title: Stem cell-derived systems in toxicology assessment.
abstract: Industrial sectors perform toxicological assessments of their potential products to ensure human safety and to fulfill regulatory requirements. These assessments often involve animal testing, but ethical, cost, and time concerns, together with a ban on it in specific sectors, make appropriate in vitro systems indispensable in toxicology. In this study, we summarize the outcome of an EPAA (European Partnership of Alternatives to Animal Testing)-organized workshop on the use of stem cell-derived (SCD) systems in toxicology, with a focus on industrial applications. SCD systems, in particular, induced pluripotent stem cell-derived, provide physiological cell culture systems of easy access and amenable to a variety of assays. They also present the opportunity to apply the vast repository of existing nonclinical data for the understanding of in vitro to in vivo translation. SCD systems from several toxicologically relevant tissues exist; they generally recapitulate many aspects of physiology and respond to toxicological and pharmacological interventions. However, focused research is necessary to accelerate implementation of SCD systems in an industrial setting and subsequent use of such systems by regulatory authorities. Research is required into the phenotypic characterization of the systems, since methods and protocols for generating terminally differentiated SCD cells are still lacking. Organotypical 3D culture systems in bioreactors and microscale tissue engineering technologies should be fostered, as they promote and maintain differentiation and support coculture systems. They need further development and validation for their successful implementation in toxicity testing in industry. Analytical measures also need to be implemented to enable compound exposure and metabolism measurements for in vitro to in vivo extrapolation. The future of SCD toxicological tests will combine advanced cell culture technologies and biokinetic measurements to support regulatory and research applications. However, scientific and technical hurdles must be overcome before SCD in vitro methods undergo appropriate validation and become accepted in the regulatory arena.
authors: 1University of Applied Sciences Northwestern Switzerland, School of Life Sciences, Muttenz, Switzerland.
authors: Laura
authors: L
authors: Suter-Dick
authors: 2iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.|3Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
authors: Paula M
authors: PM
authors: Alves
authors: 4Division of Toxicology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, the Netherlands.
authors: Bas J
authors: BJ
authors: Blaauboer
authors: 5Bayer Pharma AG, Global Drug Discovery-Global Early Development, Wuppertal, Germany.
authors: Klaus-Dieter
authors: KD
authors: Bremm
authors: 2iBET, Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.|3Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
authors: Catarina
authors: C
authors: Brito
authors: 6European Commission Joint Research Centre, Institute for Health and Consumer Protection, EURL ECVAM, Ispra, Italy.
authors: Sandra
authors: S
authors: Coecke
authors: 7BASF SE, Experimental Toxicology and Ecology, Ludwigshafen, Germany.
authors: Burkhard
authors: B
authors: Flick
authors: Paul
authors: P
authors: Fowler
authors: 9Institut for Neurophysiology, University of Cologne, Cologne, Germany.
authors: Jürgen
authors: J
authors: Hescheler
authors: 10Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors: Magnus
authors: M
authors: Ingelman-Sundberg
authors: 11Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Austria.
authors: Paul
authors: P
authors: Jennings
authors: 12InSphero AG, Schlieren, Switzerland.
authors: Jens M
authors: JM
authors: Kelm
authors: 13European Partnership for Alternative Approaches to Animal Testing (EPAA), B-Brussels, Belgium.
authors: Irene
authors: I
authors: Manou
authors: 14Syngenta Ltd., Product Safety, Jealott's Hill International Research Station, Berkshire, United Kingdom.
authors: Pratibha
authors: P
authors: Mistry
authors: 15Dipartimento di Scienze Biochimiche e Cliniche, Università degli Studi di Milano, Milano, Italy.|16Centro Internazionale per gli Antiparassitari e la Prevenzione Sanitaria, Luigi Sacco Hospital, Milano, Italy.
authors: Angelo
authors: A
authors: Moretto
authors: 17F. Hoffmann-La Roche Ltd., Innovation Center Basel, Pharmaceutical Sciences, Basel, Switzerland.
authors: Adrian
authors: A
authors: Roth
authors: 18Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
authors: Donald
authors: D
authors: Stedman
authors: 19Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands.
authors: Bob
authors: B
authors: van de Water
authors: Mario
authors: M
authors: Beilmann
mesh_terms: D000818:Animals; D003114:Colony-Forming Units Assay / Q000379:methods; D046508:Culture Techniques / Q000379:methods*; D006801:Humans; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014116:Toxicology / Q000379:methods*