It is well-known trivia that skin is the largest organ of the human body. A lesser known fact is that skin is one of the few organs that readily regenerates itself. In fact, the skin produces an entirely new skin every 28 days or so. While skin is ever-changing and adapting to the environment in that it finds itself, the resultant properties of the skin, i.e., changes in barrier function, take from days to a week to manifest as the old dead stratum corneum (SC) is replaced with a regenerated SC.
See related sidebar: [sponsored] Performance for Sensitive Skin: Zema Propanediol
Evolution has determined that the solution to providing a sufficiently reliable and resilient barrier to the external world is to regenerate the body’s largest organ 12 times a year. This solution has survived despite its high metabolic cost and resource-intensive nature, suggesting its function is both critical but also difficult to achieve. Indeed, this complex and dynamic organ often encounters problems maintaining barrier functioning, which can lead to compromised skin.
This article explores how cleansing the skin can help, hinder and/or both when it comes to recovering the health of compromised skin. In addition to desired beneficial effects, cleansing products can damage the skin as they interact with it in multiple ways. Therefore, in order for a cleanser to be mild to the skin, it must be mild in all aspects and in all ways.
The Skin Barrier
The primary function of the skin is to keep our being inside and the world outside. More specifically, its main functions are: to provide a reasonably good barrier to water, transporting from the high concentration inside the body to a very low concentration outside the body; and to limit the entry of exogenous material. Critically, the skin must provide this important barrier function while dynamically conforming to the movement of the body. Amazingly, this life-critical barrier is only 10 to 25 cells thick, about 6 mm to 14 mm, with variation across different body sites and ages.
Like all materials, the resultant properties of the skin, i.e., mechanical and transport, are determined by its meso-scale structure and molecular organization. While the stratum corneum (SC) had long been described as a brick-and-mortar (corneocytes and lipids) structure, this analogy missed key elements of the physics of the system. A more apt analogy would be a pancake-and-butter structure;1, 2 Figure 1 shows a schematic of the skin.
Corneocytes in the SC are reasonably pancake-shaped. They are flat and thin, 0.4 mm to 1.4 mm, with a dimension parallel to the skin surface of about 30 mm to 50 mm and a surface area of about 900 mm to 1200 mm.3 The aspect ratio of corneocyte is about twice that of pancakes; i.e., corneocytes are wider and thinner. Between the corneocytes are about 5 to 12 layers of highly molecularly ordered lipids consisting of ceramides, fatty acids and cholesterol. Each lipid layer is approximately 11 nm thick. These thin lipid layers provide much of the barrier of the skin.
In order to traverse a healthy SC, a molecule must pass through highly ordered hydrophobic lipid chains, followed by a hydrophilic domain of the polar head groups, then again 5 to 12 times through the lipid layers between each corneocyte, and finally, again, across approximately fifteen pairs of corneocyte and lipid layers.
While healthy skin provides a strong barrier against water transport out of the skin, compromised skin is characterized by an impaired barrier function that is more susceptible to the transport of both waters out of the body and exogenous species into the skin, where they can come into contact with the living tissue in the dermis.
A weaker barrier can occur when the SC is thinner; i.e., has fewer layers of corneocytes or “pancakes,” as shown in Figure 1. Examples include skin in the elderly, in infants or that has been abraded through friction, such as rug burn. The SC can also lose mechanical flexibility and crack, providing paths through the epidermis. This can occur with problems in desquamation, i.e., the shedding of the outermost of corneocytes. Alternatively, the lipids between corneocytes, the “butter” in Figure 1, can be made more fluid and thus more susceptible to transport. SC lipids can be fluidized by surfactants from harsh cleansers4 or even some components of natural oils.5
Furthermore, aiding in the restoration of the native skin barrier is preferred over applying an exogenous barrier on top of the skin. That is to say, the barrier function provided by lotions are inferior to the health of the native skin barrier. The skin structure is special and purposefully built to provide the ideal barrier. Topical products can be useful in helping the skin to rebalance and restore itself, however. As such, focused efforts on balanced and gentle cleansing can support the skin’s restoration to a healthy state.6
Causes of Compromised Skin
A variety of causes can lead to a disrupted or less effective barrier and compromised skin. Some are innate; a handful of genetic mutations that can impact the epidermal barrier have been associated with atopic dermatitis; most notably, a filaggrin mutation.7 Others are related to life stage. Still others are due to the external environment and routines including what the skin is exposed to, such as harsh cleansers; the mechanics of cleansing; pollution; UV; etc.
