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Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues. publishedVersion

Funding Information: The work was performed under the JRC Exploratory Research project CIAO—Modelling COVID-19 pathogenesis using the Adverse Outcome Pathway (AOP). Julija Filipovska for her careful reading and valuable inputs. Funding: This research was funded by the Academy of Finland (grand number 322761) for D.G., G.d.G. and L.A.S. and by Fundação para a Ciência e Tecnologia through CEECIND/01049/2020 for H.S. For the other authors, this research received no external funding. Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues. publishersversion published

On April 28-29, 2021, 50 scientists from different fields of expertise met for the 3rd online CIAO workshop. The CIAO project “Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway (AOP) framework” aims at building a holistic assembly of the available scientific knowledge on COVID-19 using the AOP framework. An individual AOP depicts the disease progression from the initial contact with the SARS-CoV-2 virus through biological key events (KE) toward an adverse outcome such as respiratory distress, anosmia or multiorgan failure. Assembling the individual AOPs into a network highlights shared KEs as central biological nodes involved in multiple outcomes observed in COVID-19 patients. During the workshop, the KEs and AOPs established so far by the CIAO members were presented and posi­tioned on a timeline of the disease course. Modulating factors influencing the progression and severity of the disease were also addressed as well as factors beyond purely biological phenomena. CIAO relies on an interdisciplinary crowd­sourcing effort, therefore, approaches to expand the CIAO network by widening the crowd and reaching stakeholders were also discussed. To conclude the workshop, it was decided that the AOPs/KEs will be further consolidated, inte­grating virus variants and long COVID when relevant, while an outreach campaign will be launched to broaden the CIAO scientific crowd.

For almost fifteen years, the availability and regulatory acceptance of new approach methodologies (NAMs) to assess the absorption, distribution, metabolism and excretion (ADME/biokinetics) in chemical risk evaluations are a bottleneck. To enhance the field, a team of 24 experts from science, industry, and regulatory bodies, including new generation toxicologists, met at the Lorentz Centre in Leiden, The Netherlands. A range of possibilities for the use of NAMs for biokinetics in risk evaluations were formulated (for example to define species differences and human variation or to perform quantitative in vitro-in vivo extrapolations). To increase the regulatory use and acceptance of NAMs for biokinetics for these ADME considerations within risk evaluations, the development of test guidelines (protocols) and of overarching guidance documents is considered a critical step. To this end, a need for an expert group on biokinetics within the Organisation of Economic Cooperation and Development (OECD) to supervise this process was formulated. The workshop discussions revealed that method development is still required, particularly to adequately capture transporter mediated processes as well as to obtain cell models that reflect the physiology and kinetic characteristics of relevant organs. Developments in the fields of stem cells, organoids and organ-on-a-chip models provide promising tools to meet these research needs in the future.

Good Cell and Tissue Culture Practice (GCCP) 2.0 is an updated guidance document from GCCP 1.0 (published by ECVAM in 2005), which was developed for practical use in the laboratory to assure the reproducibility of in vitro (cell-based) work. The update in the guidance was essential as cell models have advanced dramatically to more complex culture systems and need more comprehensive quality management to ensure reproducibility and quality derived scientific data. This document describes six main principles to consider when performing cell culture including characterization and maintenance of essential characteristics, quality management, documentation and reporting, safety, education and training, and ethics. The document does not intend to impose detailed procedures but to describe potential quality issues. It is foreseen that the document will require further updates as the science and technologies evolve over time. published

