Report of the First ONTOX Stakeholder Network Meeting: Digging Under the Surface of ONTOX Together With the Stakeholders.

The first Stakeholder Network Meeting of the EU Horizon 2020-funded ONTOX project was held on 13-14 March 2023, in Brussels, Belgium. The discussion centred around identifying specific challenges, barriers and drivers in relation to the implementation of non-animal new approach methodologies (NAMs) and probabilistic risk assessment (PRA), in order to help address the issues and rank them according to their associated level of difficulty. ONTOX aims to advance the assessment of chemical risk to humans, without the use of animal testing, by developing non-animal NAMs and PRA in line with 21st century toxicity testing principles.

Pollutant exposure and myocardial injury: Protocol and progress report for a toxicological systematic mapping review.

An increasing body of evidence identifies pollutant exposure as a risk factor for cardiovascular disease (CVD), while CVD incidence is rising steadily with the aging population. Although numerous experimental studies are now available, the mechanisms through which lifetime exposure to envi­ronmental pollutants can result in CVD are not fully understood. To comprehensively describe and understand the pathways through which pollutant exposure leads to cardiotoxicity, a systematic mapping review of the available toxicological evidence is needed.

The 3Ranker: An AI-based Algorithm for Finding Non-animal Alternative Methods.

The search for existing non-animal alternative methods for use in experiments is currently challenging because of the lack of both comprehensive structured databases and balanced keyword-based search strategies to mine unstructured textual databases. In this paper we describe 3Ranker, which is a fast, keyword-independent algorithm for finding non-animal alternative methods for use in biomedical research. The 3Ranker algorithm was created by using a machine learning approach, consisting of a Random Forest model built on a dataset of 35 million abstracts and constructed with weak supervision, followed by iterative model improvement with expert curated data.

Reporting of 3Rs Approaches in Preclinical Animal Experimental Studies-A Nationwide Study.

The 3Rs aim to refine animal welfare, reduce animal numbers, and replace animal experiments. Investigations disclose that researchers are positive towards 3Rs recommendations from peers. Communication of 3Rs approaches via primary preclinical animal experimental literature may become a fast-forward extension to learn relevant 3Rs approaches if such are reported.

Establishing a health-based recommended occupational exposure limit for isoflurane using experimental animal data: a systematic review protocol.

Background: Isoflurane is used as an inhalation anesthetic in medical, paramedical, and veterinary practice. Epidemiological studies suggest an increased risk of miscarriages and malformations at birth related to maternal exposure to isoflurane and other inhalation anesthetics. However, these studies cannot be used to derive an occupational exposure level (OEL), because exposure was not determined quantitatively and other risk factors such as co-exposures to other inhalation anesthetics and other work-related factors may also have contributed to the observed adverse outcomes.

Comparing translational success rates across medical research fields - A combined analysis of literature and clinical trial data.

Many interventions that show promising results in preclinical development do not pass clinical tests. Part of this may be explained by poor animal-to-human translation. Using animal models with low predictability for humans is neither ethical nor efficient.

From critical appraisal to risk of bias assessment: clarifying the terminology for study evaluation in JBI systematic reviews.

The foundations for critical appraisal of literature have largely progressed through the development of epidemiologic research methods and the use of research to inform medical teaching and practice. This practical application of research is referred to as evidence-based medicine and has delivered a standard for the health care profession where clinicians are equally as engaged in conducting scientific research as they are in the practice of delivering treatments. Evidence-based medicine, now referred to as evidence-based health care, has generally been operationalized through empirically supported treatments, whereby the choice of treatments is substantiated by scientific support, usually by means of an evidence synthesis.

Methodological quality assessment should move beyond design specificity.

Objective: This study aimed to assess the utility of a unified tool (MASTER) for bias assessment against design-specific tools in terms of content and coverage.

Methods: Each of the safeguards in the design-specific tools was compared and matched to safeguards in the unified MASTER scale. The design-specific tools were the JBI, Scottish Intercollegiate Guidelines Network (SIGN), and the Newcastle-Ottawa Scale (NOS) tools for analytic study designs.

Recommendations for robust and reproducible preclinical research in personalised medicine.