Young children and the elderly, for example, typically have a thinner SC and weaker barrier. Young children are still developing their skin barrier and transitioning from life in utero and a wet physiological interface with the SC.8 While an infant’s dermal cell proliferation is high, they are also rapidly expanding their skin surface area as they grow bigger.9 In contrast, the elderly have slower cell proliferation, which leads to thinner skin and a thinner SC barrier.
It is useful to consider the interventions used experimentally to disrupt the skin barrier to relate compromised skin properties. These include:
- Removing layers of the SC; i.e., tape-stripping to remove layers of corneocytes and lipids;10 and
- Disrupting SC lipid organization through:
- Organic solvents, to swell lipid bilayers of the SC;11 and
- Aggressive surfactants; often a sodium dodecyl sulfate insert and the fluidization of SC lipids.12
Changing Skin Dynamics
As the external environment changes with the seasons, the skin continually responds to this change but there is a time lag in the skin barrier response. Additionally, when the external environment changes, the problems of the skin change. While it is experimentally inconvenient to conduct clinical studies over an entire year in order to observe these changes, observing human behavior in the real-world through natural experiments is increasingly possible.
One source of data on real-world behavior is Google search trends. Figure 2 shows the dynamic environment outside that the skin must respond to (top), and correspondingly, the dynamic nature of skin problems (bottom). Google search trends of skin-related problems over the last five years were normalized across topics and averaged by week of the year. On top, the corresponding weekly averaged daily high and low temperatures are shown.
One can readily observe seasonal effects in skin problems based on consumer searches on Google. Skin rash and itch are correlated, and their search frequency is much higher in the summer, with the rise in search frequency occurring about ten weeks after the first rise in allergies. Dry skin increases in the colder, drier winter months, with a corresponding rise in search frequency.
While this search intent data is averaged across the large geographic area of the U.S., in fact the climate and weather vary significantly across much shorter distances. To this point, Figure 3 shows how pollen levels change by month throughout the course of a year at the state level. Here, a wave of pollen can be seen moving across the U.S., starting in the warmer southern states in February and moving north through the spring.
To Cleanse or Not, and With What
With the perspective that skin is dynamic, adaptable and seeking balance, it probably comes as no surprise that cleansing the skin does both good and harm. And, depending on the cleanser formulation, it does both good and harm to different extents, which are also variable. These are explored next in greater depth.
It is interesting to note that clinical guidelines for compromised skin, where they exist, typically advocate for skin cleansing with a mild, skin-compatible cleanser. There is general agreement to avoid standard alkaline soaps, for example, although guidelines also suggest that more robust scientific evidence is needed.
Guidelines for older, mature skin state that “guidance is based on clinical expertise rather than on robust trial evidence.”13 In the case of infants, the Association for Women’s Health Obstetric and Neonatal Nurses (AWHONN) guidelines recommended bathing babies with a mild, pH-neutral cleanser.14
Cleansing: The ‘Good’—Removing Unwanted Species
Humans have approximately two square meters of skin, are there two ways in that this large surface area is refreshed: by cleansing or by removing the top layer of SC cells. A variety of materials are undesired on the skin, and since compromised skin allows for easier transport into the living dermis, cleansing and removing them becomes all the more important. Figure 4 depicts the undesired materials for removal. It also highlights the complicated goal cleansers must achieve; these species cover a wide range of scales and chemical compositions.
The surfactants in cleansers remove unwanted materials due to their amphiphilic, i.e., water-loving and oil-loving nature. This dual molecular structure allows surfactants to stabilize oil interfaces in water and allows for the emulsification of dirt, proteins, enzymes, etc., into the aqueous phase, to be washed away.
Unfortunately, determining the effectiveness of a cleanser at removing material is difficult. Cleansing is a non-equilibrium process and requires the addition of mechanical forces. There are not easily repeatable tests, and while cleanser foaming is associated with efficacy, these two properties are only slightly related.
There are many ways to cleanse but the mechanical action of cleansing can also be damaging to compromised skin, especially if a solid surface is involved—e.g., a wipe, wash cloth, cotton ball or other implement. In fact, the friction of cotton and water on skin has been shown to cause damage to compromised skin. This has been better explored in wound cleansing and lavage, where solid materials are avoided when possible.
