A Review of Anti-irritants, Part II: Moisturizer, Anti-irritant Efficacy and Overall Interpretation

Apr 1, 2011 | Contact Author | By: Howard I. Maibach, MD, and Hongbo Zhai, MD, University of California School of Medicine
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Title: A Review of Anti-irritants, Part II: Moisturizer, Anti-irritant Efficacy and Overall Interpretation
anti-irritantsx moisturizer efficacyx TEWLx ureax lipidsx skin carex atopic akinx barrier functionx natural anti-irritantsx
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Keywords: anti-irritants | moisturizer efficacy | TEWL | urea | lipids | skin care | atopic akin | barrier function | natural anti-irritants

Abstract: his column is the second of a two-part series about anti-irritants. Part I appeared in the March 2011 issue and covered anti-irritants, irritant reaction and barrier cream efficacy. The present column summarizes the efficacy of moisturizers and anti-irritant substances and provides an overall interpretation.

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HI Maibach H Zhai, A Review of Anti-irritants, Part II: Moisturizer, Anti-irritant Efficacy and Overall Interpretation, Cosm & Toil 126(4) 264 (2011)

Evaluating Moisturizers

Wash test method: Hannuksela and Kinnunen1 developed a wash test method to determine the effect of moisturizers in preventing irritant contact dermatitis (ICD). Twelve healthy female students washed the outer aspects of their upper arms with a liquid dishwashing detergent for one minute twice daily for one week. Eight commercial moisturizers were applied to the left upper arm just after each washing while the other arm was left untreated. During the second week, the left upper arm only was treated with the moisturizers twice daily.

Transepidermal water loss (TEWL) was found to increase during the washing period by 13 g/m2/hr in the untreated arm, while the increase in the treated areas was only 3 g/m2/hr. Further, visible dermatitis appeared on the untreated arm while the treated areas remained objectively and subjectively free from symptoms and signs. Blood flow also increased significantly in the washed, untreated arm, but did not change in the arm treated with moisturizers.

During the second week, the dermatitis on the washed, untreated arm disappeared and the laser Doppler values normalized. The TEWL values also decreased to near normal. The mean decrease was more pronounced when moisturizers with a high fat content were used but due to inter-individual variations, the differences between the results for the eight moisturizers were not statistically significant. Comparing the effects of a moisturizer to no treatment after the one-week wash out period revealed that the use of moisturizers enhanced the healing process significantly.

Cross-over design: Halkier-Sørensen and Thestrup-Pedersen2 utilized a cross-over design to evaluate the efficacy of a moisturizera used by 111 cleaners and kitchen assistants during their everyday work. The population was divided into two groups—56 workers who used the test moisturizer only on their hands for the first two weeks and no emollient during the subsequent two weeks, and 55 workers using the same protocol but in reverse; i.e. no test moisturizer for the first two weeks and the same moisturizer as the first group during the subsequent two weeks. The moisturizer was found to prevent the development of skin dryness, as indicated by electrical capacitance (epidermal hydration), which decreased significantly when the subjects were not using the moisturizer.

Newborn skin: Lane and Drost3 examined the effect of a water-in-oil emollient moisturizer in comparison with its blank control on 34 premature newborns. Seventeen of the neonates were treated twice daily with a test moisturizer for up to 16 days, and the other 17 served as a control. Results were statistically significant and showed less dermatitis on the hands (days 2–11), feet (days 2–16), and abdomens (days 7–11) of newborns on the sites treated with moisturizer.

Urea effects on TEWL and irritation: Loden4 showed that repeated applications of urea-containing moisturizers influenced both TEWL and apparent susceptibility of subjects to SLS-induced irritation. Three applications of 5% urea increased TEWL, whereas treatments with 10% urea for 10 and 20 days decreased TEWL. Based on this study, the researchers concluded it is possible that a greater amount of urea alters the binding capacities of the SC, retarding SLS penetration.

Topical lipids: Loden and Andersson5 observed the effect of topically applied lipids on surfactant-irritated skin in 21 healthy subjects and showed that canola oil and its sterol-enriched fraction reduced the degree of SLS-induced irritation. Neither fish oil, rich in eicosapentaenoic acid, nor borage oil, rich in GLA and linoleic acid, influenced inflammation caused by SLS.

