Integrating mathematical approaches (IMAS): Novel methodology for predicting dermal absorption rates of chemicals under finite dose conditions.

Quantitative structure permeation relationship (QSPR) models have gained prominence in recent years owing to their capacity to elucidate the influence of physicochemical properties on the dermal absorption of chemicals. These models facilitate the prediction of permeation coefficient (Kp) values, indicating the skin permeability of a chemical under infinite dose conditions. Conversely, obtaining dermal absorption rates (DAs) under finite dose conditions, which are crucial for skin product safety evaluation, remains a challenge when relying solely on Kp predictions from QSPR models. One proposed resolution involves using Kroes' methodology, categorizing DAs based on Kp values; however, refinement becomes necessary owing to discreteness in the obtained values. We previously developed a mathematical model using Kp values obtained from in vitro dermal absorption tests to predict DAs. The present study introduces a new methodology, Integrating Mathematical Approaches (IMAS), which combines QSPR models and our mathematical model to predict DAs for risk assessments without conducting in vitro dermal absorption tests. Regarding 40 chemicals (76.1 ≤ MW ≤ 220; -1.4 ≤ Log Ko/w ≤ 3.1), IMAS showed that 65.0% (26/40) predictions of DA values were accurate to within twofold of the observed values in finite dose experiments. Compared to Kroes' methodology, IMAS notably mitigated overestimation, particularly for hydrophilic chemicals with water solubility exceeding 57.0 mg/cm3. These findings highlight the value of IMAS as a tool for skin product risk assessments, particularly for hydrophilic compounds.

Sensory irritation to methylparaben is caused by its low metabolism in the skin.

Sensitive skin is a well- known skin condition showing sensory irritation to daily used products such as cosmetics or pharmaceuticals, possibly containing sensory irritants. Methylparaben (MP), widely used as a preservative, is a representative sensory irritant and hydrolyzed in the skin. We aimed to clarify the relationship between MP sensory irritation and MP hydrolysis. First, we investigated the percutaneous penetration and hydrolysis of MP by using an ex vivo pig skin system and confirmed that topically applied MP was immediately hydrolyzed to p-hydroxybenzoic acid (PHBA). We next evaluated whether MP or PHBA causes sensory irritation using a well-used stinging test in human skin and found that MP, but not PHBA, induced irritation. Additionally, MP, but not PHBA, increased intracellular calcium in cultured TRPA1-expressed HEK293 cells, supporting the stimulatory activity of MP. Five and 10 individuals with sensitive and non-sensitive skin, respectively, were selected by a questionnaire and stinging test. In their biopsied skin samples, MP hydrolytic activity was significantly lower in sensitive than non-sensitive skin. Finally, we examined the activity of carboxylesterase (CES), which promptly hydrolyzes MP to PHBA. By using specific inhibitors of CES and CES2, we found that CES1 was responsible for MP metabolism. Our study suggests that low skin metabolism of topical agents is one of the causes of skin sensory irritation and resultant sensitive skin.

Evaluating the applicability of the Ames test for cosmetic packaging assessment by comparing carcinogenic risk levels of migrants from plastics with biological detection limits.

Risk assessments for cosmetic packaging are required according to the EU Cosmetics Regulation (EC) No. 1223/2009, however, the assessment method is well-established for food packaging but limited for cosmetic packaging. In food packaging assessments, Cramer class III TTC (90 µg/day) is applied as the threshold for systemic toxicity when the Ames test including the process of sample concentration steps provides the negative results. However, the human health risks of mutagenic and carcinogenic migrants at exposure levels where the Ames test with the concentrated samples cannot detect are unclear. In the present study, to confirm the applicability of the Ames test for cosmetic packaging assessments, the toxicological data on 37 candidate migrants with Ames test-positive results was collected. For these migrants, the carcinogenic risk levels through cosmetics use were compared to the detection levels of the Ames test for concentrated samples. Regarding at least 32 migrants, the case study showed the negative result from the Ames test incorporating the sample concentration process would indicate negligible mutagenic and carcinogenic risks of packaging extracts. Therefore, application of the Ames test to cosmetic packaging assessments would be helpful to ensure the safety for mutagenicity and carcinogenicity as well as use Cramer-TTC for systemic toxicity.

A Mathematical Approach Using Strat-M® to Predict the Percutaneous Absorption of Chemicals under Finite Dose Conditions.

