LOCAL TOLERANCE SEMINAR

A Review by Uwe Rossow

The local tolerance seminar was the latest addition to already existing educational events provided by proDERM. As in the years before the proDERM Academy Local Tolerance Workshop brought together another wide faculty of experts from diverse backgrounds covering all aspects of dermatology, clinical testing and safety. The workshop, welcomed by proDERM Academy host Klaus Peter Wilhelm, opened with some lectures on basic principles of dermatology and safety followed by some presentations on specific skin reaction like skin irritation and skin allergy.
The second day started with another lecture session on other intolerance reactions and a lecture on practical strategies regarding local tolerance testing in humans.
The seminar ended with a practical session at the proDERM Clinical Research Centre in the afternoon. Demonstrations and practical knowledge were given on how to perform clinical testing focusing on certain aspects of local skin tolerance: patch testing, stinging test, measurement of skin barrier function via trans-epidermal water loss (TEWL) or skin redness determination and phototoxicity and photosensitization testing methods.

The lecture session on day 1 started with dermatology fundamentals and legal framework. The keynote lecture was given by Erhardt Proksch (Department of Dermatology, University of Kiel, Germany) on the barrier function of human skin. Erhardt first described the principle structure of the skin barrier and its function against external assaults (microbes, chemicals, irradiation, etc.) as well as an internal barrier against excessive water loss. Following this, he gave some examples of typical skin diseases due to impaired or destroyed skin barrier. The presentation ended with some examples for pathologically induced skin barrier weakness and specific ingredients in skin care products supporting to strengthen skin barrier function and to diminish the symptoms.

In the second presentation Uwe Rossow (CCR GmbH & Co. KG, Germany) gave some insights in legal requirements regarding product safety of cosmetic products. Uwe put his focus on certain aspects of cosmetic products like microbiological stability, purity of cosmetic ingredients, normal and reasonably foreseeable use and labelling which might influence especially the local tolerance of cosmetic products. His key message was to involve the safety assessor as early as possible in product development, raw material selection and evaluation as well as in product labelling in order to avoid bad surprises at the end of the product development process.

The next session looked at the regulatory aspects of Cosmetovigilance. Uwe Rossow (CCR GmbH & Co. KG, Germany) emphasized the importance of the cosmetovigilance process during the lifetime of cosmetics which is often underrated by companies. Uwe summarized the legal background for cosmetovigilance and gave examples how to calculate a complaint rate and how to define threshold limits for complaint rates based on product type and consumer group. Finally he presented very recent not yet published statistics on serious adverse events collected by the German Federal Office of Consumer Protection and Food Safety (BVL) showing real case reports. This supported the relevance of a proper cosmetovigilance system needed to be implemented by the companies.
The last presentation of the dermatology fundamentals and legal framework session was held by Elisabeth Gerber (Beiersdorf AG, Germany) on assessment strategies for natural ingredients. Natural ingredients become more and more important and sales volumes increase for natural and organic cosmetics in the EU. Against the prevailing sentiment that natural substances are “naturally” safer than synthetic ingredients Elisabeth first gave some examples of highly toxic natural components. In the light of the animal test ban she afterwards highlighted the difficulties of the safety assessment of natural ingredients which are usually mixtures of several components with often unknown composition. Elisabeth presented a strategy how to do a safety assessment of such raw materials if direct toxicological info on the raw material itself, its ingredients and/or single components is incomplete or not available. Bottom line was that there is no difference between risk assessment of natural and synthetic ingredients.
The second session of the day was opened by a lecture of Klaus-Peter Wilhelm (proDERM Institute for Applied Dermatological Research, Germany) on clinical aspects of skin irritation. Consumer often mix up irritation with allergy and Klaus started his presentation with a typical consumer phrase: “I am allergic to my new deodorant”. During his lecture Klaus-Peter gave some insights into the differentiation between skin irritations and allergic skin reactions. Following this, he described some well-known parameters like dose-response, exposure time, skin type or the seasons influencing irritative skin reactions. One of the major reasons for skin irritation is an impaired/reduced skin barrier function which perfectly corresponds to the keynote lecture at the beginning of the seminar. Finally Klaus-Peter gave some examples for typical irritants. As a conclusion he stated that most of the so called allergic reaction are “only” skin irritations and finally the consumer phrase of the beginning has to be modified into “I am allergic have a local intolerance reaction to my new deodorant”.
In the following presentation, also on skin irritation, David Basketer (DABMED Consultancy Ltd., UK) provided an overview on in vitro testing methods for skin irritation and the relevance and reliability of those tests vs. the existing animal tests. First David noted that the skin irritation process as such is a very complex phenomenon with different symptoms. In that context in vivo toxicology is essentially useless. In vitro tests like some OECD validated methods for the determination of skin irritation using e.g. human reconstructed epidermis are useful for a first evaluation. Most important is the good performance of such in vitro tests and a well-trained stuff in order to receive reliable results. Defined protocols, the choice of relevant positive and negative controls as well as the practical relevance and reliability of the test method (e.g. market surveillance data) are additional mandatory needs. At the end David concluded that even if in vitro tests are a very good tool they never can reflect all aspects of consumer responses to skin care products. So it´s likely that after all well designed human studies are finally needed.

