Historical perspective on the use of visual grading scales in evaluating skin irritation and sensitization

Visual assessment of skin reactions has long been used to evaluate the safety of chemicals and preparations that contact the skin, and to meet regulatory requirements. This article reviews the history of visual grading scales, and the results of investigations into the reliability of the method. Some examples are provided to illustrate the diverse array of protocols that use visual scoring to evaluate skin irritation. Furthermore, as bioengineering methods are developed that can quantitate certain aspects of skin irritant and sensitization reactions, it is important to consider whether such measures should supplement or replace visual assessment. Examples of investigations comparing the outcomes of studies that use visual scoring and those that use bioengineering methods are discussed. These examples provide little evidence that bioengineering measures provide an improvement in overall quality in comparison with current testing methods that rely on visual assessment. In addition, such measuring techniques can add considerably to the complexity of testing protocols. When benefits and cost are weighed in the balance, the visual assessment scales popularized by Draize and others remain an effective, practical method of evaluation.     

Correlation between laser Doppler perfusion imaging and visual scoring of patch test sites in subjects with experimentally induced allergic and irritant contact reactions

Purpose: To compare laser Doppler perfusion imaging (LDPI) measurements in experimentally induced allergic contact reactions and irritant contact reactions. The degree of correlation between visual scores and LDPI measurements was also studied.
Methods: Fifteen patients with known contact allergy to nickel or fragrance were patch tested with nickel sulfate 5% pet., fragrance mix 8% pet., sodium lauryl sulfate (SLS) 0.5% pet., SLS 1.0% pet. and two empty control chambers. Visual readings and LDPI measurements were taken at 0, 48 and 96 h.
Results: There was a positive correlation between visual scores and LDPI measurement in the nickel sulfate and fragrance mix patch test sites. However, no correlation between visual scores and LDPI measurements was seen in the SLS 0.5% and SLS 1.0% patch test sites. There was no significant difference ( P =0.125) in LDPI measurements between contact-allergic reactions and contact-irritant reactions.
Conclusion: LDPI correlates with visual scoring in contact-allergic reactions, but not in irritant reactions. LDPI is not useful in distinguishing between allergic and irritant reactions.     

Variation in response of human skin to irritant challenge

A major obstacle to the establishment of a protocol for in vivo irritant skin testing in humans is the apparent variability of responses between individuals. This study of the threshold response of normal human skin to a standard irritant (sodium lauryl sulfate 0.3–10%), in a group of 22 subjects, revealed a marked interindividual variation in their threshold reaction. The results demonstrate that this phenomenon does exist and that it will have to be allowed for in future human irritant test systems or assays.     

Efficacy of topical corticosteroids on irritant skin reactions

Topical corticosteroids are frequently used in the treatment of irritant contact dermatitis (ICD). The efficacy of this treatment has, however, not been thoroughly established, and experimental studies on the topic have provided conflicting results. The aim of the present study was to evaluate the effect of potent topical corticosteroids on experimentally-induced irritant skin reactions in a double-blind, vehicle-controlled study. 16 healthy volunteers had sodium lauryl sulfate patch tests symmetrically applied to the upper arms. After removal of patch tests, a potent topical cortico-steroid (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 2 × daily for 7 days. Reactions were evaluated by measurement of transepidermal water loss (TEWL) and erythema. After 7 days, statistically significant lower values of TEWL and erythema were found in corticosteroid-treated, compared to the vehicle-treated, skin reactions. The results indicate that topical corticosteroids improve healing of ICD.     

Post-application occlusion substantially increases the irritant response of the skin to repeated short-term sodium lauryl sulfate (SLS) exposure

Occlusion often, but not always, enhances percutaneous absorption and thus may facilitate skin irritation. Quantitative data about the impact occlusivity may have on minimal irritant stimuli to which the skin is exposed in daily life, and which may lead to chronic irritant contact dermatitis, are however lacking. Irritant stimuli were administered by repeated application of sodium lauryl sulfate (SLS) in an open application procedure. After the open exposure, the skin was either left open or occluded with plastic. Skin irritancy was assessed by means of visual grading and by transepidermal water loss (TEWL) measurements. Post-exposure occlusive treatment markedly enhanced the irritant response. 5 consecutive daily applications produced more irritation, with or without occlusion, than alternate day application. Occlusion may be a relevant factor in the development of irritant contact dermatitis from certain chemicals.     

