Skin exposed to low humidity often shows hypersensitivity to sensory stimuli. The aim of this study was to identify the mechanism underlying such hypersensitivity to sensory stimuli using reconstructed epidermal equivalents (RHEEs) exposed to low humidity.

RHEEs exposed to low humidity were identified to be an appropriate model of dry skin by their secretion of interleukin (IL)-1α and carbonylated proteins (CPs). Oxidative situations and protein expression levels of nerve growth factor (NGF) and semaphorin3A (Sema3A) in RHEEs exposed to low humidity were compared with control RHEEs. It was found that RHEEs exposed to low humidity synthesized superoxide anion radicals (·O₂⁻) in a higher level. RHEEs exposed to low humidity also showed a higher level of NGF and a lower level of Sema3A compared to those of control RHEEs. In addition, treatment with the conditioned medium of RHEEs exposed to low humidity stimulated axon elongation in N1E-115 neuroblastoma cells. These phenomena were abolished by superoxide dismutase.

Thus, ·O₂⁻ generated in RHEEs exposed to low humidity caused an imbalance of NGF and Sema3A, which can result in creating a higher susceptible conditions against sensory stimuli.

We first investigated psychosomatic effects of hydrogen inhalation in humans. Psychologically, anti-stress action and an increase in ability to concentrate were observed. Physiologically, it was suggested that hydrogen inhalation increases the sedative effects and brain activity by suppressing sympathetic nervous activity. Thus, the effects of continuous hydrogen inhalation for 2 weeks on the psychological effects and skin properties were investigated. In addition to reduction of awareness of stress and negative emotions, improvement of skin firmness and blotches was observed. These findings suggested that continuous hydrogen inhalation exhibits regulating effects on skin conditions.

The system for pharmaceuticals and cosmetics is basically classified into only pharmaceuticals and cosmetics in some countries/regions, and some countries/regions have intermediate categories between them. The expression “cosmetics having functionality” falls into this intermediate category, and in the case of Japan, quasi-drugs are included in this category. Of the countries/regions that are closely related to Japan in the import and export of cosmetics, only EU and ASEAN do not have intermediate categories, it exits as “special cosmetics” in China, “Cosmetic Drugs” in the United States, “functional cosmetics” in South Korea, and “specific purpose cosmetics” in Taiwan. The types, actions, and functions of these intermediate categories may differ depending on the country/region, but many are common. Sunscreens are in the intermediate category in all countries/regions.

For products in these intermediate categories, the registration system is in the United States, but the approval system is the basis in many countries/regions, and each has its own application and approval standards. There are also differences in the safety materials that need to be attached at the time of application, depending on the country/region.

More than eight years have passed since the ban on animal testing in the EU in 2013, but no alternative method has been developed that can be used for all safety evaluations. It is very difficult at this stage to prepare application materials for quasi-drugs without conducting animal experiments, but guidance on alternative studies for application is gradually being prepared in Japan. In addition, since safety evaluation methods using in vitro and in silico are advancing day by day, we hope that it will be possible to apply for approval of quasi-drugs without relying on animal experiments in the not to distance future.

Animal tests of cosmetic ingredients and products have been banned in the EU since 2013. However, in Japan, the application of new quasi-drugs requires the animal data regarding several toxicity tests.

To resolve this concern, we have been coordinating guidance on the use of alternative test methods for the safety assessment of cosmetics and quasi-drugs since 2012. Dermatologists and representatives of cosmetic companies as well as specialists from both the Pharmaceuticals and Medical Devices Agency (PMDA) and the National Institute of Health Sciences (NIHS) have drafted guidance documents for a number of alternative test methods based on the OECD (Organisation for Economic Co-operation and Development) test guidelines and Japanese Center for the Validation of Alternative Methods (JaCVAM) evaluation documents. The development of new ones without animal testing are progressing the step-by-step process in Japan.

By next year, it is promising to gain approval of guidance document for additives to quasi-drug products and cosmetic ingredients without data from animal testing for regulatory acceptance.