Enzymes: Enzymes originating in food or feces can degrade proteins in the SC. Long term exposure of the skin to excess water, often from urine but also from perspiration and wounds, can cause barrier degradation. This is referred to as moisture-associated skin damage. Enzymes and excess water can cause diaper rash or diaper dermatitis15 in babies or perineal dermatitis in incontinent adults. Occlusion of the skin often exacerbates these problems.16
Pollen and allergens: Pollen and other allergens, often from food, cause a specific immune response and inflammation in skin. In order for allergens and other external irritants to cause skin problems, the proteins must transport through the SC to living tissue. With an intact SC, this takes significant time, which allows for skin cleansing to remove proteins on the skin surface that could cause and allergenic response. Allergen transport through compromised skin is faster, suggesting that more frequent cleansing, with a mild cleanser, to remove allergens would be beneficial. In addition to removal, cleansers can also denature allergen proteins.
Pollution: Often reported as PM10 or PM2.5—i.e., diameters of less than 10 mm and 2.5 mm, respectively, particulate air pollution is commonly comprised of carbon species from incomplete combustion from both natural and anthropogenic sources such as forest fires and transportation.17 Pollution typically causes a non-specific response, often through the generation of reactive oxygen species when exposed to UV.18 This can oxidize SC components by creating more hydrophilic moieties and reducing lipid order and barrier function. There also is increasing evidence connecting air pollution to atopic dermatitis.19, 20
Malodor: Less related to managing compromised skin, another main consumer goal of cleansing is to remove and/or eliminate malodor typically caused by bacteria on the skin or endogenous excretions. These are mostly small molecule volatile organic compounds, and studies have compiled the set of common VOCs found on the skin.21, 22 An additional goal is to remove sebum, which is composed of triglycerides, fatty acids and squalene. Sebum can serve as food for bacteria and, once metabolized, become other smaller molecule VOCs that are desirable to remove.
Bacteria: Even on dynamic skin, it appears the skin microbiome maintains a relatively stable equilibrium over time.23 As skin is cleansed and the surface is removed, the populations of bacteria present are fairly constant; in fact, there are more body site and intersubjective variabilities than temporal changes within an individual.
During cleansing, bacteria are removed and washed off the surface of the SC but many remain, which is good—a healthy skin microbiome has a diverse ecology of bacteria. Generally, the microbiome of skin does not change with washing unless the cleanser causes changes to the skin barrier. In this case, if the cleanser damages the skin barrier and TEWL increases, conductance also increases and the SC pH increases; here, the environment of the microbiome has changed and hence, the microbiome is more likely to change.
Viruses: Repeated or exaggerate washing studies are often used to assess cleanser mildness; the skin barrier is monitored while undergoing repeated frequent washing. In the current age of COVID-19 precautions, the world is undergoing repeated handwashing but compared with more robust bacteria, viruses are susceptible to inactivation by surfactants.24
Unfortunately, common hand cleansers tend to be harsher (and typically cheaper) surfactant systems, more similar to adult shampoo surfactant systems. And, a hand cleanser with an aggressive surfactant system that damages the skin barrier could allow for the easier transport of viruses through the skin. Baby and facial cleansers tend to milder and less damaging to the skin barrier,25 and these milder cleansing formulas would be advantageous for frequent handwashing to limit the potential for compromising the skin barrier.
Cleansing: The ‘Bad’—Degrading the Barrier
Unfortunately, the same molecular structure of surfactants that enables cleansing can also cause problems for the skin barrier. Surfactants can readily incorporate into the skin lipids and disrupt the lipid order, thereby degrading the skin barrier4, 26 and washing its components away. Furthermore, these ingredients may remain in the skin after rinsing. A surfactant that has entered the SC can disrupt lipid order and increase permeability, from which users can experience a host of negative attributes from their cleansers. These include tightness, stinging, dryness, redness, irritation and further exacerbation of pre-existing conditions and sensitivities.
Surfactant disruption of the SC barrier can occur in healthy skin but this damage is exaggerated in compromised skin. The transport of surfactant into compromised skin is easier, and hence more surfactant can enter compromised skin and further degrade the native skin barrier.
To ensure cleansers will not negatively impact the barrier, a few modern tools can be used to investigate the SC lipid order. Vibrational spectroscopy is one;27 also, quartz crystal microbalance can directly measure water transport into and out of SC lipids;28 electron microscopy can image lipid order and spacing;29 and X-ray scattering can determine the spacing between order lipids.30
Formulating Cleansers for Compromised Skin
While a multitude of ingredient options is available to develop a suitable mild skin cleanser, it is important to note it is not simply about avoiding certain harsher surfactants. The solution properties of a surfactant system overall are directly related to how aggressive or mild a cleansing system is to skin; Figure 5 summarizes surfactant solution characteristics as well as how they can be probed.