Study of cumulative irritant contact dermatitis in man utilizing open application on subclinically irritated skin

We evaluated the effect of subclinical irritation on the cutaneous reaction elicited by cumulative short-term (30-min) application of sodium lauryl sulphate (SLS), by measuring transepidermal water loss (TEWL) and assigning visual scores. 11 healthy adult volunteers, free of skin disease and with no history of atopic dermatitis, were treated with SLS solution (1%, 2%, 5%, 7.5%). On a Monday, we applied 80 μl of 1% SLS solution and deionized water (control), using large aluminum chambers with filter paper discs, for 30 min. We measured TEWL values 2x before and after patch application of control and 1% SLS solution, and then applied 80 μl of SLS solution (2%. 5%. 7.5%) using filter paper discs. From Tuesday to Friday, we applied 80 μl of each solution, using filter paper discs, and measured TEWL before and after open application of test solutions. Compared with each corresponding group, TEWL values of SLS patch groups (S-2.0, S-5.0, S-7.5) were higher than, those of water patch groups (W-2.0, W-5.0, W-7.5), respectively. TEWL values of each groups increased stepwise and the final (hour 97) TEWL values were higher than those of baseline (hour 0) TEWL. The mean visual scores of the vehicle control were lower than those of other test groups, but there were no statistically significant differences in visual scores between each test group. These findings suggested that impaired skin barrier function, elicited by subclinical irritation from short-duration contact with some irritants, might augment the cumulative irritant contact dermatitis caused by repeated open exposure to other surfactants. Relatively short-term and minimal exposure, not in great excess of many daily surfactant exposures, produced cumulative irritation. TEWL measurements were more discriminating than visual grading.     

Population differences in skin structure and physiology and the susceptibility to irritant and allergic contact dermatitis: implications for skin safety testing and risk assessment

Skin safety testing and risk assessment utilize a comparative toxicological approach whereby the inherent toxicity (irritation or sensitization) is related to exposure to determine the potential risk to a consumer population. However, consumers cover a broad spectrum of individual characteristics in terms of skin types and functions, as well as their basic habits and practices in use of consumer products. Thus, we try to use very conservative estimates for both inherent susceptibility to the toxic effect as well as the potential worst-case exposures. While the inherent variation can be considerable even within a country, it is magnified even further when products are marketed globally. Questions have arisen, therefore, as to whether a skin safety testing approach conducted locally or regionally can adequately predict for adverse effects for the global consumer. A good deal of speculation exists that population differences are real and should mandate population-specific safety testing prior to marketing products in certain regions of the world. In an attempt to address this question, this review has summarized extensive literature covering basic skin biology and function and susceptibility to irritant and allergic skin responses. Throughout this literature, there are individual studies demonstrating population differences in skin properties or in the responsiveness to chemical insult. Some of the research on this topic has pointed fairly convincingly to a demonstrable population difference. The best example of this is the tendency for blacks to have a lesser skin reactivity than Caucasians, likely due to a more impenetrable barrier. In contrast, the comparative data for Caucasians and Asians, for males and females, and for different age clusters are far less compelling. In terms of tendencies, there are little data to support any real difference in skin barrier function or in skin irritation responsiveness between Caucasians and Asians or between males and females. Comparing different age profiles, there does appear to be a slight decline in reactivity to irritants among the elderly (> 65 years). Susceptibility to skin sensitization tends to be more related to exposure than any inherent susceptibility, though some data exist to suggest a slightly increased sensitivity in females versus males. On the basis of these data, standard procedures for skin safety testing and risk assessment can be considered relatively conservative. Most clinical skin safety studies are conducted in test populations that are comprised primarily of female Caucasians between the ages of 18 and 65 years. If anything, the skin reactivity “character” of this population cohort tends to skew toward the more reactive. This is not to say that population-specific safety testing should not be done. There may be important reasons to pursue a population-specific testing strategy in certain situations, perhaps due to regional, sex-specific, or age-specific marketing or to satisfy a regulatory or external relations need. However, there is yet no scientific justification to mandate such a strategy, based on our current knowledge of skin responsiveness and how it compares across diverse populations. There are clearly gaps in our understanding of population differences, particularly in regard to skin irritation that should guide future clinical research efforts. Side-by-side population testing for both acute and chronic skin irritation, more comparative testing of Asian subpopulations, testing for neurosensory irritation, and testing objective skin responses among hyperreactive subpopulations of multiple races are all areas in which additional research is needed. While current testing strategies have provided an excellent track record of success in providing safe and effective products to the world's consumers, results of such research will, in the future, help us to refine and further improve our skin testing and risk assessment capabilities.     

