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Acute fish toxicity is an ecotoxicological endpoint which provides important information about a chemical's potential to elicit adverse effect(s) on fish. These effects are typically studied using in vivo tests but for animal welfare reasons as well as the quest for increased species relevance, biological coverage, mechanistic understanding of effects and throughput, there have been significant efforts in recent years to reduce or replace the use of animals in (eco)toxicological hazard assessment, by developing defined approaches (DA) or integrated approaches to testing and assessment (IATA). To this end, a novel score-based DA has been developed, which integrates three in silico predictions from freely available (Q)SARs: the VEGA Fish (KNN-Read-Across) and Fathead Minnow (KNN-IRFMN) models and the United States Environmental Protection Agency (USEPA) ECOSAR Fish 96-h LC50 model, along with in vitro RTgill-W1 data. The DA provides a categorical output aligned with the United Nations Globally Harmonized System of Classification and Labelling (GHS) framework (Acute Category 1, Acute Category 2, Acute Category 3 or Not Classified) with an overall accuracy of 80%, offering a reliable alternative to traditional in vivo testing methods for acute fish toxicity., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Society of Environmental Toxicology and Chemistry.)

Background: The global coronavirus 2019 (COVID-19) pandemic began in early 2020, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In mid-2020 the CIAO (Modelling the Pathogenesis of COVID-19 Using the Adverse Outcome Pathway Framework) project was established, bringing together over 75 interdisciplinary scientists worldwide to collaboratively investigate the underlying biological mechanisms of COVID-19 and consolidate the data using the Adverse Outcome Pathway (AOP) Framework. Neurological symptoms such as anosmia and encephalitis have been frequently reported to be associated with infection with SARS-CoV-2., Objective: Within CIAO, a working group was formed to conduct a systematic scoping review of COVID-19 and its related neurological symptoms to determine which key events and modulating factors are most commonly reported and to identify knowledge gaps., Design: LitCOVID was used to retrieve 86,075 papers of which 10,244 contained relevant keywords. After title and abstract screening, 2,328 remained and their full texts were reviewed based on predefined inclusion and exclusion criteria. 991 studies fulfilled the inclusion criteria and were retrieved to conduct knowledge synthesis., Results: The majority of publications reported human observational studies. Early key events were less likely to be reported compared to middle and late key events/adverse outcomes. The majority of modulating factors described related to age or sex. Less recognised COVID-19 associated AO or neurological effects of COVID-19 were also identified including multiple sclerosis/demyelination, neurodegeneration/cognitive effects and peripheral neuronal effects., Conclusion: There were many methodological and reporting issues noted in the reviewed studies. In particular, publication abstracts would benefit from clearer reporting of the methods and endpoints used and the key findings, to ensure relevant papers are included when systematic reviews are conducted. The information extracted from the scoping review may be useful in understanding the mechanisms of neurological effects of COVID-19 and to further develop or support existing AOPs linking COVID-19 and its neurological key events and adverse outcomes. Further evaluation of the less recognised COVID-19 effects is needed., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ishita Virmani reports financial support was provided by a. RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic., (Copyright © 2024. Published by Elsevier B.V.)

REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) is a European Union regulation that aims to protect human health and the environment from the risks posed by chemicals. Article 25 clearly states that: "[i]n order to avoid animal testing, testing on vertebrate animals for the purposes of this Regulation shall be undertaken only as a last resort." In practice, however, the standard information requirements under REACH are still primarily filled using animal studies. This paper presents examples illustrating that animal testing is not always undertaken only as a last resort. Six over-arching issues have been identified which contribute to this: (1) non-acceptance of existing animal or non-animal data, (2) non-acceptance of read-across, (3) inflexible administrative processes, (4) redundancy of testing, (5) testing despite animal welfare concerns and (6) testing for cosmetic-only ingredients. We, members of the Animal-Free Safety Assessment (AFSA) Collaboration, who work together to accelerate the global adoption of non-animal approaches for chemical safety assessment, herein propose several recommendations intended to aid the European Commission, the European Chemicals Agency and registrants to protect human health and the environment while avoiding unnecessary animal tests - truly upholding the last resort requirement in REACH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

