), which accounts for 80% of daily UV and can easily reach dermal-epidermal junction in skin, air pollutants (in particular, PAHs) were phototoxic even at very low concentrations (nanomolar range) on cultured cells or in reconstructed epidermis.  Thus, the impact of PAHs reacting to long UVA synergistically increases the oxidative stress, which may impair cutaneous homeostasis and aggravate sunlight-induced skin damage.

Exposure to pollution also decreases skin quality and exacerbates existing skin conditions, such as atopic dermatitis (AD) and acne.[25]  Various scientific studies show an undeniable link between air pollution (including cigarette smoke) and pigmentation, loss of elasticity and wrinkles.  These factors share a common mechanism involving the aryl hydrocarbon receptor (AhR).[26]  Based on available studies, many of the adverse effects caused by air pollution may be mediated via AhR signaling in human skin.  In addition to topical exposure, humans are exposed to PAHs via systemic accumulation in the body.  This is evident by measuring the pollutants in the hair fibers.[27]  Naudin et al. have confirmed that speed of naturally occurring hair-cortex degradation and cuticle delamination is increased in fibers with increased PAH concentrations.  Further, hair fiber with exposure to UV irradiation leads to more pronounced cuticle damage, especially around samples with higher PAH concentrations.  This detrimental effect of PAHs together with UV irradiation, i.e., photo-pollution, is likely to be seen with other human tissues.

3. Diet / Nutrient

Dietary factors and nutritional supplements may influence skin health.  Eating unhealthy food has been associated with numerous skin problems, ranging from acne to signs of skin aging.  On the other hand, a healthy diet rich in antioxidants may delay chronological aging effects.  In a study of facial aging in twins, twins who avoid excessive alcohol intake have a younger perceived age.[28]  Consuming too much sugar is suggested to contribute to wrinkles, due to a natural process, known as glycation,[29] where sugar in the blood stream binds to proteins to form harmful molecules called “advanced glycation end products” (AGEs), aka. the Maillard reaction.  Another risk factor associated with food consumption is unintentional ingestion of PAHs.  In addition to inhalation and skin contact of PAHs as a result of air pollution, people can be exposed to PAHs by consuming charbroiled foods (smoke meat, or grilled over charcoal, diesel exhausts, etc.).[30]  Such consumption may contribute to skin damages following systemic exposures.

4. Stress and Sleep Deprivation

It is known that stress creates elevated levels of cortisol hormones which cause inflammation in the body.  Inflammation leads to increased collagen breakdown and exacerbation of skin conditions such as acne, rosacea, eczema and wound healing.  Though it may seem intuitive to link physiological stress and skin aging, the underlying mechanisms are not well defined.  However, one plausible mechanism was demonstrated by studies of the correlation between psychological stress and permeability barrier homeostasis in human cutaneous functions, thus explaining how psychological stress can lead to a decline in epidermal permeability and deterioration in barrier disruption and recovery, followed by the induction, exacerbation, and propagation of inflammatory skin disorders. [31]^, [32]

Further to acute psychosocial stress, sleep deprivation is associated with increased signs of intrinsic skin aging (fine lines, uneven pigmentation, reduced elasticity), most likely due to its disruption of skin barrier function homeostasis, and that this disruption may lead to much slower recovery rates after skin barrier disruption and lower satisfaction with appearance.[33]

Exposome and Acne

Acne is caused by inflammation of the pilosebaceous follicle, occurring commonly in adolescents and some adults.  Clinically, inflammatory acne causes skin damages and formation of skin lesions, including micro-comedones, papules, and pustules.  In some people, scarring from acne can be persistent.[34]

Several exposome factors, including diet, pollution, medication, microbiota, and cosmetics, have been implicated in development and exacerbation of acne (Figure 3).²³ This argument is confirmed in a recent international survey with 11,000 participants, aged between 15 and 39 years, with clinically confirmed acne or without acne.  Consumption of dairy products, sweets, alcohol or whey proteins, as well as exposure to pollution, stress, certain mechanical factors and humid or hot weather or sun exposure, were significantly (all P ≤ 0.05) more frequently reported for the acne group than for the control group.[35]  Some topical skincare and makeup products containing essential oils, powders, and alkaline skin cleansers and soaps have been associated with acne.²³  Use of mild cleansers on a regular basis to keep the skin surface free of oil, dirt and debris can help prevent acne.