Higher micelle surface charge,31 smaller micelles32 and higher surfactant monomer concentration are associated with more aggressive and more damaging surfactant systems. These physical properties also suggest less stable and more dynamic surfactant systems.
As micelles are made more stable, surfactant systems become more compatible with the skin and cause less damage to tissue and the SC barrier. There are a few strategies to improve micelle stability. The addition of hydrophobic material helps form larger and more stabilized micelles. Also, the addition of polymers with hydrophobic domains that can associate surfactants results in slower surfactant dynamics and creates milder cleansers.33, 34
Reducing the repulsive charge at the micelle surface also increases micelle stability and can be achieved by the inclusion of amphoteric surfactants.35 The addition of nonionic surfactants like PEG-80 sorbitan laurate32 also stabilizes the micelle surface.
In addition to the surfactant system, glycerin has been shown to reduce surfactant penetration into the SC.36 Hard water and water with high levels of divalent counterion, such as Ca2+ and Mg2+, has been associated with AD in a number of studies.37, 38 Chelators that bind divalent counterions could provide additional skin benefits by limiting surfactant residue left on the skin and also reducing divalent counterion adsorption into the SC.39
Preservatives also are important to avoid microbial contamination. Finally, other formulation considerations include pH and buffering, isotonicity and the overall avoidance of allergens and irritants. Taking these approaches, the formulator can mitigate or eliminate the different routes of surfactant-induced skin disruption. Figure 1 shows an example of cleanser formulation that provides the benefits of cleansing while supporting the natural function of the native skin barrier. Alternatively, lotion cleansers or high-water-content, low-surfactant-load cleansers are appropriate for compromised skin.
Most tests for cleanser mildness involve an exaggerated exposure, either in time or concentration, to the cleanser in order to create a sufficiently large signal or to change a skin property to be measured. Recently, with increasingly sensitive instrumentation, more subtle changes can be observed. In fact, after a two-minute wash, Perticaroli, et al., showed increased water uptake and a change in lipid lamellar structures with confocal Raman spectroscopy and small-angle X-ray scattering.40
As the skin is trying to adapt to every changing environment, problems can occur that compromise its barrier integrity. Cleansing is therefore an important contribution to help manage these adaptations.
For example, in winter, as the weather becomes colder and drier, the SC is struggling to enhance the barrier, so using a mild cleanser to avoid barrier disruption is important. On the other hand, in the spring, as the weather becomes warm and humid, and pollen is more prevalent, the removal and denaturation of allergens is important. For these reasons, some skin care brands are delivering personalized solutions to users. Examples include Atolla, MÜD, Prose, Prove, Skinsei (from Unilever) and Y’OUR.
The needs and problems of healthy skin, much less compromised skin, are dynamic and change over the course of the year. This suggests that treatment and cleansing should also change with the needs of the skin. Personalized solutions to match these needs in different and changing environments could be the way forward to lead to better skin health outcomes.
- Sanders, J. E., Goldstein, B. S., & Leotta, D. F. (1995). Skin response to mechanical stress: adaptation rather than breakdown-a review of the literature. J Rehabil Res Dev 32(3) 214-214.
- Del Rosso, J. D., Zeichner, J., Alexis, A., Cohen, D., and Berson, D. (2016). Understanding the Epidermal Barrier in Healthy and Compromised Skin: Clinically Relevant Information for the Dermatology Practitioner Proceedings of an Expert Panel Roundtable Meeting. J Clin Aesthet Dermatol 9(4 Suppl 1) S2-S8.
- Stamatas, G. N., Walters, R. M., and Martin, K. (2011). Formulating for the unique needs of baby skin. Personal Care 31-36.
- Saad, P., Flach, C. R., Walters, R. M., and Mendelsohn, R. (2012). Infrared spectroscopic studies of sodium dodecyl sulphate permeation and interaction with stratum corneum lipids in skin. Intr J Cosm Sci 34 36-43.
- Mack Correa, M.C., Mao, G., Saad, P., Flach, C.R., Mendelsohn, R. and Walters, R.M. (2014). Molecular interactions of plant oil components with stratum corneum lipids correlate with clinical measures of skin barrier function. Exp Dermatol 23(1) 39-44.