Beneficial effects of a skin tolerance-tested moisturizing cream on the barrier function in experimentally-elicited irritant and allergic contact dermatitis

In experimentally-induced irritant (ICD) and allergic (ACD) contact dermatitis, an oil-in-water (o/w) cream was applied to investigate its effects on a disturbed barrier function compared to untreated physiological barrier repair. Transepidermal water loss (TEWL) measurements were performed. Before the start of the experiments, the skin tolerance of the cream was examined, revealing the non-irritating characteristics of the ingredients and the absence of any contact allergic patch test reaction. In the ICD study, sodium lauryl sulfate (SLS) patches were applied to the forearms of young female volunteers. Consequently, it was observed that repeated cream application (14 days, 2x/day) significantly improved the TEWL of SLS-damaged skin, leading to a complete recovery on day 15. In the ACD study, disruption of skin barrier function was obtained by a nickel-mediated contact allergy patch (CAP) test. The cream was then applied 2x/day for 4 consecutive days. Assessment of TEWL clearly showed that recovery of the disrupted skin significantly improved after cream application in comparison to untreated barrier repair.     

Sensitive skin: closing in on a physiological cause

The phenomenon of ‘sensitive skin’ is a relatively recent complaint in which certain individuals report more intense and frequent adverse sensory effects than the normal population upon use of cosmetic (personal‐care) products. Originally defined as a minority complaint, sensitive skin is now claimed by a majority of women in industrialized countries and nearly half of men. Sensitive skin is self‐diagnosed and typically unaccompanied by any obvious physical signs of irritation, and the number of individuals who claim sensitivity has risen steadily with the number of consumer products targeted towards this supposedly uncommon group. Believed by many dermatologists, therefore, to be a ‘princess and the pea’ phenomenon, the problem of sensitive skin has largely avoided focussed research. Over the last few years, however, the evidence of documentable biophysical changes associated with the largely sensory symptoms of this disorder has accumulated, including some gained by improved methods of identifying subclinical signs of skin irritation. Although the understanding of the aetiology of this phenomenon is as yet incomplete, existing research now supports a biophysical origin for this disorder. Effective methods of diagnosis, intrinsic and extrinsic contributors to exaggerated neural sensitivity, and the specific mechanisms of the discomfort associated with the compliant are required, as are appropriate means of prevention and treatment.     

Evaluation of an experimental patch test model for the detection of irritant skin reactions to moisturisers

Background/aims: Moisturisers are used daily by a large number of people to prevent dryness of the skin. Irritant skin reactions to moisturisers are, however, known to occur. In order to prevent such irritant reactions reliable test methods for irritancy testing of moisturisers are needed. This study was undertaken to evaluate a non‐invasive patch test model for the detection of irritant skin reactions to moisturisers. Methods: Twenty healthy volunteers were patch tested with three different moisturisers: empty chamber, sodium lauryl sulphate and a moisturizer known to be non‐irritating. Skin reactions were evaluated by visual scoring, measurement of transepidermal water loss (TEWL) by an Evaporimeter, blood flow by laser Doppler flowmetry and electrical capacitance by a Corneometer. Results: A statistically significant increase in blood flow was found 48 h after application of one of the moisturisers tested, indicating an irritant effect of the product. A statistically significant decrease in skin hydration was found for the same moisturiser after 48 h. No statistically significant differences between the moisturisers were found by visual scoring. None of the products tested had any negative effect on the skin barrier function. Conclusion: The non‐invasive patch test model was found useful for detecting irritant skin reactions to moisturisers.     

Artificial disruption of skin barrier prior to irritant patch testing does not improve test design

BACKGROUND: Irritant patch testing is often performed as a 24- or 48-h occlusive patch test with low concentrations of sodium lauryl sulphate (SLS). OBJECTIVES: The aim of this study was to investigate potential ways to shorten this test procedure and obtain precise test results. PATIENTS AND METHODS: Thirty-six healthy volunteers underwent irritant patch testing with different pretreatments (PT) of the test fields. Occlusive test chambers were applied on the upper back with SLS 0.5%, 1%, 2% and 5% in large Finn Chambers(R). The patches were removed after 4 and 24 h, respectively, depending on the concentration used. Test fields were pretreated as follows: PT 0, field without any PT (control); PT 1, prick with lancet; PT 2, prick with test stamp; PT 3, scratch with lancet; PT 4, incision with standardized incision instrument (0.1-0.2 mm depth). Skin reactions were evaluated by transepidermal water loss (TEWL), skin erythema and skin hydration and as well by a visual score (VS) at 4, 24 and 72 h. RESULTS: Our data show an obvious distinction between PT 0-2 and PT 3-4 at all measurement methods. The average TEWL values with PT 3-4 were higher than those with PT 0-2, especially on the 4-h course. This distinction may derive from the shape and size of the skin impairment achieved by PT 3-4, leading to a mechanical barrier disruption. However, SLS may infiltrate directly into deeper skin layers supported by capillarity. Consequently, no or little penetration through the epidermis and interaction with its structures occurs, which is responsible for irritant skin reactions. The SLS dose in the upper skin layers is therefore lower at these PTs. The lower remaining dose of SLS also explains this distinction, especially for the VS. Additionally, there are presumed reactions in deeper layers of the epidermis and dermis at PT 3-4. CONCLUSIONS: In summary, all data suggest a different reaction pattern from the classical irritant response. Therefore, application without any PT seems to be best suited for irritancy skin testing, especially for visual assessment. PTs prior to irritant patch testing have been shown to be unjustifiable.     