Soap-induced xerosis model: El Gammal et al.6 assessed the efficacy of moisturizers by a soap-induced xerosis human model. The lower legs of 22 women were washed daily for 10 days with soap to induce the xerosis. After washing, one side received a moisturizer, the other served as an untreated control. The values of clinical scaling, electrical conductance, and skin desquamationb were compared on each evaluation day. On the moisturizer-treated legs, a significant decrease in dryness grades and scaling indicates was observed at all time points. Conductance was significantly increased on days 8 and 11.

Cream and barrier recovery, skin susceptibility: In a single-blind study,7 Lodén investigated a moisturizing cream for its influence on both barrier recovery in surfactant-damaged skin and on the susceptibility of normal skin to exposure to the irritant SLS on 13 healthy individuals. Skin irritation was induced by a 14% SLS solution, then the test cream was applied onto the SLS-damaged sites for 14 days. Results indicated that the moisturizing cream decreased TEWL and normalized skin corneometer values more rapidly during the treatment. In normal skin, use of the test cream significantly reduced TEWL after 14 days of treatment as well as irritant reactions to SLS.

Prevention and therapeutic studies on irritated skin: Ramsing and Agner8 tested the effects of a moisturizer on experimentally irritated human skin in two studies. In a prevention study, both hands of 12 volunteers were immersed in a 0.375% SLS solution for 10 min, twice daily for two days. Before each immersion, one hand was treated with a test moisturizer and the other served as control. In a therapeutic study, the same immersion procedure was used and after the last immersion, one hand was treated with the moisturizer for five days while the other hand served as control. A significant preventive effect was obtained on the treated hand while TEWL and blood flow significantly increased and electrical capacitance significantly decreased on the control hand. A significant therapeutic effect was also observed on the treated hand while TEWL increased and electrical capacitance decreased on the control hand on day eight.

Long-term moisturizer use: Held et al.9 sought to determine whether long-term daily use of a moisturizer on normal skin would affect skin barrier function, hydration state or susceptibility to SLS. Healthy volunteers used a moisturizer on one forearm three times daily for four weeks. The other forearm served as a control. At the end of the treatment time, both forearms were challenged with an SLS patch test. Electrical capacitance was found to significantly increase on the treated arm during the treatment period and after the SLS challenge, TEWL was significantly higher on the arm treated with moisturizer than on the control arm. This suggested that long-term treatment with moisturizers on normal skin may increase skin susceptibility to irritants.

Moisturizers on atopic skin: Lodén et al.10 measured the efficacy of a moisturizer on patients afflicted with atopic skin. One forearm was treated with a moisturizing cream twice daily for 20 days. On day 21, the skin was exposed to SLS and on day 22, the irritant reaction was measured noninvasively. Skin capacitance was significantly increased by the treatment, indicating an increase in skin hydration. In addition, as reflected by TEWL and superficial skin blood flow values, the skin susceptibility to SLS was significantly reduced. The researchers concluded that certain moisturizers could improve skin barrier function in atopic patients and reduce skin susceptibility to irritants.

Moisturizers on compromised skin: Held and Jorgensen11 investigated whether applying a moisturizer to compromised skin before wearing an occlusive glove could reduce skin irritation. The hands of 12 healthy volunteers were immersed in an SLS solution twice daily for two days. After each immersion, a moisturizer was applied to one hand and both hands were placed in occlusive gloves for two hours. The researchers found that the moisturizer exhibited a statistically significant positive effect on both the barrier function and hydration level of the skin. Although not statistically significant, less inflammation also was observed on the moisturizer-treated hand. Results suggested that use of a moisturizer under an occlusive glove may diminish irritation from exposure to a detergent followed by glove-wearing.

Moisturizer on skin recovery: Held and Agner12 compared two experimental moisturizer efficacy models to assess the recovery of irritated skin on the hands and volar forearms. The hands of 12 healthy volunteers were immersed in SLS for 10 min, twice daily for two days. At the same time, patch tests with SLS (0.125%, 0.25% and 0.5%) were applied to the forearms of volunteers for 24 hr. After the skin was irritated, moisturizer was applied on one arm/hand of the volunteers three times daily for the following nine days. The other arm/hand served as an untreated control. Both models were found useful, and the moisturizer was found to accelerate regeneration of the skin barrier function in both the hands (day 8) and volar forearms (0.5% SLS, days 5 and 8).