- Walters, R.M., Mao, G., Gunn, E. and Hornby, S. (2012). Cleansing formulations that respect skin barrier integrity. Derm Res Pract.
- Liang, Y., Chang, C. and Lu, Q. (2016). The genetics and epigenetics of atopic dermatitis—filaggrin and other polymorphisms. Clin Rev Allergy immunol 51(3) 315-328.
- Nikolovski, J., Stamatas, G. N., Kollias, N., and Wiegand, B. C. (2008). Barrier function and water-holding and transport properties of infant stratum corneum are different from adult and continue to develop through the first year of life. J Invest Dermatol 128(7) 1728-36.
- Walters, R. M., Khanna, P., Chu, M., and Mack, M C. (2016). Developmental Changes in Skin Barrier and Structure during the First 5 Years of Life. Skin Pharmacol Phys 29(3) 111-8.
- Davies, D. J., Heylings, J. R., McCarthy, T. J. and Correa, C. M. (2015). Development of an in vitro model for studying the penetration of chemicals through compromised skin. Toxicol In Vitro 29(1) 176-181.
- Tsai, J. C., Sheu, H. M., Hung, P. L., and Cheng, C. L. (2001). Effect of barrier disruption by acetone treatment on the permeability of compounds with various lipophilicities: implications for the permeability of compromised skin. J Pharm Sci 90(9) 1242-1254.
- Jakasa, I., Verberk, M. M., Bunge, A. L., Kruse, J., and Kezic, S. (2016). Increased permeability for polyethylene glycols through skin compromised by sodium lauryl sulfate, Exp Dermatol 15(10) 801-7.
- Cowdell, F. and Steventon, K. (2015). Skin cleansing practices for older people: a systematic review. Int J Older People Nurs 10(1) 3-13.
- Lund C. H., Osborne J. W., Kuller J., Lane A .T., Lott J. W., and Raines D. A. (2001). Neonatal skin care: clinical outcomes of the AWHONN/NANN evidence-based clinical practice guideline. Association of Women’s Health, Obstetric and Neonatal Nurses and the National Association of Neonatal Nurses. J Obstet Gynecol Neonatal Nurs 30(1) 41-51.
- Pogacar, S. M., Maver, U., Varda, M. and Miceti´c–Turk, D. Diagnosis (2018). Management of diaper dermatitis in infants with emphasis on skin microbiota in the diaper area. Int J Dermatol 57(3) 265-275.
- Farage M.A., Miller K.W., Berardesca E., Maibach H.I. (2015). Cutaneous effects and sensitive skin with incontinence in the aged. In: Farage M., Miller K., Maibach H., eds, Textbook of Aging Skin. Springer, Berlin, Heidelberg.
- Wu, Z., Liu, F. and Fan, W. (2015). Characteristics of PM10 and PM2.5 at Mount Wutai buddhism scenic spot, Shanxi, China. Atmosphere 6(8) 1195-1210.
- Rinnerthaler, M., Bischof, J., Streubel, M. K., Trost, A. and Richter, K. (2015). Oxidative stress in aging human skin. Biomolecules 5(2) 545-589.
- Guo, Q., Xiong, X., Liang, F., Tian, L., Liu, W., Wang, Z. and Pan, X. (2019). The interactive effects between air pollution and meteorological factors on the hospital outpatient visits for atopic dermatitis in Beijing, China: a time-series analysis. J Eur Acad Dermatol Venereol 33 2362-2370.
- Kabashima, K., Otsuka, A. and Nomura, T. (2017). Linking air pollution to atopic dermatitis. Nat Immunol 18 5–6.
- Gallagher, M. B., Wysocki, C. J., Leyden, J. J., Spielman, A. I., Sun, X-K. and Preti. G. (2008). Analyses of volatile organic compounds from human skin. British J Derm 159(4) 780-91.
- Mitro S., Gordon A. R., Olsson M. J. and Lundström J. N. (2012). The Smell of age: Perception and discrimination of body odors of different ages. PLoS ONE 7(5).
- Oh, J., Byrd, A. L., Park, M., Kong, H. H., Segre, J. A. and NISC Comparative Sequencing Program. (2016). Temporal stability of the human skin microbiome. Cell 165(4) 854-866.
- Kawahara, T., Akiba, I., Sakou, M., Sakaguchi, T. and Taniguchi, H. (2018). Inactivation of human and avian influenza viruses by potassium oleate of natural soap component through exothermic interaction. PloS ONE 13(9).