Following the lectures on skin irritation, Klaus-Peter Wilhelm started with the topic skin allergy and the clinical aspects of this kind of skin reaction. In contrast to skin irritations skin allergies are immunological responses to specific allergenic substances. Within the four defined allergy types, Type IV allergies are those ones related to topical cosmetics or topical applied pharmaceuticals.  First Klaus-Peter gave some general information on the cellular process of Type IV allergies like the immunological barrier in the skin by Langerhans cells, the two steps of allergy induction and elicitation and, once again, the main differences between skin irritations and allergic skin reactions. After this basic introduction Klaus-Peter talked about the procedure of allergy detection e.g. via epicutaneous patch test and the interpretation of test results and certain pitfalls. He closed his session with typical examples of topical allergens, the hit list of preservative allergens and the explanation of the so called Dillarstone effect.

In the last presentation of the first day, as well on skin allergy, David Basketer (DABMED Consultancy Ltd., UK) addressed the issue of the animal test ban for cosmetics finished products and raw materials and skin sensitization. After a short review about the differences between skin irritation and skin allergy and a brief summary about risk, hazard and exposure David first looked on the history of allergy testing starting with animal testing in guinea pigs, then followed by in vitro testing via LLNA and currently by a combination of different in vitro test. In the following David had a closer look at some new state-of-the-art methods like h-CLAT, SENS-IS or DPRA, some of them already validated by the OECD. He explained the different test strategies of these vitro methods and their validity and predictively with regard to practical human safety assessment concerning skin sensitization. David ended with some critical thoughts on human sensitization tests like HRIPT or patch testing in atopic volunteers.
Klaus-Peter Wilhelm opened the second day´s session with a lecture about sensory irritation and other local intolerance reactions. Topics of his presentation were besides others, sensitive skin, eye/mucosal irritation, acneiform dermatosis and urticaria. Klaus-Peter started his presentation with sensitive skin by presenting some definitions for sensitive skin and talking about the various causes responsible for sensitive skin.
With regard to eye irritation he summarized for which product types eye tolerability is relevant and should be evaluated/confirmed by specific eye and/or mucous membrane tolerance tests. In the following Klaus-Peter continued his session with Mallorca Acne and Acne Cosmetica, two specific forms of acneiform dermatoses. Mallorca Acne is considered to be a special case of polymorphous light eruption triggered by specific ingredients in cosmetic products in combination with UVA light. Acne Cosmetica is a skin reaction on lipid components in cosmetic products resulting in the formation of comedones in sebum rich skin areas. Finally Klaus-Peter gave some insight into the main differences between the non-immunological contact urticaria and the immunological form of contact urticaria and the substances eliciting such skin reactions.

The second session of the day was held by Pauline McNamee (Procter & Gamble, UK) on in vitro evaluation of eye irritation. Due to the animal test ban for cosmetic raw materials and finished products the cosmetic industry has been working for years on in vitro methods to replace the well-established animal tests used for decades. As the chair of the Cosmetics Europe Animal Alternative Programme Eye Irritation Task Force Pauline presented a summary of activities, approaches and the current status around in vitro methods for eye irritation.
Starting with the morphology of the mammalian eye, Pauline explained the typical eye responses to injury, the basic mechanisms of such in vivo responses and some typical modes of action of chemicals like acids, alkalines or surfactants when getting into contact with the eye.
In the following Pauline summarized the different in vitro test methods available and applied for determining eye irritation, the characteristic approach and timeframe of a validation procedure for a new method, the state-of-the-art of alternative methods for eye irritation and finally tiered approaches to testing strategies as well as to use of alternative methods in order to replace animal tests.

The last presentation of the day was on local tolerance testing strategies in humans presented by 2 lecturers, Klaus-Peter Wilhelm (proDERM, Germany) and Elisabeth Gerber (Beiersdorf AG, Germany). Klaus-Peter started this combined session by presenting a general framework, test strategies and methodology of tolerance tests followed by Elisabeth who focused mainly on interpretation of test results and subsequent consequences for safety evaluations. Beginning with the legal framework like SCCS Notes of Guidance for the testing of cosmetic ingredients or the standardized protocol for local tolerance studies for medicinal products Klaus-Peter explained the benefits of human tolerance testing which is e.g. close to reality, highly credible and gives an optimum of compliance. Subsequently he highlighted the requirements of a well-defined and reliable human study like choosing the right test/study design or a valid reporting/documentation.
Klaus-Peter finished his presentation with a short review on commonly used human tolerance tests and a test strategy how to plan meaningful tolerance tests depending on the irritation potential of the test product and the provocation level of the test method.
In the second part of this session Elisabeth gave some practical examples how to develop test strategies for tolerance tests for finished cosmetic products with regard to safety confirmation and approval for release. Starting with the raw material safety and compliance evaluation the second step of this strategy is the performance of specific in vitro tests. Based on the results of these tests, further in vivo testing in humans will be approved or rejected. After in vitro as well as in vivo testing is completed the final decision whether a product can be assessed as safe and approved for release based on a robust and valid interpretation of the test results is a mandatory prerequisite. During her presentation Elisabeth involved the auditorium actively by asking them whether the test results presented in their examples do support a product release or not.
Finally Elisabeth highlighted that safety assessors should be permanently involved in product development to save costs, time and resources. Additionally Market surveillance is obligatory as there is no guarantee that every product is accepted by the consumer.

The workshop ended with a practical session at the proDERM Clinical Research Centre. Live demonstrations of routine and advanced in vivo testing designs on skin and eye tolerance as well as practical knowledge on how to interpret test results were given.
All in all this event was yet another excellent success, and judging from the feedback the course, delivered as part of proDERM Academy programs, will become essential for anyone (especially marketing, R&D and legal) involved in product development, advertising and tolerance testing.