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Udgivelsesdato: 2006-Sep So-called anti-irritants (AI) are widely used in cosmetic formulations, with the aim of reducing irritation from substances in the formulation. It may also be claimed that they are 'soothing' and 'healing' ingredients. However, the proof for these claims is circumstantial. The dose-response effect of 4 alleged AI (nifedipine, (-)-alpha-bisabolol, canola oil and glycerol) was studied on experimentally induced acute irritation in healthy volunteers, and only glycerol showed dose-related response and effects potentially better than no treatment. The acute irritation model only allowed a small window of opportunity in which to demonstrate efficacy. Therefore, the effect of AI was studied in a cumulative irritation model by inducing irritant dermatitis with 10 min daily exposures for 5+4 days (no irritation on weekend) to 1% sodium lauryl sulfate on the right and 20% nonanoic acid on the left volar forearm. AI ointments were applied twice daily. Clinical scoring was performed daily, evaporimetry (Trans Epidermal Water Loss), hydration and colourimetry 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 vehicle.

Udgivelsesdato: 2006-Sep The term 'anti-irritant' (AI) was coined in 1965 by Goldemberg to describe a diverse group of topical product ingredients, which were able to reduce the irritation potential of other more irritating ingredients in the same product. 'AIs' are being added to cosmetic formulations in order, allegedly, to benefit tolerability of the products and allow claims such as 'soothing' and 'healing' ingredients. Limited documentation in favour of the efficacy of AIs is published. We studied the dose-related effect of 4 alleged AIs (nifedipine, (-)-alpha-bisabolol, canola oil and glycerol) on experimentally induced acute irritation in healthy volunteers. Each AI was used in 3 concentrations. Acute irritation was induced by occlusive tests with 1% sodium lauryl sulfate and 20% nonanoic acid in N-propanol. The irritant reactions were treated twice daily with AI-containing formulations from the time of removal of the patches. Evaluation of skin irritation and efficacy of treatments were performed daily for 4 days using clinical scoring, evaporimetry (transepidermal water loss), hydration measurement and colourimetry. Only glycerol showed dose-response and effects potentially better than no treatment. There was no significant effect and no difference between the three other AIs.

In this study of 152 women, comparison of patch test responses between 2 irritants over 96 h at 2 symmetrical anatomical sites is studied. 2 irritants, each at 4 different concentrations (nonanoic acid (NAA) 80%, 40%, 20%, 10%; sodium lauryl sulfate (SLS) 3%, 2%, 1% and 0.5%) and using propan-1ol and 'water for injection' as the respective controls, were placed as 15 microl aliquots, soaked onto filter paper discs in Finn Chambers, on the volunteer's left and right lower back. The patches were removed at 47, and read at 48 and 96 h. Irritant reactions were evaluated for erythema and surface changes by degree and area affected. Statistical analysis of the results showed that erythema decreased with time for all concentrations of NAA, and at higher concentrations for SLS. Surface changes increased with time for SLS and at higher concentrations of NAA. There was no statistically significant difference comparing left and right sides. Traditionally in patch testing, reactions which fade after 48 h have been regarded as irritant rather than allergic. This study refutes that assumption. Data from our left to right comparisons, made in the same individuals at the same time, show that irritant reactions may be more reproducible than previously appreciated.

The epidermal response to 2 different irritants, nonanoic acid (NAA) and sodium lauryl sulfate (SLS), was investigated with 2 different methods. NAA 80% and SLS 4% were applied under occlusion for up to 24 h. Elemental changes were determined in cryosections by x-ray microanalysis. Compared to unexposed skin a significantly higher sodium/potassium ratio was found after 6 h in NAA-exposed skin and a lower ratio in SLS-exposed. At 24 h both substances had induced similar changes, compatible with a cell injury. The findings demonstrate a time-dependent NAA and SLS response. With reverse transcription polymerase chain reaction, the mRNA expression of interleukin-1 alpha (IL-1 alpha), -1 beta (IL-1 beta), -6 (IL-6), and -8 (IL-8), tumor necrosis factor alpha (TNF alpha) and granulocyte macrophage colony stimulating factor (GM-CSF) in shave biopsies from irritated and unexposed skin was studied at 0. 4. 8 and 24 h. NAA, but not SLS, induced an increase in mRNA expression for IL-6 mRNA-expression for GM-CSF was increased after SLS exposure, but not after NAA. These findings indicate a time and substance dependent difference in the up-regulation of mRNA for different cytokines in epidermis during the first 24 h of the irritant reaction. This might be the effect of differences in the irritants action on the cell membranes, which is also reflected by the differences found in the elemental content at 6 h.