- Walters, R. M., Gandolfi, L., Mack, M. C., Fevola, M., Martin, K., Hamilton, M. T., ... & Raabe, H. A. (2016). In vitro assessment of skin irritation potential of surfactant-based formulations by using a 3-D skin reconstructed tissue model and cytokine response. Alternatives to Laboratory Animals 44(6) 523-532.
- Mao, G., Flach, C. R., Mendelsohn, R. and Walters, R. M. (2012). Imaging the distribution of sodium dodecyl sulfate in skin by confocal raman and infrared microspectroscopy. Pharma Res 29(8) 2189-2201.
- Boncheva, M., Damien, F., and Normand, V. (2008). Molecular organization of the lipid matrix in intact Stratum corneum using ATR-FTIR spectroscopy. Biochim Biophys Acta 1778(5) 1344-55.
- Lee, D., Ashcraft, J. N., Verploegen, E., Pashkovski, E, and Weitz, D. A. (2009). Permeability of model stratum corneum lipid membrane measured using quartz crystal microbalance. Langmuir 25(10) 5762.
- Iwai I., Han H., den Hollander L., Svensson S., Ofverstedt L. G., Anwar J., Brewer J., Bloksgaard M., Laloeuf A., Nosek D., Masich S., Bagatolli L. A., Skoglund U. and Norlén L. (2012). The human skin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. J Invest Dermatol 132(9) 2215-25
- Bouwstra J.A., Gooris G.S., Dubbelaar, F.E. and Ponec, M. (2001). Phase behavior of lipid mixtures based on human ceramides: coexistence of crystalline and liquid phases. J Lipid Res 42(11) 1759-70.
- Lips, A., Ananthapadmanabhan, K.P., Vethamuthu, M., Hua, X. Y., Yang, L., Vincent, C., Deo, N. and Somasundaran, P. (2006). Role of surfactant charge in protein denaturation and surfactant-induced skin irritation, in Rhein, L. D., Schlossman, M., O’Lenick, A., and Somasundaran, P. eds, Surfactants in Personal Care Products and Decorative Cosmetics. Boca Raton, FL USA: CRC Press 177-187.
- Walters, R. M., Fevola, M., LiBrizzi, J. J. and Martin, K. (2008). Designing cleansers for the unique needs of baby skin. Cosmet & Toilet 123(12) 53.
- Draelos, Z., Hornby, S., Walters, R.M. and Appa, Y. (2013). Hydrophobically-modified polymers can minimize skin irritation potential caused by surfactant-based cleansers. J Cos Derm 12(4) 314-321.
- Hornby, S., Walters, R. M., Tierney, N., Appa, Y., Dorfman, G. and Kamath, Y. (2015). Effect of commercial cleansers on skin barrier permeability. Skin Res & Tech 22(2) 196-202.
- Ananthapadmanabhan, K.P., Moore, D.J., Subramanyan, K., Misra, M. and Meyer, F. (2004). Cleansing without compromise: the impact of cleansers on the skin barrier and the technology of mild cleansing. Dermatol Ther 17(1) 16-25.
- Ghosh, S., Kim, D., So, P. and Blankschtein, D. (2008). Visualization and quantification of skin barrier perturbation induced by surfactant-humectant systems using two-photon fluorescence microscopy. J Cosmet Sci 59(4) 263-289.
- Engebretsen, K. A., Bager, P., Wohlfahrt, J., Skov, L., Zachariae, C., Andersen, A. M. N., ... and Thyssen, J. P. (2017). Prevalence of atopic dermatitis in infants by domestic water hardness and season of birth: cohort study. J Allergy and Clin Immunol 139(5) 1568-1574.
- Danby, S. G., Brown, K., Wigley, A. M., Chittock, J., Pyae, P. K., Flohr, C. and Cork, M. J. (2018). The effect of water hardness on surfactant deposition after washing and subsequent skin irritation in atopic dermatitis patients and healthy control subjects. J Invest Derma 138(1) 68-77.
- Walters, R. M., Anim-Danso, E., Amato, S. M., Capone, K. A., Mack, M. C., Telofski, L. S. and Mays, D. A. (2016). Hard water softening effect of a baby cleanser. Clinical, Cosmetic and Investigational Dermatology 9 339.
- Perticaroli, S, Meyers, JL, Wireko, FC, et al. (2020). Cleansers’ mildness: Stratum corneum lipid organization and water uptake after a single wash. J Raman Spectrosc 1–12.