Short-term moisturizer use: Held and Agner13 evaluated the short-term use of two different moisturizers on normal skin: cream A, with a high lipid content, and cream B, with a moderate to low lipid content. Nineteen healthy volunteers applied the moisturizers on their upper arms/forearms three times daily for five days, while the other upper arms/forearms served as symmetrical control. The day after the moisturizer treatment ceased, the skin was challenged with an SLS patch test. Skin reactions were evaluated by bioengineering measuring methods and clinical scoring. Skin’s response to SLS was increased on the cream A-treated arms, compared with the control, while the response was not statistically significant with cream B. These results confirmed previous indications that some moisturizers, when used on normal skin, may increase skin susceptibility to irritants.

Commercial moisturizers and skin recovery: Held et al.14 assessed the effect of six commercial moisturizers on the recovery of irritated human skin. Thirty-six healthy volunteers had 0.5% SLS patch tests applied to their forearms/upper arms for 24 hr. After irritation of the skin, moisturizer was applied to all volunteers on one forearm/upper arm, respectively, three times daily for the following five days. The other forearm/upper arm served as an untreated control. Each moisturizer was tested on 12 volunteers and each volunteer tested two moisturizers at the same time. All six moisturizers accelerated regeneration of the skin barrier function, compared with the irritated, non-treated skin. The most lipid-rich moisturizers improved barrier restoration more rapidly than the less lipid-rich moisturizers.

Long-term moisturizer use and barrier function: Buraczewska et al.15 investigated the impact of long-term treatments with moisturizers on the barrier function of normal skin, as measured by TEWL and susceptibility to an irritant, to relate the observed effects to the compositions of the experimental moisturizers. Seventy-eight volunteers were randomized into five groups. Each group treated one volar forearm for seven weeks with one of the following preparations: a) one of three simplified creams containing only a few ingredients in order to minimize the complexity of the system; b) a lipid-free gel; and c) one ordinary cream containing 5% urea. The lipids in the simplified creams were either hydrocarbons or vegetable triglyceride oil; one also contained 5% urea.

After seven weeks, the forearms were exposed for 24 hr to SLS using a patch test. TEWL, blood flow and skin capacitance of both SLS-exposed and undamaged skin were evaluated 24 hr after the removal of patches. Results showed the simplified creams and lipid-free gel increased TEWL and skin response to SLS while the ordinary cream had the opposite effect.

Efficacy of Anti-Irritant Substances

Natural anti-irritant ingredients: Alirezai et al.16 tested the effects of a low-salt mineral water on acne-affected, retinoid treated areas in a controlled, open-labeled and randomized study. Patients with moderate to severe acne were given either a retinoid treatment alone (n = 34) or retinoic acid and mineral water (n = 35) to spray ad libitum at least four times daily. After 28 days, patients treated with retinoic acid and mineral water showed reduced scaling—only 46% of patients treated with retinoic acid and mineral water complained of scaling, whereas 79% of patients treated with retinoic acid alone complained of scaling. The overall tolerance of retinoic acid treatment improved with mineral water. Results suggested that mineral water did not alter the therapeutic action of retinoic acid. Rather, those patients treated with both retinoic acid and mineral water showed a slight reduction in overall acne; whether this was due to the combined therapy or increased compliance secondary to decreased unpleasant side effects was not elucidated.

In a separate study, Wilson and Steck17 tested the action of 1% hydro-cortisone, 0.2% plant extract (FPI-1115), formulation base control, and water (blank control) on six fair-skinned subjects. Skin erythema was induced by 15% lactic acid, then the test treatments were applied and skin redness was measured at 0.5, 1.0 and 24 hr using a colorimeterc. The plant extract showed the greatest reduction of redness post-application at each measured time point.

Similar to the plant extract, Schliemann-Willers et al.18 studied the effects of natural fats against SLS-induced irritation in a randomized study of 20 healthy volunteers tested with repeat insult testing (RIT). Rapeseed and palm fats showed a significant beneficial effect against SLS-induced irritation; rapeseed decreased erythema by a visual score of 2.7 (visual score), and palm fats decreased erythema by a visual score of 2.5 and TEWL by 25.1% compared with the control.

