With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

https://www.wellbeingintlstudiesrepository.org/cgi/viewcontent.cgi?article=1109&context=acwp_arte

Toxicity testing in the 21st century: a vision and a strategy

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

/pdf/alternative-non-animal-methods-for-cosmetics-testing-current-u3dtxjb56j.pdf

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

Methods of in vitro toxicology.

From 1996 to 2000, ZEBET (Centre for Documentation and Evaluation of Alternative Methods to Animal Experiments at the BgVV, Berlin, Germany) coordinated the European Centre for the Validation of Alternative Methods (ECVAM) prevalidation and validation study on three embryotoxicity tests: a) a test employing embryonic stem cell lines (EST); b) the micromass (MM) test; and c) the postimplantation rat whole-embryo culture assay (WEC test). The main objectives of the study were to assess the performance of these three in vitro tests in discriminating between non- embryotoxic, weakly embryotoxic and strongly embryotoxic compounds. Phase I of the study (1997) was designed as a prevalidation phase, for test protocol optimisation, and for the establishment of a comprehensive database of in vivo and in vitro data on embryotoxic compounds. Phase II (1998-2000) involved a formal validation trial, conducted under blind conditions on 20 test compounds selected from the database, which were coded and distributed to the participating laboratories. In the preliminary phase of the validation study, six chemicals out of the 20, which showed embryotoxic potential, were tested. These results were used to define new biostatistically based prediction models (PMs) for the MM and WEC tests, and to evaluate those developed previously for the EST. As a next step, the PMs were evaluated by using the results for the remaining 14 chemicals of the definitive phase of the validation study. The three in vitro embryotoxicity tests proved to be applicable to testing a diverse group of chemicals with different embryotoxic potentials (non-embryotoxic, weakly embryotoxic, and strongly embryotoxic). The reproducibility of the three in vitro embryotoxicity tests were acceptable according to the acceptance criteria defined by the Management Team. The concordances between the embryotoxic potentials derived from the in vitro data and from the in vivo data were good for the EST and the WEC (PM2) test, and sufficient for the MM test and the WEC (PM1) tests according to the performance criteria defined by the Management Team before the formal validation study. When applying the PM of the EST to the in vitro data obtained in the definitive phase of the formal validation study, chemicals were classified correctly in 78% of the experiments. For the MM and the WEC tests, the PMs provided 70% and 80% (PM2) correct classifications, respectively. And, very importantly, an excellent predictivity (100%, except for PM1 of the WEC test, with 79%, considered as good) was obtained with strong embryotoxic chemicals in each of the three in vitro tests.

The ECVAM international validation study on in vitro embryotoxicity tests: results of the definitive phase and evaluation of prediction models. European Centre for the Validation of Alternative Methods

The currently developed and validated in vitro tests for female and male fertility and also for developmental toxicity are described and evaluated according to their potential use as screening or replacement alternatives to the established in vivo tests in reproductive and developmental toxicology. Alternative methods today can only be used to evaluate a few specific components of the integrated reproductive functions in both females and males. However, in the field of developmental toxicity testing there is a strong theoretical and empirical basis for the predictive power of in vitro screens using mammalian embryos as well as embryonic cells and tissues. Several of these assays have been validated or are currently undergoing validation in several laboratories and are > 80% concordant with in vivo results. Failure to achieve 100% accuracy reflects the inherent limitations of these systems, which are manageable, as the concordance rates are still good. The level of concordance suggests that these assays are adequate for screening purposes to complement traditional in vivo testing. The use of these assays as screens will save valuable in vivo testing resources for those compounds most likely to enter the market and to which people will be exposed.

Reproduction and development.

MRC Experimental Embryology and Teratology Unit, St. George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK; ZEBET, BgW, Diedersd01fer Weg 1, 12277 Berlin, Germany; Sandoz Pharma Limited, Drug Safety Assessment, 4002 Basle, Switzerland; Bristol-Myers Squibb, Pharmaceutical Research Institute, 6000 Thompson Road, Syracuse, NY 13221, USA; 7SmithKline Beecham Consumer Healthcare, StGeorge's Avenue, Weybridge, Surrey KT13 ODE, UK; 8Department of Histology and Emb1yology, 3rd Medical Faculty, Charles University, Ruska 87, 100 00 Prague 10, Czech Republic; Freie University of Berlin, Institute for Toxicology and Emb1yopharmacology, Gmystrasse 5, 1000 Berlin 33, Germany; GlaxoWellcome Research and Development, Genetic and Repl'Oductive Toxicology, Ware, Herts. SG12 ODP, UK,· 11Huntin;;don Research Centre, Department of Toxicology, Huntingdon, Cambs. PElS 6ES, UK; RhOne-Poulenc Rorer, Drug Safety NW 9, 500 Arcola Road, Collegeville, PA 19426-0107, USA; 1•1Rh6ne-Poulenc, Secteur Agro, 06903 Sophia Antipolis Cedex, France; BgVV, Thielallee 88-92, 14191 Berlin, Germany; 15National Institute of Public Health, Department of Environmental Medicine, Geitmyrsveien 75, 0462 Oslo 4, Norway

Screening Chemicals for Reproductive Toxicity: The Current Alternatives: The Report and Recommendations of an ECVAM/ETS Workshop (ECVAM Workshop 12)1,2

Toxicokinetics and metabolism.

In vitro methods in toxicology: Sub-mammalian and sub-vertebrate models in teratogenicity screening

The remit of this Working Party was to review and assess the current scientific and regulatory requirements in the field of reproductive toxicology. Attention was given to compliance with the Three Rs in current testing methods and the achievement of reduction, refinement and replacement in animal testing by both current methods and research development. This report will comprise three sections covering regulatory aspects, in vitro and in vivo prescreens, and research. Recommendations are listed at the end of each section, and a list of specific recommendations is included at the end of the report, which are directed at industry and the regulatory authorities for their consideration.

Stuart J. Freeman

Papers

Screening Chemicals for Reproductive Toxicity: The Current Alternatives: The Report and Recommendations of an ECVAM/ETS Workshop (ECVAM Workshop 12)1,2

Toxicokinetics and metabolism.

In vitro methods in toxicology: Sub-mammalian and sub-vertebrate models in teratogenicity screening

The Future of Alternative Approaches in Reproductive Toxicity Testing