On safety evaluation of cosmetics, certification of its safety done by cosmetic companies is required. In addition, through abolition of animal testing, they acquire necessary data on safety evaluation without animals. Then, here, out of safety evaluation testing methods for cosmetics products, human patch testing and skin sensitization testing are mentioned. Also, under the difficult condition of animal testing, the most important method on the way to human testing is institutional review board. So, institutional review board should be mentioned here.

In the application for manufacturing and marketing approval of quasi-drugs and the request for revision of cosmetic standards, safety tests using animals have been most commonly used in accordance with the safety evaluation of pharmaceuticals. However, several useful alternative methods for animal testing have been reported, some of which have been adopted as the OECD Test Guidelines (TG). In Japan as well, the regulatory use of alternative methods for animal testing will be promoted by the guidance issued after discussions at the “Committee to discuss the guidance on safety testing methods for quasi-drugs, etc.,” whose secretariat is the Japanese Center for the Validation of Alternative Methods (JaCVAM). To date, guidance for alternative methods such as phototoxicity tests, eye irritation tests and skin sensitization tests has been issued. In this presentation, we will introduce the status of guidance discussed at the “Committee to discuss the guidance,” especially about the status of discussion for the guidance for “skin irritation” and “single dose toxicity.”

[About the guidance for skin irritation]

The in vitro tests using a reconstructed human epidermis (RhE) model have been adopted as OECD TG439. However, these tests might be insufficient for regulatory use of quasi-drugs application that require a 24 h skin irritation test. This problem was resolved by comparison data between the TG439 and the 24 h patch test, and set of applicability domain, and the guidance for skin irritation was issued.

[About the guidance for single-dose toxicity]

Regarding the in vitro tests for the single-dose toxicity, we examined the use of cytotoxicity assay introduced in OECD Guidance No. 129. Although it is not possible to evaluate all of the acute toxicity by cytotoxicity alone, we examined the evaluation by combining with other information, not by the cytotoxicity test alone, and created the guidance including the evaluation flow.

Psychosocial stress sometimes affects skin conditions. In contrast, poor skin condition also affects psychological state in human being. It is suggested that there are basically conditioning responses between somatic state and psychological state. But it is still unknown in detail. This manuscript is described how psychological stress induce skin condition change and vice versa within current knowledge. It is also described the relationship between stress and some skin disorders including atopic dermatitis, psoriasis and acne.

HPA (hypothalamic-pituitary-adrenal)-axis contains central HPA-axis and skin HPA-axis. Central and skin HPA-axis have an important role of skin change with psychological stress. There are many interactions among hormones, cytokines and neuropeptides. Epitherial cells and sebaceous cells are affected skin HPA-axis.

Psychodermatological disorders are clinically classified into four groups. The first is psychosomatic disorders, the second is primary psychiatric disorders, the third is secondary psychiatric disorders and the fourth is mucocutaneous dysesthesia. These are treated not only by dermatological therapy but psychological or psychiatric therapy. However, there are a few psychodermatologists in Japan. Most psychodermatological patients are not actually treated by psychosomatic approach.

The skin has been explored in various fields such as physiology, neuroscience, psychology, and philosophy. However, considering its multi-layered functions, it will be ideal to study the skin on multidisciplinary arena. The tactile sensation captured by the skin has unique characteristics compared to other four types of senses among the five senses. Tactile sensation is perceived as reality, reciprocity, sense of unity, and as an interoception. Therefore, if touching is applied to contact with other people, it is possible to quickly build an intimate relationship. Interestingly, self-touch has the effect of directing one’s inner consciousness and has characteristics that are different from what is produced by touching others. The skin has tactile nerves that produce sense of pleasure, which respond only to touches applied at a slow speed of about 3 cm to 10 cm per second. When this nerve ignites, oxytocin is secreted in the brain. Oxytocin has various roles that contribute to physical and mental health, such as relieving stress reactions and promoting fat metabolism. One can even promote oxytocin secretion by oneself. Oxytocin is secreted by physical contact, volunteer activities, and enjoying the five senses and so on. Recently, it has been known that oxytocin affect not only general health but also life expectancy. Due to various difficulties caused by COVID-19, the secretion of oxytocin is suppressed in people in general, and especially women are suffering from its adverse effects.