In addition, Han et al.19 investigated the anti-irritant capacity of aloe vera gel by combining it with varying strengths of SLS on 15 volunteers. SLS was dissolved in distilled water to a 1% concentration. Aloe vera gel was also diluted in water to 10%, 20%, 50% and 100%, then the SLS solution was mixed with each of the aloe solutions in a 1:1 ratio. This mixture was applied in a randomized manner to the subjects’ volar forearms for 24 hr. Both the TEWL and erythema index decreased significantly with the 100% aloe vera gel and SLS mixture. The researchers concluded that aloe vera had a positive effect on both the recovery of the skin barrier and erythema induced by irritants such as SLS. They further noted that it is only effective with high concentrations of aloe vera.

Glycolic acid: Perricone and DiNardo20 tested the anti-inflammatory and photoprotective effects of topical glycolic acid by exposure of short-wave ultraviolet light (UVB). Skin treated with glycolic acid daily for seven days and untreated skin each were exposed to UVB and their reactions compared. A 16% reduction in irritation was observed when had been pre-treated with glycolic acid. The researchers concluded that topical glycolic acid applied to skin before UV exposure imparts a photoprotective effect. In addition, when glycolic acid was applied to irradiated skin, it accelerated the resolution of erythema.

Strontium salts: Sensory irritation, i.e., sting, burn, and/or itch, are the subjective signs and symptoms of ICD, and while it is relevant to clinical problems, it is especially important as a major patient concern. Hahn21 defined that topical application of strontium salts to intact skin produced potent suppression of sting, burn and itch caused by many irritant chemicals. In multiple ways—i.e., double-blind, vehicle-controlled and random-treatment assignment trials—a chemically and biologically unrelated irritant was applied with or without strontium salts to the skin of healthy female subjects having self-reported sensitive skin, then sensory irritation was assessed. As a pre-treatment or when mixed with the irritant, strontium application substantially suppressed the sensory irritation without local anesthetic side-effects.

Similarly, Zhai et al.22 evaluated the efficacy of strontium nitrate in reducing chemically induced skin sensory irritation in eight subjects. In a double-blind and random manner, 20% strontium nitrate in 70% glycolic acid was applied to the volar aspect of the forearm as well as a 70% glycolic acid positive control to the contralateral forearm. The irritation sensation was evaluated on a scale from 0–4 for each minute for the first 20 min after topical application. The duration of the irritation sensation in minutes was also recorded. Strontium nitrate mixed with glycolic acid, in comparison with glycolic acid alone, was found to markedly shorten the duration of the irritation sensation, from 24.4 min to 8.9 min, and significantly reduced the mean magnitude of the irritation sensation at all time points (overall). The researchers concluded that strontium nitrate potently suppresses the sensation of chemically induced irritation.

Phosphodiesterase inhibitors: Kucharekova et al.23 compared the effects of cipamfylline, a phosphodiesterase 4 inhibitor, with a mild strength corticosteroid, betamethasone-17-valerate, in an ointment and with a placebo ointment in a blind, randomized pilot study using single and repeated exposures to an irritant. Volunteers were patch-tested with 0.2% sodium dodecyl sulphate (SDS) for 4 hr daily for four consecutive days. The sites were treated once daily with these ingredients and one site was left untreated. The erythema scoring, TEWL and several immunohistochemical markers for epidermal proliferation and differentiation were measured. Betamethasone-17-valerate was found to significantly reduce erythema and TEWL, compared with cipamfylline and the placebo, which did not in this human model of ICD.

Corticosteroids: van der Valk and Maibach24 assessed the efficacy of a corticoid formulation and vehicle on chronic ICD in human beings. The ICD was produced by repeated applications of an SLS solution to the forearm. Subsequently, these sites were treated repeatedly with a corticoid formulation or vehicle. Neither corticoid nor vehicle was found to inhibit the visible response to the irritant. Barrier function, as measured by TEWL, also was impaired. Further, the corticoid formulations and vehicles did not significantly influence barrier function.