Maskne

For decades in some Asian countries, people regularly wear face masks to reduce the inhalation of pollution-related particles.  It has nowadays taken another facet, i.e., to limit the spread of harmful viruses such as COVID-19.  However, the negative impact of repetitive and prolonged mask wearing may cause “maskne” or mask-related acne and other skin issues, including breakouts, clogged pores, redness, itchiness and imperfections.  Maskne is essentially a subset of acne mechanica, due to friction/rubbing from the mask, causing local pressure on the sweat glands and irritation of the skin barrier.[36]^, [37]  Further exacerbation is induced by increased temperature and trapped moisture in the mask area due to the continuous use of face masks.  No studies to date have evaluated “maskne”, however, current data suggests maskne is likely a result of local temperature changes and skin microflora dysbiosis.[38]  General advise for dealing with maskne includes: (1) avoid wearing makeup under the mask area, (2) use mild facial cleanser containing salicylic acid, (3) topical moisturizer to hydrate and maintain skin barrier functions, and (4) change masks regularly.

Taking on the Exposome

In a 2016 review article, Dr. Sainani summarized progress in exposome research, including Environment-Wide Association Studies and novel data collection techniques, as well as significant remaining challenges in collecting, analyzing, and interpreting exposome data.  The article concludes with a call to adopt a “big science” approach akin to the Human Genome Project, with investments in improving measurement techniques, establishing public databases with agreed upon standards, and strong community leadership.[39]

In a recent JEADV paper, Appenzeller et al. studied hair samples from 204 women from two Chinese cities with different levels of pollution.  The hair analysis, together with “omics” data (metabolomics, proteomics, genomics and microbiome), provided access to information for assessing chronic exposure to pollution (particularly, PAHs) and shed light on the molecular mechanisms of the combined effects of exposome factors, including solar radiation and other environmental exposure.[40]

Further to the study on hair samples, De Vecchi et al. have evaluated the impact of several environmental aggressors on human surfaces, using portable and wearable devices for monitoring exposome.[41]  The work was carried out by two bicyclists wearing multiple sensors to capture the meteorological conditions by biking through urban areas in summer and in winter in Brazil.  Correlated with GPS and monitoring data, all these results provide insights on how environmental stressors affect the quality of different hair types and body surface according to exposure routine.  Additional study was designed to quantify environmental exposures during routine daily activities to provide quantitative metrics that inspire future studies on exposome and human health.[42]

Summary and Conclusions

Based on several reviewed articles, it is undeniable that most skin aging processes are affected by numerous different exposome factors.  In order to mitigate the negative impacts of such factors, further development of the nascent holistic approach will be important for the cosmetic field.  In particular, a comprehensive approach is essential to understanding how the sum of all factors are affecting skin health and skin aging on the individual level and how to further define the appropriate recommendations, such as lifestyle changes, nutritional adjustments, adequate cosmetic formulations, and personalized beauty routine, to alleviate the negative impacts of such factors.  While exposome factors cannot be completely avoided, a conscious awareness, limited exposure and healthy lifestyle can help reduce their negative effects on skin health.

Acknowledgement

The authors are most grateful to Luc Aguilar for his review and suggestions for the manuscript.  In addition, we would like to thank the kind review and comments from Giorgio Dell’Acqua, Ronni Weinkauf, Jean-Baptiste Galey, Gustavo Luengo, and the L’Oréal Reading Committee.

Figure 1.  The skin aging exposome.  These factors have been identified to have detrimental effects on skin health.  Exposure to sunlight, pollution and tobacco smoking are shown to trigger molecular processes that damage the skin structure, leading to premature skin aging.  Other factors, recently recognized and thus less studied, have also shown to be potentiators for skin aging.  These factors can act independently or interact synergistically with each other to accelerate the skin aging process.  [J. Krutmann, et al., The Skin Aging Exposome, J Dermatol Sci (2017)].

Figure 2.  The solar spectrum with various wavelengths, which penetrate skin at different levels.  The longer the wavelengths the deeper the rays penetrate the skin.  Each wavelength has both different and overlapping effects.  UV = Ultraviolet radiation, ROS = Reactive Oxygen Species, RNS = Reactive Nitrogen Species.  [Modified from J. Krutmann, et al., The Skin Aging Exposome, J Dermatol Sci (2017) with updated data from H. Lim publications].

