Sarah AdlerDavid BasketterStuart CretonOlavi PelkonenJan van BenthemValerie Zuang • Klaus Ejner AndersenAlexandre Angers-LoustauAynur AptulaAnna Bal-PriceEmilio Benfenati • Ulrike BernauerJos BessemsFrederic Y. BoisAlan BoobisEsther BrandonSusanne Bremer • Thomas BroschardSilvia CasatiSandra CoeckeRaffaella CorviMark CroninGeorge Daston • Wolfgang DekantSusan FelterElise GrignardUrsula Gundert-RemyTuula HeinonenIan Kimber • Jos KleinjansHannu KomulainenReinhard KreilingJoachim KreysaSofia Batista LeiteGeorge Loizou • Gavin MaxwellPaolo MazzatortaSharon MunnStefan PfuhlerPascal PhrakonkhamAldert Piersma • Albrecht PothPilar PrietoGuillermo RepettoVera RogiersGreet SchoetersMichael Schwarz • Rositsa SerafimovaHanna TahtiEmanuela TestaiJoost van DelftHenk van LoverenMathieu Vinken • Andrew WorthJose ´-Manuel Zaldivar

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Alternative (non-animal) methods for cosmetics testing: current status and future prospects—2010

In the embryonic stem cell test (EST), differentiation of mouse embryonic stem cells (mESCs) is used as a model to assess embryotoxicity in vitro. The test was successfully validated by the European Center for the Validation of Alternative Methods (ECVAM) and models fundamental mechanisms in embryotoxicity, such as cytotoxicity and differentiation. In addition, differences in sensitivity between differentiated (adult) and embryonic cells are also taken into consideration. To predict the embryotoxic potential of a test substance, three endpoints are assessed: the inhibition of differentiation into beating cardiomyocytes, the cytotoxic effects on stem cells and the cytotoxic effects on 3T3 fibroblasts. A special feature of the EST is that it is solely based on permanent cell lines so that primary embryonic cells and tissues from pregnant animals are not needed. In this protocol, we describe the ECVAM-validated method, in which the morphological assessment of contracting cardiomyocytes is used as an endpoint for differentiation, and the molecular-based FACS-EST method, in which highly predictive protein markers specific for developing heart tissue were selected. With these methods, the embryotoxic potency of a compound can be assessed in vitro within 10 or 7 d, respectively.

The validated embryonic stem cell test to predict embryotoxicity in vitro

Significant advances in biomaterials, stem cell biology, and microscale technologies have enabled the fabrication of biologically relevant tissues and organs. Such tissues and organs, referred to as organ-on-a-chip (OOC) platforms, have emerged as a powerful tool in tissue analysis and disease modeling for biological and pharmacological applications. A variety of biomaterials are used in tissue fabrication providing multiple biological, structural, and mechanical cues in the regulation of cell behavior and tissue morphogenesis. Cells derived from humans enable the fabrication of personalized OOC platforms. Microscale technologies are specifically helpful in providing physiological microenvironments for tissues and organs. In this review, biomaterials, cells, and microscale technologies are described as essential components to construct OOC platforms. The latest developments in OOC platforms (e.g., liver, skeletal muscle, cardiac, cancer, lung, skin, bone, and brain) are then discussed as functional tools in simulating human physiology and metabolism. Future perspectives and major challenges in the development of OOC platforms toward accelerating clinical studies of drug discovery are finally highlighted.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/adhm.201800734

Organ-On-A-Chip Platforms: A Convergence of Advanced Materials, Cells, and Microscale Technologies.

Predicting human developmental toxicity of pharmaceuticals using human embryonic stem cells and metabolomics.