Skin reactions to 40% nonanoic acid in propanol (NON) and to 4% hydrochloric acid were evaluated by image analysis of 20 MHz B scan recordings (Dermascan C, Cortex Technology). 18 women, aged 18 to 45, were patch tested with 24-h application time, and clinical and instrumental evaluations were performed at the beginning of the experiment, and 24 and 48 h after patch testing. To check possible regional variations in reactivity to NON and HCl, both substances were applied 2 x on the same forearm. As control tests, saline solution, propanol and sodium lauryl sulfate (SLS) 3% were applied. Echographic images were processed by a program enabling numerical representation of picture data, based on attribution of fictional values to the echoes' amplitudes, selection of amplitude bands of interest, binary transformation of the image, and calculation of the extension of areas reflecting within the same amplitude range. Sonographic recordings were evaluated by an amplitude interval marking hyporeflecting parts of the dermis (corresponding to edema and inflammatory infiltration), and by a band highlighting the entrance echo (epidermis). Our evaluations showed that extension of the hypoechogenic area of the dermis increases according to intensity of inflammatory reaction for all irritant substances. A clear decrease in reflectivity of the epidermis echo at 24 h was visible at SLS patch test test sites, whereas at patch test sites performed with NON and HCl, there was a trend towards an increase in values of hyperreflecting pixels. No significant variations between data recorded at proximal compared to distal skin sites were observed for NON and HCl. In conclusion, the echographic technique provides a method for quantification of the dermal inflammatory reaction, and also for description of skin reactions induced by irritant substances, according to their specific epidermal effects.

The rabbit has been used for decades for predictive testing of skin irritancy, but in recent years, the guinea pig has been suggested as an alternative, especially for assessment of one of the components of the irritant reaction: edema (fluid accumulation). A method based on skin-fold measurements with Harpenden calipers has been developed and modified. In previous papers, experience with sodium lauryl sulphate, nonanoic acid and industrial solvents was reported. The present results concern the use of cutting fluids, buffered and unbuffered acid and alkaline solutions, formalin and dimethyl sulfoxide. This inexpensive and comparatively unsophisticated method afforded clear dose-response relationships and good discriminating power. The only exception was the acid and alkaline solutions, where no changes in skin-fold thickness were observed despite their documented irritant potential. The appearance of erythema (visual scoring) and the increase in skin-fold thickness, and their relationship, are discussed with some illustrative examples. The method described is now well standardized and is suited for predictive testing of the edema-inducing capacity of chemicals and products.

Patch testing and safety evaluation processes to assess the allergic or irritant potential of substances are usually performed on normal skin. However, the reactivity of compromised skin may be different. Consequently, it is important to have a test procedure which acts as a model for compromised skin and which reproduces on the target sites the cumulative insult which results from repeated exposure, working temperatures, hydration and the action of surfactants. The procedure described uses regular immersion of forearm skin in an aqueous solution of sodium dodecyl sulphate until an identifiable alteration of skin condition is produced. In this first report, the model system has been described in detail and the influence of skin compromise on the response to 3 irritants, citral, sodium dodecyl sulphate and nonanoic acid, has been assessed. The irritation potential of the materials varied, but each irritant produced a greater degree of reaction on skin compromised to be within the normal clinical range one might expect from housework.

Irritant contact dermatitis is defined as a non-immunological skin reaction following exposure to various chemical, mechanical and physical factors. It is known that the skin response to irritants depends on the irritant applied and differs between chemically different irritants. Sodium lauryl sulfate (SLS) is an anionic detergent and the most frequently used substance in experimental irritant contact dermatitis. In 1980, it was suggested that nonanoic acid (NNA) could be used as a positive control when patch testing. Since then, NNA has been used as an experimental irritant in several studies and has been used as a chemically different substance compared to SLS. The present article presents a review of the application of NNA in studies on skin irritancy and experimental irritant contact dermatitis.