Figure 3.  The exposome factors impacting acne.  [B. Dreno, et al., J Eur Acad Dermatol Venereol, (2018)]

References:

[1] CDC = Centers for Disease Control and Prevention, NIOSH = National Institute for Occupational Safety and Health.

[2]https://www.cdc.gov/niosh/topics/exposome/default.html#:~:text=The%20exposome%20can%20be%20defined,from%20environmental%20and%20occupational%20sources (Accessed on April 1, 2021)

[3]  http://alliance.nautil.us/article/242/mapping-the-human-exposome (Accessed on April 4, 2021)

[4]  Van Beek, J.H.G.M., Kirkwood, T.B.L., Bassingthwaighte, J.B. ‘Understanding the physiology of the ageing individual: computational modelling of changes in metabolism and endurance’, Interface Focus.06 April 2016.  http://doi.org/10.1098/rsfs.2015.0079

[5]  Krutmann, J., Bouloc, A., Sore, G., Bernard, B.A., Passeron, T. ‘The skin aging exposome’, J Dermatol Sci. 2017 Mar; 85(3):152-161. doi: 10.1016/j.jdermsci.2016.09.015.

[6]  https://www.vichyusa.com/vichy-exposome (Accessed on April 6, 2021)

[7]  Friedman, O., ‘Changes associated with the aging face’, Facial Plast Surg Clin North Am. 2005 Aug; 13(3):371-80.

[8]  Soeur, J., Belaïdi, J.P., Chollet, C., Denat, L., Dimitrov, A., Jones, C., Perez, P., Zanini, M., Zobiri, O., Mezzache, S., Erdmann, D., Lereaux, G., Eilstein, J., Marrot, L. ‘Photo-pollution stress in skin: Traces of pollutants (PAH and particulate matter) impair redox homeostasis in keratinocytes exposed to UVA1’. J Dermatol Sci. 2017 May;86(2):162-169. doi: 10.1016/j.jdermsci.2017.01.007. Epub 2017 Jan 16. PMID: 28153538.

[9]  Note that IR rays do not trigger pigmentation.  See Geisler, A.N., Austin, E., Nguyen, J., Hamzavi, I., Jagdeo, J., Lim, H.W. ‘Visible light. Part II: Photoprotection against visible and ultraviolet light’, J American Academy of Dermatol, Volume 84, issue 5 (May 2021).

[10]  Dupont, E., Gomez, J., Bilodeau, D. ‘Beyond UV radiation: a skin under challenge’, Int J Cosmet Sci. 2013 Jun;35(3):224-32. doi: 10.1111/ics.12036. Epub 2013 Feb 14. PMID: 23406155.

[11] Marionnet, C., Tricaud, C., Bernerd, F. ‘Exposure to non-extreme solar UV daylight: spectral characterization, effects on skin and photoprotection’, Int J Mol Sci, 2014, 16: 68-90

[12] Battie, C., Jitsukawa, S., Bernerd, F., Del Bino, S., Marionnet, C., Verschoore, M. ‘New insights in photoaging, UVA induced damage and skin types’, Exp Dermatol, 2014, 23 Suppl 1: 7-12.

[13] Kligman, L. H., Kligman, A.M., ‘The nature of photoaging: its prevention and repair’, Photodermatol, 1986, 3: 215-27.

[14] Flament, F., Bazin, R., Laquieze, S., Rubert, V., Simonpietri, E., Piot, B., ‘Effect of the sun on visible clinical signs of aging in Caucasian skin’, Clin Cosmet Investig Dermatol, 2013, 6: 221-32

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AUTHORS

Catherine CHIOU,^a Gabrielle SORE,^b Stephen LYNCH^a

^a L’Oréal Research and Innovation, Clark, NJ, USA

^b L’Oréal Research and Innovation, Chevilly Larue, France

Catherine Chiou, PhD.

Dr. Catherine Chiou holds a BS degree in Chemistry from National Taiwan University and a Ph.D. in Bioinorganic Chemistry from the University of Minnesota.  Catherine’s NIH Postdoctoral fellowship training in Synthetic Chemistry took place at Harvard University.  Her first industrial position was with Unilever Research US in the laundry bleach research program and machine dishwashing detergent research, including I&I applications.

Catherine began her career in cosmetic field at L’Oréal USA in 2001 in the DIMP (International Raw Materials Department).  She worked on all aspects of “innovative raw material” functions, including scouting new supplier innovations, and managing supplier relationships.  In addition, Catherine served a stint within the PCPC INCI Committee.

