Clarifying the absence of evidence regarding human health risks to microplastic particles in drinking-water: High quality robust data wanted

In a recently published article, Leslie and Depledge (2020) raise concerns regarding statements on the risk that microplastic particles represent to human health and which have been attributed to reports published by both the Science Academies’ Group, Science Advice for Policy (SAPEA) (part of the European Commission’s Science Advice Mechanism) and the World Health Organization (WHO) (SAPEA. Science Advice for Policy by European Academies, 2019, WHO, 2019). Leslie and Depledge (2020), for instance, suggest that WHO (2019) conclude that there is ‘no evidence to indicate a human health concern.’ This statement, taken out of context from the WHO report (WHO, 2019), is then used to imply that the WHO conclude there is ‘no risk’ related to the exposure of microplastic particles (Leslie and Depledge, 2020). While, Leslie and Depledge (2020) highlight the importance of debate and systematic assessment of claims related to the assessment of risk, observations that we agree are important to highlight, there are a number of points raised in the article that require clarification

Protocol for designing INVITES-IN, a tool for assessing the internal validity of <i>in vitro</i> studies

This protocol describes the design and development of a tool for evaluation of the internal validity of in vitro studies, which is needed to include the data as evidence in systematic reviews and chemical risk assessments. The tool will be designed specifically to be applied to cell culture studies, including, but not restricted to, studies meeting the new approach methodology (NAM) definition. The tool is called INVITES-IN (IN VITro Experimental Studies INternal validity). In this protocol, three of the four studies that will be performed to create the release version of INVITES-IN are described. In the first study, evaluation of existing assessment tools will be combined with focus group discussions to identify how characteristics of the design or conduct of an in vitro study can affect its internal validity. Bias domains and items considered to be of relevance for in vitro studies will be identified. In the second study, group agreement on internal validity domains and items of importance for in vitro studies will be identified via a modified Delphi methodology. In the third study, the draft version of the tool will be created, based on the data on relevance and importance of bias domains and items collected in Studies 1 and 2. A separate protocol will be prepared for the fourth study, which includes the user testing and validation of the tool, and collection of users’ experience

Cross-mapping of terms used in chemical risk assessment with those used in systematic review : research protocol

The focus on implementation of systematic review (SR) principles in chemical risk assessments (CRAs) is growing as it has the potential to advance the rigour and transparency of the CRAs. However, the SR and CRA communities use their own specific terminologies. Understanding the meaning of core SR and CRA terms and where they overlap is critical for application of SR methods and principles in CRAs. Moreover, it will increase the possibility for cross-sectorial collaboration, avoid misunderstandings, and improve communication among risk assessors, researchers, and policy makers. We present a process for the cross-mapping of core CRA terms and core SR terms. Core terms for study appraisal, evidence synthesis and integration used in the SR and CRA communities will be included. The outcome will be an overview of how core SR terms map onto core CRA terms and vice versa, and a description of the relationship and conceptual overlap between the terms. The cross-mapping is divided in three phases, where in the first phase the core SR and CRA terms will be identified. In the second phase, existing SR and CRA definitions will be mapped. In the third phase, descriptions of the relationship and conceptual overlap between the terms will be derived. The third phase will include weekly 1-h online meetings for SR and CRA experts

Developing TK databases and tools to support food safety assessment

International audiencerequirements for pre-market authorisation of pesticides (regulation 283-284/2013) for which comparative in vitro metabolism (rat) human and in vivo rat TK data are required. As a consequence, EFSA has been involved in collaborative research to develop TK tools and databases for food safety in the human health, animal health and ecological area. After problem formulation, risk assessors may start at low tier (e.g. basic information and default values) under time and resource constraints, or use all data available for a particular chemical. In this situation, ADME and toxicity information may allow sound dose response modelling and a full quantitative assessment. In a broad context, developing generic tools and databases allow replacing default values with quantitative metrics for physiological, TK and toxicity parameters in any data situation. First, physiological parameters for species of interest are collected and integrated, within a set of differential equations, into generic models. These range from allometric scaling, one compartment model to full physiologically-based TK models (PB-TK). Third, databases reporting physico-chemical and ADME properties, TK parameters and bioaccumulation provide input data to run the models for predicting blood concentrations or elimination patterns. Applications are illustrated including modelling interspecies differences in renal elimination using allometric scaling, integrating variability in human metabolism into generic PB-TK models and development of a modelling platform: TKplate (Wiecek et al., 2018, Darney et al., 2018). Future perspectives include the development of guidance and case studies to use TK tools in routine risk assessment and training programmes

Establishing a systematic framework to characterise in vitro methods for human hepatic metabolic clearance

