Review of the Availability ofIn VitroandIn SilicoMethods for Assessing Dermal Bioavailability

Abstract

The exposure of the skin to consumer products, drugs, and environmental chemicals can result in their penetrating the skin barrier and entering systemic circulation, potentially resulting in adverse effects in the skin and other organs. The assessment of dermal penetration and bioavailability (including penetration, metabolism, and entry into the systemic circulation) is therefore an important consideration in the risk assessment of chemicals. The skin is a heterogeneous organ with a multilayer structure. Based on its architecture and physiology, substances can penetrate through three major ways but can also be blocked in the different skin layers and in the skin appendages, which act as reservoir. In addition to that, as the skin is a metabolically competent organ, substances can undergo metabolism. After a brief description of the skin architecture, this review will focus on the skin penetration mechanisms and skin metabolic capacities. The skin absorption has traditionally been tested in vivo on animals. However, with the new legislation (i.e., Registration, Evaluation, Authorisation, and Restriction of Chemicals Regulation or Cosmetics Regulation), alternatives to animal testing have to be implemented. In a second part, this review will provide a description of the main in vitro and in silico or computational models available to study skin absorption and skin metabolism (i.e., ex vivo skin models, artificial membrane barriers, primary cells and cell lines, Quantitative Structure-Activity Relationship [QSAR], simulators for the prediction of skin metabolism).

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…Various overviews of in silico models for dermal absorption of chemicals can also be found in the literature (Fitzpatrick et al, 2004;Geinoz et al, 2004;Moss et al, 2002;Dumont et al, 2015). However, to date none of the available models are deemed acceptable from a regulatory viewpoint (EFSA, 2012;OECD, 2011).…”

Skin-on-a-chip model simulating inflammation, edema and drug-based treatment

“…The proinflammatory factors IL-1β, IL-6, IL-8 and TNF-α play a key role in the initial phase of inflammation1314151617. Although tissue engineered skin and in vitro human skin models have been developed for a variety of applications, such as constructing skin-related disease models and assessing the penetration of chemicals or transdermal drugs during the past three decades7181920212223, it has been one of challenges to mimic skin disease model including inflammation and edema. Most of the current commercially available human skin models consist of integrated epidermal keratinocytes and dermal fibroblasts used for pharmaceutical testing in the epidermal or dermal compartment alone or in both72023242526.…”

Skin toxicology and 3Rs—Current challenges for public health protection

“…(Q)SAR models for skin sensitisation are either based on chemical class or mechanism, or are derived empirically using statistical approaches . Modelling of dermal absorption of chemicals has recently been improved by modelling the transport and disposition kinetics of chemical compounds in multilayered skin at the cellular level . Molecular dynamics simulation of chemical binding to keratin at the subcellular level can be used to model transport and disposition properties of epithelia .…”

“…[126,127] Modelling of dermal absorption of chemicals has recently been improved by modelling the transport and disposition kinetics of chemical compounds in multilayered skin at the cellular level. [128,129] Molecular dynamics simulation of chemical binding to keratin at the subcellular level can be used to model transport and disposition properties of epithelia. [130] This represents significant improvement to earlier permeability models that were not acceptable from a regulatory point of view.…”