In relation, Ramsing and Agner25 evaluated the effect of potent topical corticosteroids on experimentally induced ICD in a double-blind, vehicle-controlled study. On 16 healthy volunteers, SLS patch tests were symmetrically applied to the upper arms. After removal of patch tests, a potent topical corticosteroid, betamethasone-17-valerate, was applied to the irritant skin reaction on one arm, while the corresponding vehicle was applied to the irritant skin reaction on the opposite arm twice daily for 7 days. Reactions were evaluated by measurement of TEWL and erythema. After 7 days, statistically significant lower values of TEWL and erythema were found in the corticosteroid-treated skin reactions, compared with the vehicle-treated skin reactions. The results indicated the topical corticosteroids improved ICD healing.

Levin et al.26 also assessed the efficacy of low- and medium-potency corticosteroids on ICD. The dorsal side of subjects’ hands were irritated with 10% SLS five times in one day. Then, once on day 1 and twice daily on days 2–5, 1% hydrocortisone, 0.1% betamethasone-17-valerate and a vehicle cream (petrolatum) were applied. Visual grading, bioengineering techniques and squamometry were used to quantify skin response. Corticosteroids were found to be ineffective in treating the surfactant-induced ICD, compared with the vehicle and with the untreated control.

Nonsteroidal anti-Inflammatory agents: Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications that impart pain-relieving (analgesic) as well as inflammatory-reducing effects. Topical NSAIDs such as diclofenac and naproxen sodium are widely used in Europe and Asia as topical anti-inflammatory agents, and their efficacy has been well-established for musculoskeletal symptoms. However, their value as anti-irritants for skin requires further investigation, and few evidence-based conclusions exist regarding their dermatologic use. The major exception consists of a body of experiments documenting that NSAIDs inhibit UVB erythema when used prophylactically.27

Miscellaneous: Andersen et al.28 studied the dose-related effects of four alleged anti-irritants—i.e., nifedipine, (-)-alpha-bisabolol, canola oil and glycerol—on experimentally induced acute irritation in healthy volunteers. Each anti-irritant was used in three concentrations. Acute irritation was induced by occlusive tests with 1% SLS and 20% nonanoic acid in N-propanol. The irritant reactions were then treated twice daily with anti-irritant-containing formulations from the time of removal of the patches. Evaluation of skin irritation and efficacy of treatments was performed daily for four days using clinical scoring, TEWL, hydration measurement and colorimetry. Only glycerol showed dose-response and effects potentially better than no treatment.

Further, the authors29 studied the effects of the anti-irritants in a cumulative irritation model by inducing ICD with 10-min daily exposures for five and four days (no irritation on the weekend) using 1% SLS on the right and 20% NA on the left volar forearm. Anti-irritant ointments were applied twice daily. Clinical scoring was performed daily; TEWL, hydration and colorimetry were measured at baseline (D0), in the middle, and at the end of treatment. The glycerol ointment was the only treatment statistically better than both no treatment and the vehicle.


The term anti-irritant described by Goldemberg30 refers to a diverse group of topical product ingredients that are able to reduce the irritation potential of other, more irritating ingredients in the same product. They typically are added to cosmetic formulations to allegedly benefit the tolerability of the products and allow claims such as soothing and healing ingredients. However, limited documentation exists in favor of the efficacy of anti-irritants.

Considering both parts of this extensive review, the authors conclude that the use of skin-protection products such as barrier creams (BCs) and moisturizers may help to avoid or reduce the intensity of skin irritations caused by irritants at home and in the workplace. The industry should educate that BCs should not be used as the primary protection against high-risk substances or corrosive agents, but instead to provide protection against low-grade irritants. However, wet workers utilizing water, soaps and detergents daily may benefit by applying BCs frequently. Furthermore, BCs may also shield skin from chemicals, oils and other substances and make them easier to wash off at the end of the work day.31 To achieve optimal protective effects, BCs should be used with careful consideration of the types of substances they are designed to protect against based on a specific exposure conditions; also, the proper education for their use is essential.32, 33 Inappropriate BC application may exacerbate irritation34–38 and using BCs on diseased skin may lead to increased irritation.37, 39