Allergic and irritant patch test reactions and atopic disease

This study presents a profile of patients with chronic recalcitrant eczematous disease referred by dermatologists for contact allergy evaluation. Allergic contact dermatitis (ACD) and irritant responses were carefully defined, as was the presence or absence of atopy obtained by history. Of 410 patients studied, 44% had no history of atopic disease and 46% were classed as definitely atopic. Among relevant ACD patch lest reactors ( n = 198). 51.5% had atopy, compared with 40.9% with no atopy but this difference was not significant. Likewise, among atopics ( n = 189). 54% had definite, relevant ACD patch test responses while 33.9% had negative ACD (again not significant). Significance was seen in the higher mean number of positive allergic patch tests in the atopic group (2.7 versus 2.0. p =0.0223). Irritant patch tests were highest among patients with both ACD and atopy ( p = U.0308) and the proportion of irritant responses correlated with increasing numbers of positive ACD tests. We conclude that atopics are at least as likely to have ACD as are non-u topics. Irritancy is increased in these patients with chronic dermatitis and the frequency of irritant reactions correlates with both greater numbers of ACD responses and with presence of atopy.     

Effect of an antioxidant (quercetin) on sodium-lauryl-sulfate-induced skin irritation

Quercetin is a bioflavonoid with antioxidant and anti-inflammatory activity. The purpose of this study was to examine the effect of quercetin on acute skin irritation, with special interest in the skin barrier function recovery. Acute irritant contact dermatitis was induced in 15 patients by 24-h occlusion of 2% sodium lauryl sulfate (SLS) (day (D) 1). The influence of application on SLS-irritated skin of topical quercetin for 5 consecutive Ds, compared to vehicle and controls, was studied. Parameters measured were transepidermal water loss (TEWL) and erythema index. Final measurements were taken on D 7 after a 1-D rest period. TEWL and the erythema index continued to rise 2 D after application of SLS and 1 D after treatment with quercetin, vehicle or controls. Both TEWL and erythema values at D 7 did not return to values before the SLS barrier disruption at all the test sites. Therefore, quercetin topically applied after induction of irritant contact dermatitis does not appear to increase the recovery of barrier function and erythema caused by SLS.     

The effect of topically applied corticosteroid on irritant and allergic patch test reactions

The purpose of the study was to assess the effect of topical corticosteroid on the patch test response in patients with known positive allergens and also to study any effect on the irritant response. In Study 1, 10 patients with known positive allergens had their backs pre-treated 2× daily for 3 days with either betamethasone dipropionate 0.5% or the equivalent ointment base. On day 4, previous known allergens and dilutions of sodium lauryl sulfate (5% and 10%) as an irritant were applied to each side of the back. In Study 2 (4 patients), a 1:4 dilution of betamethasone dipropionate was substituted for the full-strength preparation. Betamethasone dipropionate 0.05% caused total or partial suppression of the allergic reaction in 8 of in eases. The 1:4 dilution caused partial suppression in 3 cases. The irritant reaction was totally suppressed by betamethasone dipropionate in 1 of 10 cases and partially suppressed in 7 of 10. The 1:4 dilution decreased the intensity of the irritant reaction in 3 of 4 cases. The relevance of these results to clinical practice is discussed.     

Effect of mineral oil and linoleic-acid-containing emulsions on the skin vapour loss of sodium-lauryl-sulphate-induced irritant skin reactions

This study evaluates the influence of mineral oil and linoleic-acid-containing emulsions on the skin vapour loss (SVL) of detergent-induced irritant skin reactions. During a period of 2 weeks, 2 x 45 min applications of a sodium lauryl sulphate solution of low molarity were performed on the forearm of 9 volunteers. In the same period, a standard amount of each emulsion was applied on the induced irritant skin reactions, 3 times each day. The effect of the emulsions on the barrier function of the skin was evaluated by means of SVL measurements. The emulsion based on mineral greases significantly reduced SVL values during both weeks, possibly because of an occlusive effect. The emulsion with 15% of linoleic acid significantly reduced SVL values during the 1st week but not during the 2nd week. The emulsion with 38% of linoleic acid did not reduce SVL values at all.