Estimation of the percutaneous absorption is essential for the safety assessment of cosmetic and dermopharmaceutical products. Currently, an artificial membrane, Strat-M®, has been focused on as the tool which could obtain the permeation parameters close to the skin-derived values. Nevertheless, few practical methodologies using the permeation parameters for assessing percutaneous absorption under in-use conditions are available. In the present study, based on Fick's first law of diffusion, a novel mathematical model incorporating the permeation parameters as well as considering the water evaporation (Teva) was constructed. Then, to evaluate the applicability domain of our model in the case where Strat-M®-derived parameters were used, the permeation parameters were compared between the skin from edible porcine and Strat-M®. Regarding chemicals (-0.2 ≤ Log Kow ≤ 2.0), their permeation profiles were equivalent between Strat-M® and porcine skin. Therefore, for these chemicals, the percutaneous absorption was calculated using our model with the permeation parameters obtained using Strat-M® and the Teva determined by measuring the solution weight. The calculated values revealed a good correlation to the values obtained using porcine skin in finite dose experiments, suggesting that our mathematical approach with Strat-M® would be useful for the future safety assessment of cosmetic and dermopharmaceutical products.

Positional differences and aging changes in Japanese woman epidermal thickness and corneous thickness determined by OCT (optical coherence tomography).

BACKGROUND/PURPOSE: A number of studies of the internal structure of Japanese woman's skin are now performed by means of optical coherence tomography (OCT) as a technique capable of visualizing the internal structure in a non-invasive manner. METHODS: We measured the epidermal and corneous thicknesses at 11 sites in 116 healthy female volunteers aged from teens to sixties to examine possible positional differences and aging changes. RESULTS: The epidermal thickness determined at the 11 sites averaged 68.6 ± 23.0 µm (mean ± SD) and the corneous thickness averaged 14.1 ± 1.80 µm, the values of which were thinner than those presented in conventional textbooks on the subject. It was also revealed that, with advancing age, the epidermal thickness becomes less at some sites but showed no change at other sites, and the comparison between age groups suggested that a thinning trend is generally observed up to the thirties with no continuous changes thereafter. CONCLUSION: Aging changes in the epidermis appeared to occur in the granular to basal layers, and the results obtained by OCT, which can viably determine the skin thickness, seemed to be very important for understanding the skin more accurately.

Confocal laser microscopic imaging of conspicuous facial pores in vivo: relation between the appearance and the internal structure of skin.

BACKGROUND/PURPOSE: Conspicuous facial pores are one of the more serious esthetic defects of most concern to women. Previous microscopic observations of the skin surface around conspicuous pores have discovered large hollows and uneven skin tone. In this study, the observation area was extended from the skin surface to deeper skin to find the characteristic features of conspicuous pores in a wider spectrum. METHODS: First, a magnified surface image of the cheek skin was obtained using a video microscope. Second, replicas were collected from the same area. Third, the horizontal cross-sectioned images of the epidermis and papillary dermis in different depths were non-invasively obtained using in vivo confocal laser scanning microscopy. These images were compared with each other to find a correlation between features of the skin surface and those of deeper layers. RESULTS: In cross-sectioned images of conspicuous pores, a strongly undulated epidermal-dermal junction was commonly observed around a pore's opening. Areas with this feature correlated well to the areas with larger hollows and an uneven skin tone. CONCLUSION: Our results indicate that there is a positive correlation between the incidence of the characteristic feature at the epidermal-dermal junction and the visual appearance of a pore.

Development of a new evaluation method for cheek sagging using a Moire 3D analysis system.

BACKGROUND/AIMS: Facial sagging becomes progressively noticeable with aging. Previously developed methods to study facial sagging measure the shape of sagging skin, evaluate skin properties such as elasticity or flexibility or visually score the degree of sagging using a photo scale. However, the practical use of these methods has shortcomings and is thus limited to advanced levels of sagging. In this study, we attempted to overcome the shortcomings of those previous methods. METHODS: Fourteen points were marked on the cheek of each subject and photographed using a Moire three-dimensional (3D) camera with the subject facing first frontward and then downward. The absolute 3D coordinates (x, y, z) of the 14 points from the control point (0, 0, 0) were calculated. Subsequently, the skin surface displacements at the 14 points between the frontward and downward images were analyzed along the x, y, and z axes. The values were compared by age and by sag scores obtained from the photo scales. RESULT: The displacement values strongly correlated with age and with the sag score. In addition, this new method revealed characteristic differences of sagging between women in their 60s and those in their 70s. CONCLUSION: This method, using Moire 3D analysis, revealed slight, continuous and characteristic changes of cheek skin sagging without causing any discomfort to the subjects. These results are consistent with people's visual impression. The results indicate the usefulness of this method in skin research.