Altex-Alternatives To Animal Experimentation最新文献

Systematic reviews (SRs) contribute to implementing the 3Rs in preclinical research. With the ever-increasing amount of scientific literature, SRs require increasing time investment. Thus, using the most efficient review tools is essential. Most available software tools aid the screening process; tools for data extraction and/or multiple review phases are relatively scarce. Using a single platform for all review phases allows auto-transfer of references from one phase to the next and enables work on multiple phases at the same time. We performed succinct formal tests of four multiphase review tools that are free or relatively affordable: Covidence, Eppi, SRDR+ and SYRF. Our tests comprised full-text screening, sham data extraction, and discrepancy resolution in the context of parts of a systematic review. Screening was performed as per protocol. Sham data extraction comprised free text, numerical and categorial data. Both reviewers logged their experiences with the platforms throughout. These logs were qualitatively summarized and supplemented with further user experi­ences. We show value of all tested tools in the SR process. Which tool is optimal depends on multiple factors, comprising previous experience with the tool but also review type, review questions, and review team member enthusiasm.

Chemical safety assessment still heavily relies on animal testing, which is associated with ethical dilemmas and has limited human predictive value. New approach methodologies (NAMs), including in vitro and in silico techniques, offer alternative solutions. In silico toxicology has made progress in predicting chemical effects but frequently lacks biological mechanistic founda­tions. Recent developments focus on the mechanistic understanding of adverse effects caused by chemicals, as embedded in (quantitative) adverse outcome pathways (AOPs). However, there is a demand for more detailed mechanistic insights at the gene and cell levels, encompassing both pathology and physiology. Drawing inspiration from the Disease Maps Project, this paper introduces physiological maps (PMs) as comprehensive graphical representations of biochemical processes related to specific organ functions. PMs are standardized using Systems Biology Graphical Notation (SBGN) and controlled vocabularies and annotations. Curation guidelines have been developed to ensure reproducibility and usability. We present the methodology used to build PMs, emphasizing the essential collaboration between domain experts and curators. PMs offer user-friendly, stand­ardized visualization for data analysis and educational purposes. Enabling a better understanding of (patho)physiology, they also complement and support the development of AOPs by providing detailed mechanistic information at the gene and cell level. Furthermore, PMs contribute to devel­oping in vitro test batteries and to building (dynamic) in silico models aiming to predict the toxicity of chemicals. Collaborative efforts between the toxicology and systems biology communities are crucial for creating standardized and comprehensive PMs, supporting and accelerating the devel­opment of human-relevant NAMs for next-generation risk assessment.

Reducing the number of animals required for a given experiment is part of the 3Rs strategies for animal welfare. Sample size estimation is a critical step in efficient and ethical experimental design. It is generally believed that pilot studies can be used to estimate sample sizes, which could lead to an overall reduction in the number of animals used. As part of the standard approach to ensuring that a planned animal experiment has sufficient statistical power, estimates of effect size and popu­lation variance are required. Here we derive the distribution of the sample size estimator when both effect size and variance are unknown. We show that, in this case, it is not feasible to conduct a pre­liminary pilot study to estimate the required sample size. Our analysis indicates that the sample size of a useful pilot study will often be much larger than that of the main study itself when the effect size is unknown. Therefore, we conclude that performing pilot studies with the aim of estimating sample size will not help to minimize the overall number of animal experiments in basic or pre-clinical research. A practical example is given, and alternative approaches are proposed and discussed.

Cell- and tissue-based test systems and reagents (e.g., cells, tissues, organs, reconstructed tissue models, or cell/tissue culture reagents) are increasingly being used in regulatory and non-regu­latory testing applications due to their ability to reflect human biology. These test systems and reagents may be shipped long distances, including across international borders, from the vendor to the testing laboratory. To ensure confidence in the data obtained from testing involving these systems and reagents, it is important for the testing laboratory to confirm that quality is maintained during the shipping process and that the materials can be used for their intended application (i.e., that the test method associated with the test system and/or reagent can be effectively transferred between laboratories). This paper describes various types of shipping studies that might be conducted when transferring a method to a new laboratory and key considerations for their design that can help maintain the quality of the test systems and reagents during the shipment process. Furthermore, emphasis is placed on the need for good communication between vendors, shipping agents, and end users to ensure efficient transferability of test methods.

