Barbara Grune

Alternatives to animal testing: current status and future perspectives

On the occasion of the 20th anniversary of the Center for Alternative Methods to Animal Experiments (ZEBET), an international symposium was held at the German Federal Institute for Risk Assessment (BfR) in Berlin. At the same time, this symposium was meant to celebrate the 50th anniversary of the publication of the book “The Principles of Humane Experimental Technique” by Russell and Burch in 1959 in which the 3Rs principle (that is, Replacement, Reduction, and Refinement) has been coined and introduced to foster the development of alternative methods to animal testing. Another topic addressed by the symposium was the new vision on “Toxicology in the twenty-first Century”, as proposed by the US-National Research Council, which aims at using human cells and tissues for toxicity testing in vitro rather than live animals. An overview of the achievements and current tasks, as well as a vision of the future to be addressed by ZEBET@BfR in the years to come is outlined in the present paper.

Successful validation of in vitro methods in toxicology by ZEBET, the National Centre for Alternatives in Germany at the BfR (Federal Institute for Risk Assessment).

A short description of the history of the 3Rs concept is given, which was developed as the scientific concept to refine, reduce and replace animal experiments by Russel and Burch more than 40 years ago. In addition, the legal framework in Europe for developing alternatives to animal experiments is given and the current status of in vitro systems in pharmacology and toxicology is described including an update on metabolising systems. The decrease in experimental animal numbers during the past decade in Europe is illustrated by the situation in Germany and the contribution of international harmonisation of test guidelines on reducing animal numbers in regulatory testing is described. A review of the development of the principles of experimental validation is given and the 3T3 NRU in vitro phototoxicity test is used as an example for a successful validation study, which led to the acceptance of the first in vitro toxicity test for regulatory purposes by the OECD. Finally, the currently accepted alternative methods for standardisation and safety testing of drugs, biologicals and medical devices are summarised.

A knowledge-based search engine to navigate the information thicket of nanotoxicology

The risk assessment of nano-sized materials (NM) currently suffers from great uncertainties regarding their putative toxicity for humans and the environment. An extensive amount of the respective original research literature has to be evaluated before a targeted and hypothesis-driven Environmental and Health Safety research can be stipulated. Furthermore, to comply with the European animal protection legislation in vitro testing has to be preferred whenever possible. Against this background, there is the need for tools that enable producers of NM and risk assessors for a fast and comprehensive data retrieval, thereby linking the 3Rs principle to the hazard identification of NM. Here we report on the development of a knowledge-based search engine that is tailored to the particular needs of risk assessors in the area of NM. Comprehensive retrieval of data from studies utilising in vitro as well as in vivo methods relying on the PubMed database is presented exemplarily with a titanium dioxide case study. A fast, relevant and reliable information retrieval is of paramount importance for the scientific community dedicated to develop safe NM in various product areas, and for risk assessors obliged to identify data gaps, to define additional data requirements for approval of NM and to create strategies for integrated testing using alternative methods.

Considerations for a European animal welfare standard to evaluate adverse phenotypes in teleost fish

The EU Directive on the use animals in research requires scientists to assess and document pain, distress or lasting harm of genetically modified animals. This article proposes a detailed protocol and guidelines for assessing adverse phenotypes in teleost fish, an important model organism for biomedical research.

The animal experimentation quandary: stuck between legislation and scientific freedom More research and engagement by scientists is needed to help to improve animal welfare without hampering biomedical research

Existing national and EU regulations and laws to protect animal welfare are being challenged by the increasing importance and use of genetically modified animals in biomedical research. Scientists, veterinarians, lawyers and regulatory authorities need to adapt these laws to improve animal welfare in research while not hindering medical progress.

Rethinking 3R strategies: Digging deeper into AnimalTestInfo promotes transparency in in vivo biomedical research

In the European Union (EU), animal welfare is seen as a matter of great importance. However, with respect to animal experimentation, European citizens feel quite uninformed. The European Directive 2010/63/EU for the protection of laboratory animals aims for greater transparency and requires that a comprehensible, nontechnical summary (NTS) of each authorised research project involving animals is published by the respective Member State. However, the NTSs remain sleeping beauties if their contents are not easily and systematically accessible. The German web-based NTS database AnimalTestInfo is a unique channel for scientists to communicate their work, and provides the opportunity for large-scale analyses of planned animal studies to inform researchers and the public. For an in-depth meta-analysis, we classified the duly completed NTSs submitted to AnimalTestInfo in 2014 and 2015 according to the International Classification of Diseases and Related Health Problems (ICD) system. Indexing the NTSs with ICD codes provided a fine-grained overview of the prospective uses of experimental animals. Using this approach, transparency, especially for highly controversial animal research involving, for example, nonhuman primates, is fostered, as it enables pinpointing the envisaged beneficiary down to the level of the addressed disease. Moreover, research areas with many planned projects involving animals can be specified in detail. The development of 3R (replacement, reduction, and refinement) measures in these research areas may be most efficient, as a large number of experimental animals would benefit from it. Indexing NTSs with ICD codes can support governments and funding agencies in advancing target-oriented funding of 3R research. Data drawn from NTSs can provide a basis for the development, validation, and implementation of directed 3R strategies as well as guidance for rethinking the role of animal research models.

The Advent of the Golden Era of Animal Alternatives

Abstract The first years of the 21 st century have seen an unparalleled progress in biomedical sciences. Several dogmata that haunted scientific debate for decades were easily abandoned, and there is a fundamental shift away from eminence-based toward evidence-based assessment of preclinical models, probing their true value in predicting clinical outcomes of human diseases. Likewise, several new approaches, e.g., stem cell-based, diseases-in-a-dish and organs-on-a-chip and lab-on-a-chip technologies have revitalized the domain of alternatives to animal experimentation. In our review, we portray these and other efforts to bring forth relevant and ethically inoffensive models of human diseases.

Procedure for indexing NTS with ICD-10 codes, published in German

The general public shall be informed about planned animal experiments by non-technical summaries (NTSs) as stipulated in the European Directive 2010/63/EU. In Germany, NTS are made available in the searchable, web-based database AnimalTestInfo. In our meta-analysis, we classified duly completed German NTSs submitted in 2014 and 2015 to AnimalTestInfo according to the ‘International Classification of Diseases and Related Health Problems’ (ICD) system. Here, we present the standardised procedure for indexing NTSs with ICD-10 codes in German.

Allocated ICD-10 codes to each NTS submitted to AnimalTestInfo in 2014 and 2015

The AnimalTestInfo database was developed in Germany to make non-technical summaries (NTSs) available in a searchable, web-based format in order to address the requirements stipulated in the European Directive 2010/63/EU regarding transparency and publication of animal experiments. In our meta-analysis, we classified duly completed NTSs submitted in 2014 and 2015 to AnimalTestInfo according to the ‘International Classification of Diseases and Related Health Problems’ (ICD) system. This dataset contains the allocated ICD-10 codes for each NTS submitted to AnimalTestInfo in 2014 and 2015, sorted by year and month.