Catherine is currently an Associate Principal Scientist at L’Oréal USA in the Cosmetic Application Domain, focusing on developing skin cleansing and makeup removing technologies.  Prior to the current position, she has worked in the skin care research and innovation lab as a senior formulator, contributing towards development of platform technologies and several global launches of skin care treatment products.  She is an inventor for more than 20 US and international patents.  She is a current member of scientific committee of NYSCC.

Gabrielle Sore, PhD.

Dr. Gabrielle Sore is a pharmacist with a Ph.D. in dermal pharmacology. She has been working for more than 30 years in the cosmetic industry. Dr. Sore spent the last 29 years in L’Oréal where she worked in France, in Japan, and in the United States. During Gabrielle’s career, she worked mostly in the scientific communication of skin care, make-up and specific eye products; and she was more specifically in charge of scientific communication of dermatological brands like Vichy, La Roche Posay, SkinCeuticals for which her role is to coordinate the information within the Research, Marketing and Development teams.

Stephen Lynch, PhD.

Dr. Stephen Lynch holds a PhD in organic chemistry and spent 10 years in the pharmaceutical industry conducting drug discovery research.   For the past 7 years he has worked for L’Oréal USA Research & Innovation where he currently serves as Director of Skincare Scientific Affairs.  In this capacity he helps to identify cosmetic ingredients, coordinate innovative testing, and translate scientific concepts in support of skincare product development.

The use of hand sanitizers has steadily increased over the past ten years.  Their use began in hospitals, doctor’s offices, clinics and healthcare facilities.  Then, we started seeing dispensers in building entrances, by elevators and in many common areas.  Due to the recent COVID pandemic, there was an exponential increase in the use of hand sanitizers. Dispensers were placed in most store’s entrances and in multiple locations in every store.  Hand sanitizers were no longer sold in pharmacies only, but they are sold everywhere, including hardware stores.  One can purchase a gallon of sanitizing hand lotion at a time instead of the usual 12 to 16 oz containers.

In the United States, hand sanitizers are also called “consumer antiseptic rubs” and are regulated by the Food and Drug Administration (FDA).  They are considered Over the Counter Drugs (OTC) and fall under the Consumer Antiseptic Rub Products Monograph.  This monograph is not finalized yet, but tentative final monographs have been published in the Federal Register in 2016, 2017 and 2019^1,2,3.  The most recent tentative final monograph does not classify any active as Category I (Safe and effective).  However, it classifies three actives as Category III (More data needed for safety and efficacy).  These actives are:

1. Alcohol at 60-90%.
2. Isopropyl Alcohol at 70-91.3%.
3. Benzalkonium Chloride.

The monograph requires marketers of such products to test the products for safety and efficacy.  Efficacy should be tested both in vitro and in vivo.  In vitro testing requires the determination of antimicrobial activity of the antibacterial active by conducting a battery of antimicrobial tests using certain bacterial strains.  Three tests are suggested in the monograph, namely Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC) and time-kill testing of certain strains.  Regarding in vivo testing, the monograph specifies conducting two clinical studies with a minimum enrollment of 100-person each in two separate centers to evaluate efficacy.   Efficacy is typically evaluated using bacterial log reduction after product application as compared to a placebo.

Due to the recent COVID pandemic, the FDA issued a temporary guidance for alcohol-based hand sanitizer production⁴.  The guidance allowed FDA-registered manufacturers to produce alcohol-based hand sanitizers based on the following formulation:

1. Alcohol (ethanol formulated to 80% v/v) in aqueous solution or Isopropyl Alcohol (formulated to 75% v/v) in aqueous solution.
2. Glycerin 1.45% v/v
3. Hydrogen Peroxide (0.125% v/v)
4. Sterile distilled water or boiled cold water.

The stipulation was that other additives cannot be added to this formulation, including fragrance.  The formulation is not supposed to be thickened and should be in the form of a solution only.  The formulation cannot be used as a foam or an aerosol either.

Now let’s talk about the fun stuff, formulating a hand sanitizer product.  The leading method of dispensing hand sanitizers in most facilities are the motion-sensing foam dispensers.  These dispensers typically are filled with an alcohol-based solution that foams when dispensed.  The formulation contains 70% alcohol for sanitizing and PEG-12 dimethicone as a foaming agent.  It also contains glycerin (a well-known moisturizer), tocopherol acetate and a couple of esters to replenish skin lipids as well as a mild fragrance to cover the alcohol smell.

