Characterisation of skin penetration pathways using stimulated Raman scattering microscopy.

Understanding the mechanisms governing the penetration of substances into the skin is crucial for the development of safe and effective topical drug delivery systems and skincare products. This study examined the partitioning of model permeants into human skin, by assessing six substances with diverse logP values. We employed stimulated Raman scattering (SRS) microscopy, an ambient, label-free optical imaging technique known for its ability to provide chemical distribution with subcellular resolution.

Non-animal approaches for photoallergenicity safety assessment: Needs and perspectives for the toxicology for the 21st century.

Certain chemicals and/or their byproducts are photoactivated by UV/VIS and trigger a dermal allergenic response, clinically recognized as photoallergic contact dermatitis (PACD). It is important to identify the chemicals which are potentially photoallergenic, not only for establishing the correct differential diagnosis between PACD and other photodermatoses, but also as causative agents which should be avoided as a preventative measure. Moreover, materials with photoallergenic properties need to be correctly identified to allow thorough safety assessments for their use in finished products (e.

ADME characterization and PBK model development of 3 highly protein-bound UV filters through topical application.

Estimating human exposure in the safety assessment of chemicals is crucial. Physiologically based kinetic (PBK) models which combine information on exposure, physiology, and chemical properties, describing the absorption, distribution, metabolism, and excretion (ADME) processes of a chemical, can be used to calculate internal exposure metrics such as maximum concentration and area under the concentration-time curve in plasma or tissues of a test chemical in next-generation risk assessment. This article demonstrates the development of PBK models for 3 UV filters, specifically octyl methoxycinnamate, octocrylene, and 4-methylbenzylidene camphor.

Measurement of chemical penetration in skin using Stimulated Raman scattering microscopy and multivariate curve resolution - alternating least squares.

The mechanistic understanding of skin penetration underpins the design, efficacy and risk assessment of many high-value products including functional personal care products, topical and transdermal drugs. Stimulated Raman scattering (SRS) microscopy, a label free chemical imaging tool, combines molecular spectroscopy with submicron spatial information to map the distribution of chemicals as they penetrate the skin. However, the quantification of penetration is hampered by significant interference from Raman signals of skin constituents.

PBK modelling of topical application and characterisation of the uncertainty of C estimate: A case study approach.

Combined with in vitro bioactivity data, physiologically based kinetic (PBK) models has increasing applications in next generation risk assessment for animal-free safety decision making. A tiered framework of building PBK models for such application has been developed with increasing complexity and refinements, as model parameters determined in silico, in vitro, and with human pharmacokinetic data become progressively available. PBK modelling has been widely applied for oral/intravenous administration, but less so on topically applied chemicals.

A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products.

Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new approach methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion.

Application of physiologically based kinetic (PBK) modelling in the next generation risk assessment of dermally applied consumer products.

Next Generation Risk Assessment (NGRA) is a procedure that integrates new approach methodologies (NAMs) to assure safety of a product without generating data from animal testing. One of the major challenges in the application of NGRA to consumer products is how to extrapolate from the in vitro points of departure (PoDs) to the human exposure level associated with product use. To bridge the gap, physiologically based kinetic (PBK) modelling is routinely used to predict systemic exposure (C or AUC) from external exposures.

Applying the skin sensitisation adverse outcome pathway (AOP) to quantitative risk assessment.

As documented in the recent OECD report 'the adverse outcome pathway for skin sensitisation initiated by covalent binding to proteins' (OECD, 2012), the chemical and biological events driving the induction of human skin sensitisation have been investigated for many years and are now well understood. Several non-animal test methods have been developed to predict sensitiser potential by measuring the impact of chemical sensitisers on these key events (Adler et al., 2011; Maxwell et al.

Determining epidermal disposition kinetics for use in an integrated nonanimal approach to skin sensitization risk assessment.

Development of risk assessment methods for skin sensitization in the absence of toxicological data generated in animals represents a major scientific and technical challenge. The first step in human skin sensitization induction is the transport of sensitizer from the applied dose on the skin surface to the epidermis, where innate immune activation occurs. Building on the previous development of a time course in vitro human skin permeation assay, new kinetic data for 10 sensitizers and 2 nonsensitizers are reported.

Development of a modified in vitro skin absorption method to study the epidermal/dermal disposition of a contact allergen in human skin.

In vitro skin absorption methods exist in Organisation for Economic Co-operation and Development (OECD) guideline form (No. 428) and are used to estimate the degree of systemic penetration of chemicals through skin. More detailed kinetics of permeation through skin compartments are not described well by existing methods.

Assuring consumer safety without animal testing: a feasibility case study for skin sensitisation.

Allergic Contact Dermatitis (ACD; chemical-induced skin sensitisation) represents a key consumer safety endpoint for the cosmetics industry. At present, animal tests (predominantly the mouse Local Lymph Node Assay) are used to generate skin sensitisation hazard data for use in consumer safety risk assessments. An animal testing ban on chemicals to be used in cosmetics will come into effect in the European Union (EU) from March 2009.

Optimisation of the caco-2 permeability assay using experimental design methodology.

Purpose: This study used a Box-Behnken experimental design to optimise the experimental conditions in the Caco-2 assay for a series of p-hydroxybenzoate ester compounds (log P 1.96-5.69), as highly lipophilic compounds are not handled well in this system.

Xenobiotic metabolism in human skin and 3D human skin reconstructs: a review.

In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental chemical exposure, it is also a potential target organ for adverse health effects.

Paraben transport and metabolism in the biomimetic artificial membrane permeability assay (BAMPA) and 3-day and 21-day Caco-2 cell systems.

Noncellular and cellular in vitro models for predicting intestinal absorption were used to investigate the transport and metabolism of parabens. The biomimetic artificial membrane permeability assay (BAMPA) membrane was constructed by impregnating a lipid solution on a hydrophobic filter. Caco-2 cells at passage numbers 65 to 80 were cultured in either the accelerated 3-day Biocoat system or the standard 21-day Transwell cell culture system.