The efficacy of moisturizers in the prevention of ICD has been documented.40, 41 Application of appropriate moisturizers may also accelerate the rate of healing on damaged skin.1–8, 12 Use of a moisturizer under an occlusive glove may diminish irritation from exposure to a detergent22 and it also minimizes glove-induced ICD and decreases skin dryness.42 Individuals regularly exposed to irritants should be encouraged to apply moisturizers frequently to reduce such dermatitis. However, controversial results have indicated that daily use moisturizers on normal skin might increase skin susceptibility to irritants even for five consecutive days of application.13–15

Optimal BC and moisturizer use not only prevents, but also treats, mild ICD. Mixtures of water-binding ingredients in the formulations may also provide a beneficial synergy.43 Furthermore, cosmetically functional BCs or moisturizers, in particular containing cosmetic active components, are more acceptable to the public.44, 45 The optimum time to dose moisturizers remains to be determined. In industries and individuals at low risk, dosing will likely begin after dermatitis development; conversely, in some industries and individuals at high risk, prophylaxis such as BCs may be applied prior to work.

The data on anti-irritants presented here provides certain evidence that anti-irritant ingredients may be beneficial in reducing ICD,17–23, 25, 28, 29 though some studies indicated no effect.16, 24, 26 The mechanism of action of different anti-irritants is inherently useful information in terms of refining future technologies. Some mechanisms are readily understood; for example, barriers that minimize penetration. Others are not readily comprehended in spite of decades of study. There appear to be at least two potential mechanisms to inhibiting irritation: 1) inhibition of percutaneous penetration into the epidermis and dermis; and 2) alteration of the biochemistry and metabolism of the irritant compound as it is applied to the skin. Still, the best investigation of anti-irritant compounds should be a well-controlled randomized and double-blinded study that has sufficient power, an adequate number of controls, and sufficiently tests both sensitivity and specificity of the anti-irritant to the irritant substance.

It is suggested that the ideal skin protection formulations including BC, moisturizers and anti-irritants should be non-toxic, non-comedogenic, non-irritating, non-greasy foam and colorless. They should maintain high efficacy but not interfere with the user’s manual dexterity or sensitivity. They should also be easy to apply and remove, cosmetically acceptable and economical.

Natural ingredients could be the right direction for the next generation of alternative medications,46 and plant extracts are possible sources due to their biologically active compounds in medicine. The advantages of natural products include their high structural diversity and variety of biological activity, yet the often chemically complex structures can be obtained through simple extractions; they may also be isolated in high quantities at low costs. The authors believe that optimal multiple-function skin-protection products could be developed with modern technology.

Taken together, utilizing highly controlled experiment trials provides for speed and efficacy; but as the conflicting observations summarized here suggest, well-controlled but often arduous field studies are required for confirmation. Reproduction of the article without expressed consent is strictly prohibited.

Send e-mail to hongbozhai@hotmail.com.
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44. R Kobayashi, M Takisada, T Suzuki, K Kirimura, and S Usami, Neoagarobiose as a novel moisturizer with whitening effect, Biosci Biotechnol Biochem 61 162–163 (1997)
45. GB Jemec and HC Wulf, Correlation between the greasiness and the plasticizing effect of moisturizers, Acta Derm Venereol 79 115–117 (1999)
46. C Levin and HI Maibach, Exploration of “alternative” and “natural” drugs in dermatology, Arch Dermatol 138 207–211 (2002)

*Adapted from H Maibach, Anti-Irritant Agents, in Chemistry and Manufacture of Cosmetics: Cosmetic Specialties and Ingredients, 2nd edn, ch 1, ML Schlossman, ed, Allured Business Media, Carol Stream IL USA (2010) pp 1–39



Footnotes (CT1104 Maibach)

a Locobase Repair Cream is manufactured by Astella Pharma BV.
b D-Squame discs are manufactured by Cuderm.
c The Minolta Chroma Meter CR-300 is manufactured by Konica Minolta.

Biography: Howard I. Maibach, MD, University of California, San Francisco

Howard I. Maibach, MD, is a professor of derma­tology at the University of California School of Medicine, San Francisco. His labor­atory has been interested in and has published exten­sively on derm­ato­pharma­cology and dermatotoxicology.

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