Abstract Hepatic metabolic clearance is one of the most important factors driving the overall kinetics of chemicals including substances used in various product categories such as pesticides, biocides, pharmaceuticals, and cosmetics. A large number of in vitro systems from purified isozymes and subcellular organelles to hepatocytes in simple cultures and in complex scaffold setups are available for measuring hepatic metabolic clearance for different applications. However, there is currently no approach for systematically characterising and comparing these in vitro methods in terms of their design, applicability and performance. To address this, existing knowledge in the field of in vitro human hepatic metabolic clearance methods was gathered and analysed in order to establish a framework to systematically characterise methods based on a set of relevant components. An analogous framework would be also applicable for non-human in vitro systems. The components are associated with the biological test systems used (e.g. subcellular or cells), the in vitro method (e.g. number of cells, test item solubility), related analytical techniques, data interpretation methods (based on substrate depletion/metabolite formation), and performance assessments (precision and accuracy of clearance measurements). To facilitate the regulatory acceptance of this class of methods, it is intended that the framework provide the basis of harmonisation work within the OECD

Ekonomická analýza podniku s přihlédnutím k jeho lokalizaci

Investigative Toxicology describes the de-risking and mechanistic elucidation of toxicities, supporting early safety decisions in the pharmaceutical industry. Recently, Investigative Toxicology has contributed to a shift in pharmaceutical toxicology, from a descriptive to an evidence-based, mechanistic discipline. This was triggered by high costs and low throughput of Good Laboratory Practice in vivo studies, and increasing demands for adhering to the 3R (Replacement, Reduction and Refinement) principles of animal welfare. Outside the boundaries of regulatory toxicology, Investigative Toxicology has the flexibility to embrace new technologies, enhancing translational steps from in silico, in vitro to in vivo mechanistic understanding to eventually predict human response. One major goal of Investigative Toxicology is improving preclinical decisions, which coincides with the concept of animal-free safety testing. Currently, compounds under preclinical development are being discarded due to the use of inappropriate animal models. Progress in Investigative Toxicology could lead to humanized in vitro test systems and the development of medicines less reliant on animal tests. To advance this field a group of 14 European-based leaders from the pharmaceutical industry founded the Investigative Toxicology Leaders Forum (ITLF), an open, non-exclusive and pre-competitive group that shares knowledge and experience. The ITLF collaborated with the Centre for Alternatives to Animal Testing Europe (CAAT-Europe) to organize an "Investigative Toxicology Think-Tank", which aimed to enhance the interaction with experts from academia and regulatory bodies in the field. Summarizing the topics and discussion of the workshop, this article highlights Investigative Toxicology's position by identifying key challenges and perspectives

Reconnecting exposure, toxicokinetics and toxicity in food safety : OpenFoodTox and TKplate for human health, animal health and ecological risk assessment

International audienceIn food safety, sound risk characterisation requires the integration of external dose (oral exposure), internal dose (toxicokinetics (TK) and toxicodynamic (TD) data. Here, a workflow allowing such integration is presented and illustrated with examples from the human health, animal health and ecological area. Since its creation in 2002, the European Food Safety Authority (EFSA) has performed risk assessments for more than 5000 chemicals. An open source database: OpenFoodTox, designed using OECD harmonised templates, and providing summary toxicological data used by EFSA for setting safe levels (reference points and reference values) of food and feed chemicals in humans, animals and the environment has been recently published. OpenFoodTox is available in a. EFSA's Data Warehouse as a microstrategy tool, b. EFSA's knowledge junction for full download, c. The OECD e-chem portal. Since 2014, EFSA has funded collaborative research to develop generic TK and PB-TK models in the R freeware available on an open source modelling platform: TK Plate, to support integration of exposure, TK and TD parameters under different situations (data poor, data rich). Several models have been developed including TK and PB-TK models in humans, farm and companion animals (pig, chicken, cat, sheep), fish (zebra fish, rainbow trout, fathead minnow) and Dynamic Energy Budget (DEB) models for terrestrial and aquatic organisms. The first prototype of TKPlate has been designed for human TK and PB-PK models using the US-EPA ‘httk’ package and includes variability distributions for human metabolism. Future developments of OpenFoodTox 2.0 and TK Plate include: 1. Data collection for physico-chemical properties, TK, biodegradation and bioaccumulation data, exposure data, 2. Integration of QSAR tools to predict TK and TD properties, 3. Integration of all models in TKplate for all species, 4. Development of a guidance document to illustrate the global use of TK and metabolism data in chemical risk assessment with case studies (e.g. regulated products and contaminants). In conclusion, the importance of international cooperation is emphasised, in particular between national, international scientific advisory bodies and academic institutions as the corner stone for the translation of 21st century toxicology into harmonised methodologies and tools and for the training of the next generation of risk assessors