The use of novel drugs and chemicals requires reliable data on their potential toxic effects on humans. Current test systems are mainly based on animals or in vitro–cultured animal-derived cells and do not or not sufficiently mirror the situation in humans. Therefore, in vitro models based on human pluripotent stem cells (hPSCs) have become an attractive alternative. The article summarizes the characteristics of pluripotent stem cells, including embryonic carcinoma and embryonic germ cells, and discusses the potential of pluripotent stem cells for safety pharmacology and toxicology. Special attention is directed to the potential application of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for the assessment of developmental toxicology as well as cardio- and hepatotoxicology. With respect to embryotoxicology, recent achievements of the embryonic stem cell test (EST) are described and current limitations as well as prospects of embryotoxicity studies using pluripotent stem cells are discussed. Furthermore, recent efforts to establish hPSC-based cell models for testing cardio- and hepatotoxicity are presented. In this context, methods for differentiation and selection of cardiac and hepatic cells from hPSCs are summarized, requirements and implications with respect to the use of these cells in safety pharmacology and toxicology are presented, and future challenges and perspectives of using hPSCs are discussed.

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Present state and future perspectives of using pluripotent stem cells in toxicology research

The new European chemicals policy for the Registration, Evaluation, Authorisation and Restriction of Chemicals (the REACH system), requires the routine toxicological testing of chemicals produced in volumes of more than one tonne per year, in order to enhance environmental and consumer safety (1). Under the REACH system policy, it will be most probably necessary to test several thousand chemicals for their toxicological properties.

A review of the implementation of the embryonic stem cell test (EST). The report and recommendations of an ECVAM/ReProTect Workshop.

List of Abbreviations Introduction Foreword Chapter 1: Cosmetic Products and their Current Regulatory Framework Introduction The Cosmetic Products Directive Relevant 'Vertical' EU Legislations Relevant 'Horizontal' EU Legislations References Chapter 2: Challenges Related to Cosmetic Safety Assessment in the EU Introduction Relevant Features of the General EU Risk Assessment Paradigm Actual Challenges for the European Cosmetic Safety Assessor References Chapter 3: Critical Analysis of the Safety Assessment of Cosmetic Ingredients Performed at the European Level Introduction General Analysis of Published SCC(NF)P Opinions (2000-2006) Analysis of Three Contentious Areas in the EU Safety Assessment of Cosmetic Ingredients Discussion and Conclusions References Chapter 4: Safety Assessment of Cosmetic Ingredients Present in Technical Information Files of Finished Products Introduction Database Search for Safety Information on Cosmetic Ingredients Risk Assessment of Cosmetic Ingredients in Finished Cosmetic Products in the EU Discussion and Conclusions References Chapter 5: The Cosmetic Technical Information File in Practice Introduction The Legal Requirements in Practice: a Proposal Some Practical Remarks Proposed Framework for a TIF Discussion and Conclusions References Chapter 6: The Use of Alternative Methods in the Safety Assessment of Cosmetic Ingredients Introduction Materials and Methods Animal Testing and 3-R Alternatives in SCC(NF)P Dossiers Cosmetic Animal Numbers Placed into Perspective Discussion and Conclusions References Chapter 7: Headlines of Safety Assessment of Cosmetics in Europe and Future Perspectives Appendices The Transposition of Directive 76/768/EEC into Belgian Law: a Practical Example Proposed Framework for a Cosmetic Technical Information File Data Input Forms Subject Index.

Safety Assessment of Cosmetics in Europe

This is the report of the twenty-seventh of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). ECVAMs main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures which would enable it to become well-informed about the state-of-the-art of non-animal test development and validation, and the potential for the possible incorporation of alternative tests into regulatory procedures. It was decided that this would be best achieved by the organisation of ECVAM workshops on specific topics, at which small groups of invited experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward (1). The workshop on Issues Relating to the Release of Proprietary Information and Data for Use in the Validation of Alternative Methods was held in Munich, Germany, on 911 May 1997, under the co-chairmanship of Martin Todd (ZENECA Pharmaceuticals, Macclesfield, UK) and Bernward Garthoff (Bayer, Leverkusen, Germany). The main Issues Relating to the Release of Proprietary Information and Data for Use in the Validation of Alternative Methods The Report and Recommendations of ECVAM Workshop 27

Vera Rogiers

Papers

A review of the implementation of the embryonic stem cell test (EST). The report and recommendations of an ECVAM/ReProTect Workshop.

Safety Assessment of Cosmetics in Europe

Issues relating to the release of proprietary information and data for use in the validation of alternative methods.

The Impact of REACH, The report of the CONAM / ecopa Chemical Policy Working Group.

The current regulatory context in the European Union