ALTEX - Alternatives to Animal Experimentation Copyright © 2022 the author(s). On April 28-29, 2021, 50 scientists from different fields of expertise met for the 3rd online CIAO workshop. The CIAO project “Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway (AOP) framework” aims at building a holistic assembly of the available scientific knowledge on COVID-19 using the AOP framework. An individual AOP depicts the disease progression from the initial contact with the SARS-CoV-2 virus through biological key events (KE) toward an adverse outcome such as respiratory distress, anosmia or multiorgan failure. Assembling the individual AOPs into a network highlights shared KEs as central biological nodes involved in multiple outcomes observed in COVID-19 patients. During the workshop, the KEs and AOPs established so far by the CIAO members were presented and posi­tioned on a timeline of the disease course. Modulating factors influencing the progression and severity of the disease were also addressed as well as factors beyond purely biological phenomena. CIAO relies on an interdisciplinary crowd­sourcing effort, therefore, approaches to expand the CIAO network by widening the crowd and reaching stakeholders were also discussed. To conclude the workshop, it was decided that the AOPs/KEs will be further consolidated, inte­grating virus variants and long COVID when relevant, while an outreach campaign will be launched to broaden the CIAO scientific crowd. The CIAO project is steered by the Joint Research Centre of the European Commission (EC-JRC), the Humane Society International (HSI), and the Physicians Committee for Responsible Medicine (PCRM). For Jorid Birkelund Sørli, the research is supported by FIKA, Focused Research Effort on Chemicals in the Working Environment from the Danish Government. For Daniel Jacobson, this work was supported by the Laboratory Directed Research and Development Program of Oak Ridge National Laboratory, managed by UT-Battelle, LLC for the US Department of Energy (LOIS:10074) and the National Institutes of Health 3RF1AG053303-01S2.

The annual EURL ECVAM status report describes research, development and validation activities, as well as initiatives that promote the regulatory use and international adoption of non-animal methods and approaches and their dissemination in the regulatory and research arenas. EU policies and legislation call for innovative and more efficient ways of safety testing and chemical risk assessment that do not depend on animal testing. Advanced technologies such as computational models, in vitro methods and organ-on-chip devices are being developed, evaluated and integrated to translate mechanistic understanding of toxicity into safety testing strategies. The ultimate goal is to achieve better protection of human health and the environment while supporting EU innovation and industrial competitiveness, without the use of animals. The development and use of non-animal models and methods are also essential for advancing basic, applied and translational research. Education also plays an essential role in enabling a shift to non-animal methods through the introduction of the Three Rs (Replacement, Reduction and Refinement of animal use in science) into secondary school curricula and programmes of higher education., JRC.F.3-Chemicals Safety and Alternative Methods

Complex in vitro models (CIVMs) - such as 3D cell cultures and spheroids, microphysiological systems including organ-on-chip devices, bioreactor cultures or bioprinted tissues – aim to represent higher-level anatomical and physiological aspects of human biology in experimental studies. The underpinning technologies are developing fast and the models and methods being created constitute promising approaches in several different scientific areas with many applications in research and regulatory testing. However, the successful implementation and acceptance of CIVMs is likely to require their proper characterisation, validation or qualification to demonstrate to end-users that they are fit for a particular purpose or context of use. To explore this, the EU Reference Laboratory for alternatives to animal testing (EURL ECVAM) of the European Commission's Joint Research Centre (JRC) conducted a survey to investigate stakeholder opinions and perceived needs. The outcome of the survey showed that i) there is high interest in establishing some kind of assessment approaches for CIVMs; ii) assessment approaches (even if conducted differently) should be adequate not only for regulatory use-contexts but also address applications in research; and iii) CIVMs are still under (technological and biological) development and are thus not yet mature or standardised enough to enable a consensus on how their assessment should be conducted., JRC.F.3-Chemicals Safety and Alternative Methods

The European Union Reference Laboratory for alternatives to animal testing (EURL ECVAM) is an integral part of the European Commision's Joint Research Centre. The EURL ECVAM status report informs about research and development activities, test method submissions, validation and peer reviews, activities that promote the regulatory acceptance and international adoption of alternative methods and approaches and their dissemination. Replacement, reduction and refinement of animal testing (Three Rs) in basic, applied and translational research, as well as for regulatory purposes is anchored in EU legislation. Innovative technologies (e.g., computational models, in vitro methods, organ-on-chip devices) are developed, evaluated and integrated in assessment strategies for chemicals and products safety testing in order to preserve a high level of protection for human health and the environment. Important activities to promote the development and use of alternative methods and approaches are also pursued in the areas of basic and applied research as well as for education purposes., JRC.F.3-Chemicals Safety and Alternative Methods