Consensus Report on the Future of Animal-Free Systemic Toxicity Testing

Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A general strategy for animal-free test approaches was outlined by the US National Research Council’s vision document for Toxicity Testing in the 21st Century in 2007. It is now possible to provide a more defined roadmap on how to implement this vision for the four principal areas of systemic toxicity evaluation: repeat dose organ toxicity, carcinogenicity, reproductive toxicity and allergy induction (skin sensitization), as well as for the evaluation of toxicant metabolism (toxicokinetics) (Fig. 1). CAAT-Europe assembled experts from Europe, America and Asia to design a scientific roadmap for future risk assessment approaches and the outcome was then further discussed and refined in two consensus meetings with over 200 stakeholders. The key recommendations include: focusing on improving existing methods rather than favoring de novo design; combining hazard testing with toxicokinetics predictions; developing integrated test strategies; incorporating new high content endpoints to classical assays; evolving test validation procedures; promoting collaboration and data-sharing of different industrial sectors; integrating new disciplines, such as systems biology and high throughput screening; and involving regulators early on in the test development process. A focus on data quality, combined with increased attention to the scientific background of a test method, will be important drivers. Information from each test system should be mapped along adverse outcome pathways. Finally, quantitative information on all factors and key events will be fed into systems biology models that allow a probabilistic risk assessment with flexible adaptation to exposure scenarios and individual risk factors

Advanced Non-animal Models in Biomedical Research: Breast Cancer

The European Commission's Joint Research Centre (JRC) has undertaken a study to review available and emerging non-animal models in the field of breast cancer. In this literature review around 120,000 scientific papers on breast cancer were screened and from those a total of 935 models were identified as being the most representative and promising. These models are based mainly on techniques that use cells and tissues cultured in the laboratory (in vitro), computer modelling and simulation (in silico) or cells and tissues explanted from a patient (ex vivo). This study has produced a unique and highly curated knowledge base that contains detailed descriptions of 935 non-animal models being used for breast cancer research. It is freely available to download and can serve the needs of multiple stakeholders: researchers, educators, funding bodies, and support the implementation of Directive 2010/63/EU on the protection of animals used for scientific purposes.JRC.F.3-Chemicals Safety and Alternative Method

Corrigendum to The need for strategic development of safety sciences

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The need for strategic development of safety sciences

The practice of risk assessment and regulation of substances has largely developed as a patchwork of circumstantial additions to a nowadays more or less shared international toolbox. The dominant drivers from the US and Europe have pursued remarkably different approaches in the use of these tools for regulation, i.e., a more risk-based approach in the US and a more precautionary approach in Europe. We argue that there is need for scientific developments not only for the tools but also for their application, i.e., a need for Regulatory Science or, perhaps better, Safety Science. While some of this is emerging on the US side as strategic reports, e.g., from the National Academies, the NIH and the regulatory agencies, especially the EPA and the FDA, such strategic developments beyond technological developments are largely lacking in Europe or have started only recently at EFSA, ECHA or within the flagship project EU-ToxRisk. This article provides a rationale for the creation of a European Safety Sciences Institute (ESSI) based on regulatory and scientific needs, political context and current EU missions. Moreover, the possible modus operandi of ESSI will be described along with possible working formats as well as anticipated main tasks and duties. This mirrors the triple alliance on the American side (US EPA, NIH and FDA) in revamping regulatory sciences. Moreover, this could fit the political agenda of the European Commission for better implementation of existing EU legislation rather than creating new laws.publishe

Can TTIP Improve Laboratory Animal Welfare in Safety Testing and 3Rs?

In the context of the current negotiations between the European Union (EU) and the United States under the Transatlantic Trade Investment Partnership (TTIP), there is the opportunity to look at both legislative frameworks to better pinpoint convergences, synergies, and gaps when it comes to use of laboratory animals for scientific purposes and bring together the best of both worlds. The objectives in this article are to indicate what are the current EU pieces of legislation that are relevant under TTIP regarding the uses of laboratory animals for scientific purposes under the regulations about cosmetics and chemicals, among others. The same approach will be taken to look at the relevant American legal frameworks, that is, the Food and Cosmetics Act and the Toxic Safety Control Act as well as its most recent reauthorization. In conclusion, the authors will identify future frameworks that can contribute to the harmonization of regulatory standards and further steps where TTIP negotiators should strengthen regulatory cooperation.publishe

Animal use for science in Europe

To investigate long-term trends of animal use, the EU animal use statistics from the 15 countries that have been in the EU since 1995 plus respective data from Switzerland were analyzed. The overall number of animals used for scientific purposes in these countries, i.e., about 11 million/year, remained relatively constant between 1995 and 2011, with net increases in Germany and the UK and net decreases in Belgium, Denmark, Italy, Finland, the Netherlands and Sweden. The relatively low and constant numbers of experimental animals used for safety assessment (toxicology, 8%) may be due to the particularly intensive research on alternative methods in this area. The many efficiently working NGOs, multiple initiatives of the European Parliament, and coordinated activities of industry and the European Commission may have contributed to keeping the animal numbers in this field in check. Basic biological science, and research and development for medicine, veterinary and dentistry together currently make up 65% of animal use in science. Although the total numbers have remained relatively constant, consumption of transgenic animals has increased drastically; in Germany transgenic animals accounted for 30% of total animal use in 2011. Therefore, more focus on alternatives to the use of animals in biomedical research, in particular on transgenic animals, will be important in the future. One initiative designed to provide inter-sector information exchange for future actions is the "MEP - 3Rs scientists pairing scheme" initiated in 2015 by CAAT-Europe and MEP Pietikäinen.publishe

Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines

The COVID-19-inducing virus, SARS-CoV2, is likely to remain a threat to human health unless efficient drugs or vaccines become available. Given the extent of the current pandemic (people in over one hundred countries infected) and its disastrous effect on world economy (associated with limitations of human rights), speedy drug discovery is critical. In this situation, past investments into the development of new (animal-free) approach methods (NAM) for drug safety, efficacy, and quality evaluation can be leveraged. For this, we provide an overview of repurposing ideas to shortcut drug development times. Animal-based testing would be too lengthy, and it largely fails, when a pathogen is species-specific or if the desired drug is based on specific features of human biology. Fortunately, industry has already largely shifted to NAM, and some public funding programs have advanced the development of animal-free technologies. For instance, NAM can predict genotoxicity (a major aspect of carcinogenicity) within days, human antibodies targeting virus epitopes can be generated in molecular biology laboratories within weeks, and various human cell-based organoids are available to test virus infectivity and the biological processes controlling them. The European Medicines Agency (EMA) has formed an expert group to pave the way for the use of such approaches for accelerated drug development. This situation illustrates the importance of diversification in drug discovery strategies and clearly shows the shortcomings of an approach that invests 95% of resources into a single technology (animal experimentation) in the face of challenges that require alternative approaches.publishe

Engagement of scientists with the public and policymakers to promote alternative methods

Scientists are usually good at teaching, sometimes even to lay audiences. But communicating with journalists, activists, or policymakers can be a different story – hesitancy to make mistakes as well as the temptation to disproportionally promote one’s own case come into play. The multitude of social media and other web-based outlets has diversified and accelerated the communication of science. Real-time reactions, sharing of data, tools and results, increasing invitation of personal opinion, demand for transparency, political correctness, and loss of trust in experts are challenges to researchers in general. The field of alternatives to animal testing is more political and important to lay audiences than many others, so its scientists must be especially aware of these challenges. Public engagement offers the opportunity to form community and create wide support for non-animal research and its implementation. This requires scientists to step out of the ivory tower of higher education and engage with diverse interest groups by outreach activities, interviews, and press releases, etc. by employing tailored communication.publishe

New European Union statistics on laboratory animal use : what really counts!

Seven years after the last release, the European Commission has again collated and released data on laboratory animal use. The new report is the first to correspond to the requirements of the new Directive 2010/63/EU. Beside minor problems in reporting, the new reporting format is a major step forward, with additional new categories like severity allowing insight into animal use related questions that goes far beyond the previous reports. An in-depth analysis confirms a slight decrease in animal use from 2015 to 2017, but also compared to the 2005, 2008 and 2011 reports, though the new reporting scheme makes this comparison difficult. Notable success is evident for replacing rabbit pyrogen testing but, in general, the implementation of accepted alternative methods lags behind expec-tations. Beside the roughly 10 million animals per year covered in the report, about 8 million animals were identified that fall under the Directive but are not included in this number. Their omission downplays the impact of REACH on animal use. The report, second to none in its detail internationally, represents an important instrument for benchmarking and strategi-cally focusing activities in the 3Rs.publishe

Template for the description of cell-based toxicological test methods to allow evaluation and regulatory use of the data

Only few cell-based test methods are described by Organisation for Economic Co-operation and Development (OECD) test guidelines or other regulatory references (e.g., the European Pharmacopoeia). The majority of toxicity tests still falls into the category of non-guideline methods. Data from these tests may nevertheless be used to support regulatory decisions or to guide strategies to assess compounds (e.g., drugs, agrochemicals) during research and development if they fulfill basic requirements concerning their relevance, reproducibility and predictivity. Only a method description of sufficient clarity and detail allows interpretation and use of the data. To guide regulators faced with increasing amounts of data from non-guideline studies, the OECD formulated Guidance Document 211 (GD211) on method documentation for the purpose of safety assessment. As GD211 is targeted mainly at regulators, it leaves scientists less familiar with regulation uncertain as to what level of detail is required and how individual questions should be answered. Moreover, little attention was given to the description of the test system (i.e., cell culture) and the steps leading to it being established in the guidance. To address these issues, an annotated toxicity test method template (ToxTemp) was developed (i) to fulfill all requirements of GD211, (ii) to guide the user concerning the types of answers and detail of information required, (iii) to include acceptance criteria for test elements, and (iv) to define the cells sufficiently and transparently. The fully annotated ToxTemp is provided here, together with reference to a database containing exemplary descriptions of more than 20 cell-based tests.publishe