Variable types of skin irritation were induced in 8 human female volunteers, ranging from subclinical to visible erythema with slight oedema. Skin reactions were graded clinically and objectively using transepidermal water loss (TEWL), laser Doppler flowmetry (LDF) and improved reflectance spectroscopy. This last technique enables separation of in vivo erythemas into relatively deoxygenated (venous--deoxy hem) and oxygenated (arterial--oxy hem) haemoglobin components. Compared to uninvolved skin, an empty patch increased oxy hem by 197% +/- 121% (p < 0.05). Exposure to vehicles also changes skin biophysics. At sodium lauryl sulfate (SLS) and hydrochloric acid (HCl) exposed sites, a linear correlation between concentration and oxy hem, LDF and TEWL was found. These chemicals predominantly increased TEWL values. Nonanoic acid (NON) and imipramine (IMI) also raised oxy hem, LDF and TEWL values linearly at increasing concentrations. Although IMI 2.5% clinically was graded as a type ++ response, no significant increase in TEWL was found. The improved reflectance spectroscopic technique proved valid in skin irritation studies, with a higher sensitivity than laser Doppler flowmetry, and allowed irritant vascular reactions to be discriminated into arterial and venous components. Furthermore, our observations clearly demonstrate that clinically indistinguishable skin irritation reactions induce significantly different changes in barrier function (disruption) and vascular status.

100 hospitalized patients with skin disease were patch tested with graded dilutions of nonanoic acid (NON), sodium lauryl sulfate (SLS) and benzalkonium chloride (BENZ). Smooth dose-response curves were obtained. The concentration needed to produce a discernible irritant reaction in 50% of the population (ID50) was found to be lower in cases of irritant than of allergic contact dermatitis; this finding warrants further study. Björnberg's observation that it is not possible to predict the strength of the reaction to one irritant by knowing the strength of the reaction to another was confirmed. Benzalkonium chloride caused a high frequency of pustular and/or bullous reactions with scarring as a sequela. It is suggested that this irritant could be replaced by nonanoic acid in experimental studies of topical irritancy, since the test reactions from nonanoic acid were reproducible, easy to read and left no staining or scarring.

Pathophysiological components of irritant contact dermatitis caused by 3 chemically-different irritants were investigated. 20 healthy volunteers were patch tested with sodium lauryl sulphate, nonanoic acid and hydrochloric acid on the flexor side of the upper arm. The skin response was evaluated after 24, 48 and 96 h by visual scoring and measured by the following bioengineering methods: transepidermal water loss measurement, electrical conductance for measurement of skin hydration, laser Doppler flowmetry for measurement of cutaneous blood flow and 20 MHz ultrasound A-scan for measurement of skin thickness. In spite of homogeneous inflammatory responses, significant differences in the severity of the injury to the skin barrier function caused by the different irritants were found. Also significant differences between irritants were found in the time course of development of maximum irritant reactions. Bioengineering methods indicating inflammatory responses (measurement of blood flow and skin thickness) were helpful in quantifying the irritant response in general, while bioengineering methods indicating epidermal damage (measurement of TEWL and electrical conductance) were helpful in classifying the individual irritants.

A false negative patch test can be related to errors in the testing procedure, or to a defect in the eliciting (efferent) phase of the immune response. To define this phase the application of a topical irritant (a "positive control") is suggested. Various concentrations of nonanoic acid in 1-propanol were applied to 116 healthy volunteers and to 75 dermatitis patients. Dose-response curves were obtained (concentrations 5, 10, 20 and 39.9%). Twenty percent nonanoic acid produced skin reactions in 90.1--93.9% of the subjects. The lesions consisted mainly of erythema at 48 h and pigmentation at 96 h. We suggested that the most interesting patients are those negative to this primary irritant and thay they should be further evaluated.

Patch testing with 7 irritants has been performed on a panel of 42 healthy volunteers, with the aim of determining concentrations which would induce mild to moderate reactions in at least 75% of individuals tested. The irritants studied and their optimum concentrations were as follows: benzalkonium chloride, 0.5%; sodium lauryl sulphate, 5%; croton oil, 0.8%; dithranol, 0.02%; nonanoic acid, 80%; propylene glycol, 100%; sodium hydroxide, 2%. Responder rates lower than 75% had to be accepted for benzalkonium chloride and sodium hydroxide in order to prevent overly severe reactions, whilst propylene glycol proved to have only marginal irritant properties.

Skin damage after application of experimental irritants was evaluated under blind conditions and by the use of polysulfide rubber replica. Closed patch tests with 7 different irritants, solvents and empty chambers were applied to 16 volunteers, and the skin damage was evaluated visually and by a replica technique after 24, 48 and 96 h. We found that 3 of the irritants (sodium lauryl sulphate, hydrochloric acid and croton oil) were capable of causing specific and significantly different patterns of skin damage. The patterns could be divided into papular (hydrochloric acid, croton oil) and non-papular (sodium lauryl sulphate, sapo kalinus, sodium hydroxide) types. Nonanoic acid caused a non-paular pattern, but propanol, used as a solvent, by itself also produced a non-papular pattern. The time between application of the irritant and appearance of the characteristic alteration in the skin surface differed, depending on the irritant applied.