Toxicological test methods generate raw data and provide instructions on how to use these to determine a final outcome such as a classification of test compounds as hits or non-hits. The data processing pipeline provided in the test method description is often highly complex. Usually, multiple layers of data, ranging from a machine-generated output to the final hit definition, are considered. Transition between each of these layers often requires several data processing steps. As changes in any of these processing steps can impact the final output of new approach methods (NAMs), the processing pipeline is an essential part of a NAM description and should be included in reporting templates such as the ToxTemp. The same raw data, processed in different ways, may result in different final outcomes that may affect the readiness status and regulatory acceptance of the NAM, as an altered output can affect robustness, performance, and relevance. Data management, pro­cessing, and interpretation are therefore important elements of a comprehensive NAM definition. We aim to give an overview of the most important data levels to be considered during the devel­opment and application of a NAM. In addition, we illustrate data processing and evaluation steps between these data levels. As NAMs are increasingly standard components of the spectrum of toxi­cological test methods used for risk assessment, awareness of the significance of data processing steps in NAMs is crucial for building trust, ensuring acceptance, and fostering the reproducibility of NAM outcomes.

Most complex in vitro models (CIVM) and microphysiological systems (MPS) are composed of human cells, with the goal of evaluating diseases, efficacy, safety, and pharmacokinetic ques­tions specifically for humans. The hope with CIVM/MPS is that they will eventually improve our predictivity of clinical responses and reduce or replace animal use in research, supporting the 3Rs concept of only using animals in research when necessary. Given the potential of animal-based models to advance this field by comparing existing in vivo animal data with new animal-based MPS responses, there are currently few CIVM and MPS utilizing animal tissues. Animal-based MPS may also have specific utility for cross-species comparisons or species-specific mechanistic questions on zoonotic diseases, and therapies for animals. Animal-based MPS may help expand in-vitro-to-in-vivo correlations, advance the field, and establish confidence in the predictive nature of such platforms. The IQ MPS-FDA workshop provided an interactive venue for pharmaceutical companies and regulatory agencies such as the U.S. Food and Drug Administration (FDA), NC3Rs (UK), Health Canada, NIH/NCATS, NIHS and PMDA (Japan), Danish Medicines Agency, European Com­mission, NIEHS/NICEATM, HHS, NIST, EURL ECVAM, and the IQ MPS Affiliate, a collaboration of pharmaceutical companies, to jointly discuss considerations of animal-based MPS and applica­tions where animal-based MPS are of potential value.

The effects of ten test chemicals on thyroid sodium-iodide symporter (NIS), thyroid peroxidase (TPO), and deiodinases (DIOs) type I, II, and III were evaluated and compared in in vitro rat and human systems. Test chemicals known to directly affect TH levels in vivo were confirmed to effectively inhibit at least one of the tested in vitro endpoints, without significant disparities between species, and the test compounds known to not affect thyroid function were found ineffective. Interestingly, iodide transport blocker 5, a potent non-competitive iodine uptake inhibitor, exhibited effects beyond direct NIS inhibition, impacting NIS function through ATP depletion, and also inhibited TPO and DIO1/ 2 enzymes, although to a lesser extent. Finally, of the four hepatic inducers known to affect thyroid function indirectly in rats through increased TH metabolism in the liver, dexamethasone, phenobarbital, and pregnenolone 16α-carbonitrile were found ineffective in the herein described inhibition tests, while rifampicin decreased rat and human TPO activities, suggesting a direct effect on thyroid function. This study demonstrates the usefulness of comparative data generated by rat and human in vitro NIS, TPO and DIOs test systems to support risk-based decisions.

The commitment to develop a roadmap for phasing out the use of animals for chemical safety assessments was part of the European Commission’s response to the European Citizens’ Initiative “Save Cruelty-Free Cosmetics – Commit to a Europe Without Animal Testing”. The roadmap aims to outline milestones and specific actions to be implemented in the short to long term to ultimately phase out animal testing for chemical safety assessments. To advance this goal and help define a structure of the roadmap, a multi-stakeholder roundtable workshop was organized by five animal protection non-governmental organizations in June 2024. The roundtable aimed to explore and define key elements and organizational structures for shaping the roadmap and identify pathways to facilitate the transition to a non-animal testing regulatory framework. Participants discussed a range of critical issues such as revising legislation and guidance, facilitating validation/qualification and regulatory acceptance, strengthening coordination, providing education and training in non-animal approaches, transparency and accessibility to data, establishing metrics to measure progress, and securing funding. The importance of a multi-faceted approach integrating scientific, regulatory, policy, ethical, societal, and practical dimensions was emphasized, along with the critical role of transdisciplinary collaboration and combining diverse knowledge, ideas, and technologies to achieve optimal outcomes. This report summarizes the main findings and discussion points and provides concrete recommendations. These are intended to facilitate the Commission’s work to develop the roadmap and may serve as a valuable resource for similar initiatives worldwide.