In silico models are often built solely on publicly available data which may mean that they are less predictive for proprietary chemical space. Data sharing initiatives can improve the performance of such models, but organisations are often unable to share their data due to the need to protect their business interests and maintain the confidentiality of the chemicals in their research and development programmes. In silico models like Derek Nexus, which use expert knowledge to develop structural alerts based on chemical toxicity, can use proprietary data to identify new areas of chemical space and/or refine existing alerts whilst still preserving the privacy of the confidential data. Five hundred and thirty seven proprietary chemicals with skin sensitisation data were shared which led to the implementation of 7 new alerts and 5 modified alerts, with a concomitant 19% increase in sensitivity and 3% increase in specificity of the model., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martyn Chilton reports a relationship with Lhasa Limited that includes: employment. Corresponding author (Donna Macmillan) was previously employed by, and co-author Martyn Chilton is currently employed by, Lhasa Limited. Lhasa Limited produce Derek Nexus, the in silico tool used in the data sharing project and described within the manuscript., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation was created to protect human health and the environment through the better and earlier identification of harmful intrinsic properties of chemical substances on the European market. One of its central aims was the promotion of alternatives to animal testing, yet it has instead become a long tick-box list of in vivo experiments questionable relevance to human health outcomes despite a global trend towards new approach methods (NAMs) in chemical safety assessment. The Chemicals Strategy for Sustainability (CSS), proposed by the European Commission in 2020, is a golden opportunity to revise REACH in a significant and impactful way, yet proposals presented so far have significant negative animal welfare consequences. There is still time to correct the course of the ongoing REACH revision - proposals made herein offer a path towards the promising future intended by the CSS. These proposals are anchored in three vectors of action, varying in level of complexity - from changes that ECHA can implement to improve existing processes, through technical changes aimed at minimizing animal testing and increasing NAM acceptance, to deeper structural changes to establish non-animal testing strategies as the basis for risk assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

In June 2021 the Organisation for Economic Co-operation and Development published Guideline No. 497 on Defined Approaches for Skin Sensitisation (DASS GL). There are two DAs published, known as the 2o3 and the ITS. The 2o3 uses two concordant results from either the DPRA, KeratinoSens™, or the h-CLAT assays to predict hazard (sensitiser/non-sensitiser). The ITS applies a score to results from the DPRA, the h-CLAT and an in silico model to predict United Nations Globally Harmonized System (GHS) sub-categories (1A/1B/Not Classified). The ITS can use Derek Nexus as the in silico model (known as ITSv1) or use OECD QSAR Toolbox (known as ITSv2). As limitations of the individual in chemico/in vitro assays and in silico predictions are carried through to the DAs, inconclusive predictions are possible for chemicals with results in the borderline range, and chemicals with out of domain results. However, these inconclusive predictions can be resolved by applying a weight of evidence approach. Herein, four case studies are presented, each 'inconclusive' for skin sensitisation potential according to both DAs. A weight of evidence approach was applied to each using a robust scientific approach to provide a conclusive prediction, where possible, based on several additional, non-animal lines of evidence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martyn Chilton reports a relationship with Lhasa Limited that includes: employment. Corresponding author (Donna Macmillan) was previously employed by, and co-author Martyn Chilton is currently employed by, Lhasa Limited. Lhasa Limited produce Derek Nexus, an in silico tool used in one of the defined approaches published by the OECD and described within the manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani , and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics., Competing Interests: C.J.S. and F.J.S. are part of revenue-sharing agreements with their university relating to the Strathclyde Minor Groove Binder project. Additionally, C.J.S. and F.J.S. have financial interests through shares in the company Rostra Therapeutics.

The Dermal Sensitisation Thresholds (DST) are Thresholds of Toxicological Concern, which can be used to justify exposure-based waiving when conducting a skin sensitisation risk assessment. This study aimed to update the published DST values by expanding the size of the Local Lymph Node Assay dataset upon which they are based, whilst assigning chemical reactivity using an in silico expert system (Derek Nexus). The potency values within the expanded dataset fitted a similar gamma distribution to that observed for the original dataset. Derek Nexus was used to classify the sensitisation activity of the 1152 chemicals in the expanded dataset and to predict which chemicals belonged to a High Potency Category (HPC). This two-step classification led to three updated thresholds: a non-reactive DST of 710 μg/cm 2 (based on 79 sensitisers), a reactive (non-HPC) DST of 73 μg/cm 2 (based on 331 sensitisers) and an HPC DST of 1.0 μg/cm 2 (based on 146 sensitisers). Despite the dataset containing twice as many sensitisers, these values are similar to the previously published thresholds, highlighting their robustness and increasing confidence in their use. By classifying reactivity in silico the updated DSTs can be applied within a skin sensitisation risk assessment in a reproducible, scalable and accessible manner., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)