Background: Personalised medicine is a medical model that aims to provide tailor-made prevention and treatment strategies for defined groups of individuals. The concept brings new challenges to the translational step, both in clinical relevance and validity of models. We have developed a set of recommendations aimed at improving the robustness of preclinical methods in translational research for personalised medicine.

Protocol for a systematic review of good surgical practice guidelines for experimental rodent surgery.

Objective: Surgery is an integral part of many experimental studies. Aseptic and minimal invasive surgical technique and optimal perioperative and post-operative care are prerequisites to achieve surgical success and best possible animal welfare outcomes. Good surgical practice cannot only improve the animal's postoperative recovery, but also study outcome and validity.

Reporting quality in preclinical animal experimental research in 2009 and 2018: A nationwide systematic investigation.

Lack of translation and irreproducibility challenge preclinical animal research. Insufficient reporting methodologies to safeguard study quality is part of the reason. This nationwide study investigates the reporting prevalence of these methodologies and scrutinizes the reported information's level of detail.

Identifying Key Factors for Accelerating the Transition to Animal-Testing-Free Medical Science through Co-Creative, Interdisciplinary Learning between Students and Teachers.

Even with the introduction of the replacement, reduction, refinement (the three Rs) approach and promising technological developments in animal-testing-free alternatives over the past two decades, a significant number of animal tests are still performed in medical science today. This article analyses which factors could accelerate the transition to animal-free medical science, applying the multi-level perspective (MLP) framework. The analysis was based on qualitative research, including a desk study (literature review and document analysis), lectures from experts, and nine online focus group sessions with experts on 26 July 2021.

A History of Regulatory Animal Testing: What Can We Learn?

The contemporary pharmaceutical industry is voicing growing concerns about the translatability and reproducibility of animal models. In addition, the usefulness of certain of the required regulatory safety tests in animals is being increasingly questioned. It remains difficult, however, to make the move toward alternative testing methods, not least because of legislative demands.

The Promises of Speeding Up: Changes in Requirements for Animal Studies and Alternatives during COVID-19 Vaccine Approval-A Case Study.

On 21 December 2020, the European Commission granted conditional marketing authorisation for the BNT162b2 COVID-19 vaccine 'Comirnaty', produced by Pfizer/BioNTech. This happened only twelve months after scientists first identified SARS-CoV-2. This stands in stark contrast with the usual ten years needed for vaccine development and approval.

The impact of conducting preclinical systematic reviews on researchers and their research: A mixed method case study.

Background: Systematic reviews (SRs) are cornerstones of evidence-based medicine and have contributed significantly to breakthroughs since the 1980's. However, preclinical SRs remain relatively rare despite their many advantages. Since 2011 the Dutch health funding organisation (ZonMw) has run a grant scheme dedicated to promoting the training, coaching and conduct of preclinical SRs.

A health-based recommended occupational exposure limit for nitrous oxide using experimental animal data based on a systematic review and dose-response analysis.

Background: Nitrous oxide (NO) is a common inhalation anaesthetic used in medical, paramedical, and veterinary practice. Since the mid 1950's, concerns have been raised regarding occupational exposure to NO, leading to many epidemiological and experimental animal studies. Previous evaluations resulted in the classification of NO as a possible risk factor for adverse reproductive health outcomes based on animal data.

Introduction to the EQIPD quality system.

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions.

Effects of sleep deprivation on maternal behaviour in animal models: A systematic review and meta-analysis.

Pregnancy is a period of numerous physical and emotional changes in women's lives, including alterations in sleep patterns and worsening of pre-existing sleep disturbances, which possibly lead to impaired postpartum maternal behaviour and mother-infant relationship. The effects of sleep deprivation during pregnancy in maternal behaviour have been evaluated in preclinical studies, but have provided inconsistent results. Thus, in the present study, we aimed to evaluate the effects of sleep deprivation during pregnancy on maternal behaviour of animals through a systematic review and meta-analyses.

Clinical relevance assessment of animal preclinical research (RAA) tool: development and explanation.

Background: Only a small proportion of preclinical research (research performed in animal models prior to clinical trials in humans) translates into clinical benefit in humans. Possible reasons for the lack of translation of the results observed in preclinical research into human clinical benefit include the design, conduct, and reporting of preclinical studies. There is currently no formal domain-based assessment of the clinical relevance of preclinical research.