The second most popular form of hand sanitizers on the market is the gel.  Most gels are formulations containing an alcohol level between 60-80%.  Many gels are thickened with Carbomer or an acrylate variant such as Acrylates/C10-30 Alkyl Acrylate Crosspolymer.  Due to the high level of alcohol in these formulations, the use of sodium hydroxide to neutralize Carbomer is generally not suggested. Typically, it is recommended to neutralize acrylates polymers with organic amines.  Formulators have used triethanolamine, aminomethyl propanol, and tris amino.  The use of acrylates in making the gels provides a good cost advantage and helps create crystal clear gels.  The formulations typically crumble during rub out due to the inability of acrylates to handle residual salt in hands.  Due to recent attacks on acrylates from various organizations and their potential labeling as micro-plastics, many formulators switched to cellulosics as rheology modifiers.  Cellulosics are naturally-derived and can thicken alcohol-based formulations as well.  The most commonly used thickener is hydroxypropylcellulose followed by hydroxyethylcellulose.  Cellulosics will yield transparent gels and will impart a slip to the formulation.  Cellulosic gels do not need to be neutralized and do not crumble in hands upon rubbing.

Alcohol-free hand sanitizers typically capture a small slice of the market by targeting some customers that prefer not to use alcohol.  These products are based on Benzalkonium Chloride and come in various forms like emulsions, gel-creams, and gels as well.  Due to the absence of alcohol these products could be considered Halal if they meet the rest of the criteria necessary for certification.

A myriad of ingredients can be typically added to hand sanitizer gels.  Glycerin is very popular as it helps moisturize the skin and changes the feel and application of the gel as well.  Aloe is another ingredient commonly added to the formulation due to its well-known healing and soothing properties.  Several alcohol-soluble esters have been used as well.  Esters of alpha-hydroxy acids are popular due to their high polarity and ease of incorporation into such formulations.  Such esters are lauryl lactate, myristyl lactate, and C12-15 alkyl lactate.  Other alcohol-compatible esters with high polarity include diisopropyl adipate, and isodecyl neopentanoate.

One important key ingredient present in most gels is the fragrance.  Selecting a fragrance for a hand sanitizer is not quite simple.  One must make sure that the fragrance is stable at such high level of alcohol for the duration of the accelerated stability (typically, 3 months at 45°C).  In addition, the fragrance must cover the alcohol odor without being overwhelming since many professionals apply the product more than 10 times a day.

When checking the stability of such formulations, one should not forget to store them in explosion-proof ovens.  These formulations are quite flammable, and if stored in a regular laboratory oven can cause a fire hazard.  The compatibility of these formulations with the final packaging should also be tested as the high level of alcohol could deform many types of plastics.

I hope this quick review of hand sanitizer formulations is quite helpful for formulators and would give them a head-start when formulating such products. Now it is up to the individual formulator to be creative and add his/her personal touch to make such formulations unique in this crowded undifferentiated market.

References

1. Federal register/Vol 81, No. 126/Thursday June 30, 2016 – 21 CFR Part 310
2. Federal register/Vol 82, No. 243/Wednesday December 20, 2017 – 21 CFR Part 310
3. Federal register/Vol 84, No. 71/Friday April 12, 2019 – 21 CFR Part 310
4. Temporary Policy for Certain Alcohol-based Hand Sanitizer Products During the Public Health Emergency (COVID-19) Guidance for Industry. March 2020, Updated Feb 10, 2021

Dr. Fares started his career in personal care studying the effect of solvents on sunscreen chemicals.  His interest in skin drug delivery especially from polymeric matrices grew during his graduate work at Rutgers, where he received his Ph. D.

Dr. Fares worked at Block Drug and GlaxoSmithKline where he held positions in research and development in the areas of skincare and oral care.  After that, he joined L’Oreal where he held several positions of increasing responsibility leading to AVP of skincare.  He is currently the Senior Director of skincare and oral care at Ashland Specialty Ingredients.  Dr. Fares is the author of many publications, and patents and made many presentations in national and international meetings in the areas of suncare, skincare, and oral care.  Dr Fares chairs the NYSCC scientific committee and has won multiple awards in the area of sun care and polymer chemistry.