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Notizen: There exists within the population subsets of individuals who display heightened skin reactivity to materials the majority find tolerable. In a series of investigations, we have examined interrelationships between many of the endpoints associated with the term ‘sensitive skin’. In the most recent work, 58 volunteers were treated with 10% lactic acid, 50% ethanol, 0.5% menthol and 0.1% capsaicin on the nasolabial fold, unoccluded, for 8 minutes. Sensory reactions were recorded at 2.5, 5 and 8 minutes. Urticant susceptibility was evaluated with 1 M benzoic acid and 125 mM trans-cinnamic acid applied to the volar forearm for 20 minutes. Visual assessments were taken at intervals for up to 4 hours after treatment. A 2 × 23 hour patch test was also conducted using 0.1% and 0.3% sodium dodecyl sulphate, 0.3% and 0.6% Tegobetain F50 and 0.1% and 0.2% benzalkonium chloride to determine irritant susceptibility. As found in previous studies, increased susceptibility to one endpoint was not predictive of sensitivity to another. In our hands, nasolabial stinging is a poor predictor of sensory as well general skin sensitivity. However, it may be possible to identify in the normal population individuals who are more generally sensitive to a range of non-immunologic adverse skin reactions. Whether such individuals are those who experience problems with skin care products is open to question.

Notizen: In recent years, the local lymph node assay (LLNA) has emerged as a practical option for assessing the skin sensitization potential of chemicals. In addition to accurate identification of skin sensitizers, the LLNA can also provide a reliable measure of relative sensitization potency; information that is pivotal in successful management of human health risks. However, even with the significant animal welfare benefits provided by the LLNA, there is interest still in the development of non-animal test methods for skin sensitization. Here, we have collected a large dataset of chemicals that have been tested in the LLNA, and the activity of which correspond with what is known of their potential to cause skin sensitization in humans. It is anticipated that this will be of value to other investigators in the evaluation and calibration of novel approaches to skin sensitization testing, in particular for the development of in silico methods. Prerequisite for the development of in silico models is always the availability of a large high quality data set, suitable for modeling. This dataset encompasses both the chemical and biological diversity of known chemical allergens, and provides also examples of negative controls. The data are a collection of published and non-proprietary industry data. All materials were tested in standard vehicules following the standard LLNA protocol. It is hoped that this dataset will accelerate the development, evaluation and eventual validation of new approaches to skin sensitization testing.

Notizen: Fragrance substances represent a diverse group of chemicals, some being associated with the ability to cause allergic skin reactions. In recent work, we evaluated two groups of fragrance chemicals, saturated aldehydes (aryl substituted and aliphatic aldehydes) and ?,?-unsaturated aldehydes. QSAR models relating the LLNA EC3 values to a measure of the lipophilicity of a chemical (log P) and s*(a measure of reactivity) were developed for both sets of aldehydes. The outcome was consistent with ?,?-unsaturated aldehydes reacting via Michael addition, whilst saturated aldehydes formed Schiff bases with proteins. In the present study we evaluated further aldehydes to test the robustness and extend the scope of the QSARs. The QSAR models were used to predict EC3 values for 4 new Michael addition aldehydes and 6 new Schiff base formers. LLNA data generated for these compounds demonstrated the original QSARs were fairly accurate but still required improvement. Development of the QSAR models has provided us with a better understanding of the potential mechanisms of action for aldehydes and hence how to avoid or limit allergy. Knowledge generated from this project is being incorporated into new/improved rules for sensitisation in the expert toxicity prediction system Deductive Estimation of Risk from Existing Knowledge (DEREK).

