Sex Differences in Liver Toxicity—Do Female and Male Human Primary Hepatocytes React Differently to Toxicants In Vitro?

There is increasing amount of evidence for sex variation in drug efficiency and toxicity profiles. Women are more susceptible than men to acute liver injury from xenobiotics. In general, this is attributed to sex differences at a physiological level as well as differences in pharmacokinetics and pharmacodynamics, but neither of these can give a sufficient explanation for the diverse responses to xenobiotics. Existing data are mainly based on animal models and limited data exist on in vitro sex differences relevant to humans. To date male and female human hepatocytes have not yet been compared in terms of their responses to toxicants. We investigated whether sex-specific differences in acute hepatotoxicity can be observed in vitro at a cellular level by comparing hepatotoxic drug effects in male and female primary human hepatocytes. Significant sex-related differences were found for particular parameters and individual drugs showing that the tested substances are more toxic to female hepatocytes. Moreover, our work demonstrated that high content screening is feasible with pooled primary human hepatocytes in suspension.JRC.I.5-Systems Toxicolog

Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity

This report presents the definition and detailed documentation of chosen toxicological MoAs associated with repeated dose target organ toxicity as a first step in building a "prototype" safety assessment framework. In addition to providing a detailed description of the two chosen MoAs related to chronic liver toxicity, namely "MoA from Protein Alkylation to Liver Fibrosis" and "MoA from Liver X Receptor Activation to Liver Steatosis", the report also describes the working process leading to this result including the problems that have been encountered. The exercise followed as far as possible relevant WHO-IPCS and OECD guidance. The report represents the first deliverable of a contract of work between Cosmetics Europe and the European Commission's Joint Research Centre for supplementing the work of the SEURAT-1 research cluster.JRC.I.5-Systems Toxicolog

Pathway-Based Toxicity: History, Current Approaches and Liver Fibrosis and Steatosis as Prototypes

The Human Toxicology Project Consortium (HTPC) was created to accelerate implementation of the science and policies required to achieve a pathway-based foundation for toxicology as articulated in the 2007 National Research Council report, Toxicity Testing in the 21st Century: a Vision and a Strategy. The HTPC held a workshop, “Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action,” in January, 2013, in Baltimore, MD, to further the science of pathway-based approaches to liver toxicity. This review was initiated as a thought-starter for this workshop and has since been updated to include insights from the workshop and other activities occurring in 2013. The report of the workshop has been published elsewhere in this journal (Willett, 2014).JRC.I.5-Systems Toxicolog

Towards a 21st-century roadmap for biomedical research and drug discovery:consensus report and recommendations

Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and nongovernmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathway-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this

EURL ECVAM Status Report on the Development, Validation and Regulatory Acceptance of Alternative Methods and Approaches (2013-April 2014)

The EURL ECVAM status report provides an update on the progress made in the development, validation and regulatory acceptance of alternative methods and approaches since the last report published in April 2013. It is informing on ongoing research and development activities, validation studies, peer reviews, recommendations, strategies and international acceptance of alternative methods and approaches. R&D activities are ongoing for the complex endpoints where the toxicological processes and the mechanistic understanding have not been sufficiently elucidated yet and for which 3Rs solutions are more difficult to find. On the other hand, good progress In the validation and regulatory acceptance is made in areas where non-animal alternative methods have been developed and validated and where the focus lies in an intelligent combination/ integration of the various non-animal approaches.JRC.I.5-Systems Toxicolog

EURL ECVAM Status Report on the Development, Validation and Regulatory Acceptance of Alternative Methods and Approaches (2015)

The EURL ECVAM status report provides an update on the progress made in the development, validation and regulatory acceptance of alternative methods and approaches and their dissemination since the last report published in June 2014. It is informing on ongoing research and development activities, validation studies, peer reviews, recommendations, strategies and regulatory/international acceptance of alternative methods and approaches and dissemination activities. R&D activities within large European or International consortia continued in toxicity areas where 3Rs solutions are more difficult to find due to the underlying complexity of the area. On the other hand, toxicity areas where promising non-animal approaches have been developed, their validation and regulatory acceptance/international adoption could be progressed. Particular emphasis was given to the best and most intelligent combination and integration of these different non-animal approaches to ultimately obtain the required information without resorting to animal testing.JRC.I.5-Systems Toxicolog

EURL ECVAM Status Report on the Development, Validation and Regulatory Acceptance of Alternative Methods and Approaches (2016)

Replacement, Reduction and Refinement of animal testing is anchored in EU legislation. Alternative non-animal approaches facilitate a shift away from animal testing. Cell-based methods and computational technologies are integrated to translate molecular mechanistic understanding of toxicity into safety testing strategies.JRC.F.3-Chemicals Safety and Alternative Method

Factors Modulating COVID-19 : A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework

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.publishedVersionPeer reviewe

Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action

A workshop sponsored by the Human Toxicology Project Consortium (HTPC), “Building Shared Experience to Advance Practical Application of Pathway-Based Toxicology: Liver Toxicity Mode-of-Action” brought together experts from a wide range of perspectives to inform the process of pathway development and to advance two prototype pathways initially developed by the European Commission Joint Research Center (JRC): liver-specific fibrosis and steatosis. The first half of the workshop focused on the theory and practice of pathway development; the second on liver disease and the two prototype pathways. Participants agreed pathway development is extremely useful for organizing information and found that focusing the theoretical discussion on a specific AOP is helpful. It is important to include several perspectives during pathway development, including information specialists, pathologists, human health and environmental risk assessors, and chemical and product manufacturers, to ensure the biology is well captured and end use is considered