Models of the outer epithelia of the human body - namely the skin, the intestine and the lung - have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

/pdf/non-animal-models-of-epithelial-barriers-skin-intestine-and-3rlrqitvsf.pdf

Non-Animal Models of Epithelial Barriers (Skin, Intestine and Lung) in Research, Industrial Applications and Regulatory Toxicology

One of the top priorities of the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) is the identification and evaluation of non-animal alternatives for skin sensitization testing. Although skin sensitization is a complex process, the key biological events of the process have been well characterized in an adverse outcome pathway (AOP) proposed by the Organisation for Economic Co-operation and Development (OECD). Accordingly, ICCVAM is working to develop integrated decision strategies based on the AOP using in vitro, in chemico and in silico information. Data were compiled for 120 substances tested in the murine local lymph node assay (LLNA), direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSens assay. Data for six physicochemical properties, which may affect skin penetration, were also collected, and skin sensitization read-across predictions were performed using OECD QSAR Toolbox. All data were combined into a variety of potential integrated decision strategies to predict LLNA outcomes using a training set of 94 substances and an external test set of 26 substances. Fifty-four models were built using multiple combinations of machine learning approaches and predictor variables. The seven models with the highest accuracy (89-96% for the test set and 96-99% for the training set) for predicting LLNA outcomes used a support vector machine (SVM) approach with different combinations of predictor variables. The performance statistics of the SVM models were higher than any of the non-animal tests alone and higher than simple test battery approaches using these methods. These data suggest that computational approaches are promising tools to effectively integrate data sources to identify potential skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Integrated decision strategies for skin sensitization hazard.

Predicting full thickness skin sensitization using a support vector machine.

OF THE DISSERTATION ........................................................................ii DEDICATION................................................................................................................... iv ACKNOWLEDGEMENTS .............................................................................................. v LIST OF TABLES ........................................................................................................... ix List of ILLUSTRATIONS ..............................................................................................xi ABBREVIATIONS ........................................................................................................xiii CHAPTER 1: INTRODUCTION..................................................................................... 1 1.1 CONTACT DERMATITIS ..................................................................................... 1 1.2 IN VIVO MECHANISM.......................................................................................... 3 1.3 SKIN SENSITIZERS ............................................................................................. 5 1.4 CURRENT SCREENING APPROACHES......................................................... 7 1.5 CURRENT LIMITATIONS AND CHALLENGES............................................. 15 1.6 MACHINE LEARNING.................................................................................... 18 1.7 DISSERTATION SUMMARY ............................................................................. 19 1.7 REFERENCES ................................................................................................ 21 CHAPTER 2: PREDICTING FULL THICKNESS SKIN SENSITZATION USING A SUPPORT VECTOR MACHINE........................................................................................... 27 2.

/pdf/classification-models-for-identifying-skin-sensitizers-using-4y53zb5vqo.pdf

Classification models for identifying skin sensitizers using in vitro alternatives to animal testing

In vitro methods that can replace animal testing in the identification of skin sensitisers are now a reality. However, as cell culture and related techniques usually rely on animal-derived products, these methods may be failing to address the complete replacement of animals in safety assessment. The objective of this study was to identify the animal-derived products that are used as part of in vitro methods for skin sensitisation testing. Thus, a systematic review of 156 articles featuring 83 different in vitro methods was carried out and, from this review, the use of several animal-derived products from different species was identified, with the use of fetal bovine serum being cited in most of the methods (78%). The use of sera from other animals, monoclonal antibodies and animal proteins were also variously mentioned. While non-animal alternatives are available and methods free of animal-derived products are emerging, most of the current methods reported used at least one animal-derived product, which raises ethical and technical concerns. Therefore, to deliver technically and ethically better in vitro methods for the safety assessment of chemicals, more effort should be made to replace products of animal origin in existing methods and to avoid their use in the development of new method protocols.

The Overt and Hidden Use of Animal-derived Products in Alternative Methods for Skin Sensitisation: A Systematic Review.

Most animal experiments on cosmetics safety are prohibited and since March 2013, this obligation includes sensitization tests. However, until now there has been no validated alternative in vitro method. In this work, 400 compounds used in the cosmetic industry were selected to cover the greatest diversity of structures, biological activities and sensitizing potential. These molecules were submitted to a series of tests aimed at reproducing essential steps in sensitization and to distinguish between sensitization and irritations, i.e., transcutaneous permeation (factor A), haptenation (factor B), sensitization cytokines production (factor C) and acute toxicity (factor D). The transcutaneous diffusion was measured on human skin explants using Franz cells. Haptenation was tested in solution on human serum albumin. Sensitization cytokine production was investigated by measurement of interleukin-18 release by keratinocytes. Acute toxicity was determined using an 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(75) cell viability test. As only sufficiently stable, soluble and detectable compounds are usable, 33, 72, 68 and 68 molecules were finally tested on factors A, B, C and D, respectively, and 32 were completely screened by the four factors. The individual correlation of the four factors with the reference in vivo tests was limited but the combination of these factors led to a correlation between in vivo and in vitro assays of 81.2% and the safety of the test (risk of false negative) reached 96.8%. The techniques employed are simple and inexpensive and this model of four tests appears as a promising technique to evaluate in vitro the skin sensitization potential of unknown molecules.

Development of a multiparametric in vitro model of skin sensitization

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Development of a multiparametric in vitro model of skin sensitization