Notizen: Objectives:  To identify substances and tonnage data for use for hair dyes registered in Europe. To predict the sensitization potential of each substance and to rank the substances due to their sensitization potential. Further to group the substances in clusters based on their physical chemical properties with a cluster analysis.Methods:  The Inventory list of Cosmetics Ingredients (INCI), new regulation on cosmetics, tonnage data for use and Toxnet were used to identify and quantify the hair dyes. Salts were disregarded. A QSAR (Qualitative structure-activity relationship) model called TOPS-MODE, based on local lymph node assay (LLNA) data and physical chemical properties were used to predict the sensitization potential and make a cluster analysis.Results:  Out of 315 hair dye substances 229 meet the inclusion criteria. Most of the hair dye substances 75% were predicted to be strong to moderate sensitizers. Less were predicted to be weak 22% and only a small part 3% were predicted to be extremely weak or non sensitizing. The 8 most used hair dye substances were predicted to be strong to moderate sensitizers. Ppd is the most used hair dye allergy marker but some azodyes were predicted to be more potent than para-phenylenediamine (ppd).Conclusions:  Most hair dye substances are predicted to be strong to moderate sensitizers, which explain why some people gets hair dye dermatitis. A patch test series with potent, much used azodyes, might prove useful in diagnosing ppd-negative patients, with hair dye allergy. The cluster analysis grouped the substances which can be helpful choosing substances for clinical patch test.

Notizen: For new chemicals introduced into the workplace or marketplace, and which come into contact with the skin, it is necessary, to conduct a thorough skin safety testing and risk assessment program to be certain that the exposures will be well tolerated. One vital risk assessment process involves the determination of allergic skin reactions, referred to as skin sensitization, the clinical manifestation of which is allergic contact dermatitis. The process by which low molecular weight chemicals induce and elicit skin sensitization is dependent on many factors including the ability of the chemical to penetrate the skin, react with protein, and trigger a cell-mediated immune response. Based on our chemical, cellular and molecular understanding of allergic contact dermatitis, it is possible to carry out a quantitative risk assessment. It has been well known for years that chemical allergens display dose-response characteristics regardless of whether the sensitization is induced in an experimental system or in humans. Moreover, it is well known that the critical exposure determinant for evaluating skin sensitization risk is dose per unit area of skin exposed. The skin sensitization testing and risk assessment process for new ingredients and consumer products generally follows a step-wise approach that may involve structure-activity evaluations, analytical assessments, preclinical skin sensitization testing (e.g., the mouse local lymph node assay), confirmatory clinical testing (e.g., the human repeat insult patch test), and benchmarking of resulting data against similar ingredients and product types. Essential elements for conducting a sound risk assessment involve the development of an understanding of the sensitization potential of the contact allergen and the likely dose, nature, extent and duration of exposure. With an understanding of the exposure and potency of the chemical one can assess whether the chemical, under the specific conditions of exposure, ould pose an acceptable or unacceptable risk of induction of skin sensitization. As with any test method or risk assessment approach, it is critical to understand the strengths and limitations so that one can conduct the best assessment possible and assure the skin safety of the chemical under evaluation.

Notizen: Axillary dermatitis can be associated with the use of underarm products. However the unique physiology of this region makes assessment of irritation problematic. Furthermore, given the type of products used in the underarm, the friction and occlusive nature of the site, it is necessary not only to concentrate on the area of application ie the area of hair growth, but also to examine the periphery. There is evidence that products tend to move to this area during the day possibly as a consequence of axillary physiology and mechanical effects. Consequent upon these various factors, predicting axillary irritation from acute patch tests on back or arm skin is problematic. In a recent comparison, we found that where approximately 10% of panellists reacted to a formulation by patch test, 50% developed axillary reactions during a 21 day use test. In addition, not all those who reacted in the patch test reacted in the axilla. Predicting axillary effects from repeated open tests seems better but still has challenges; currently we are assessing alternative strategies to permit rapid identification of potential issues without recourse to extended in use tests.

Notizen: We have previously reported that, with suitable training and experience, skin irritation reactions can be graded visually with a high degree of sensitivity and precision. The objective of the work presented is to demonstrate the possibilities and limitations of the grading of skin irritation reactions by subjective visual assessment. In the present work, we have recorded a wide range of relatively minor skin irritation reactions using a high quality digital camera. The skin reactions recorded have then been graded by independent observers according to their appearance on a computer monitor. The results show that very subtle degrees of both erythema and skin dryness can be accurately described by trained skin graders in a reliable and reproducible manner. Examples of the grading scales and sensitivity of scoring will be shown. We conclude that visual scoring, when conducted well, represents a rapid and accurate method for the assessment of minor degrees of skin irritation. The present evidence, taken in combination with previously presented information on bioengineering techniques, leads us to the conclusion that visual assessment is both an adequate and a robust technique, delivering information of the quality necessary for safety assessment of consumer products.