The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro - is envisaged to enable a global paradigm shift in drug development An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing Consequently, this technology could significantly affect the way drug substances are developed in the future Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agriculture, food, ecosystems or cosmetics, thus, replacing laboratory animal models used currently Thirty-six experts from academia, industry and regulatory bodies present here the results of an intensive workshop (held in June 2015, Berlin, Germany) They review the status quo of microphysiological systems available today against industry needs, and assess the broad variety of approaches with fit-for-purpose potential in the drug development cycle Feasible technical solutions to reach the next levels of human biology in vitro are proposed Furthermore, key organ-on-a-chip case studies, as well as various national and international programs are highlighted Finally, a roadmap into the future is outlined, to allow for more predictive and regulatory-accepted substance testing on a global scale

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Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing.

Synthesis and characterization of silver nanoparticles using Gelidium amansii and its antimicrobial property against various pathogenic bacteria

The U.S. Environmental Protection Agency (EPA) is considering high-throughput and computational methods to evaluate the endocrine bioactivity of environmental chemicals. Here we describe a multistep, performance-based validation of new methods and demonstrate that these new tools are sufficiently robust to be used in the Endocrine Disruptor Screening Program (EDSP). Results from 18 estrogen receptor (ER) ToxCast high-throughput screening assays were integrated into a computational model that can discriminate bioactivity from assay-specific interference and cytotoxicity. Model scores range from 0 (no activity) to 1 (bioactivity of 17β-estradiol). ToxCast ER model performance was evaluated for reference chemicals, as well as results of EDSP Tier 1 screening assays in current practice. The ToxCast ER model accuracy was 86% to 93% when compared to reference chemicals and predicted results of EDSP Tier 1 guideline and other uterotrophic studies with 84% to 100% accuracy. The performance of high-throughput assa...

Screening Chemicals for Estrogen Receptor Bioactivity Using a Computational Model

In vitro air–liquid interface (ALI) cell culture models can potentially be used to assess inhalation toxicology endpoints and are usually considered, in terms of relevancy, between classic (i.e., submerged) in vitro models and animal-based models. In some situations that need to be clearly defined, ALI methods may represent a complement or an alternative option to in vivo experimentations or classic in vitro methods. However, it is clear that many different approaches exist and that only very limited validation studies have been carried out to date. This means comparison of data from different methods is difficult and available methods are currently not suitable for use in regulatory assessments. This is despite inhalation toxicology being a priority area for many governmental organizations. In this setting, a 1-day workshop on ALI in vitro models for respiratory toxicology research was organized in Paris in March 2016 to assess the situation and to discuss what might be possible in terms of validation studies. The workshop was attended by major parties in Europe and brought together more than 60 representatives from various academic, commercial, and regulatory organizations. Following plenary, oral, and poster presentations, an expert panel was convened to lead a discussion on possible approaches to validation studies for ALI inhalation models. A series of recommendations were made and the outcomes of the workshop are reported.

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Air–Liquid Interface In Vitro Models for Respiratory Toxicology Research: Consensus Workshop and Recommendations

Exposure of cells or organisms to chemicals can trigger a series of effects at the regulatory pathway level, which involve changes of levels, interactions, and feedback loops of biomolecules of different types. A single-omics technique, e.g., transcriptomics, will detect biomolecules of one type and thus can only capture changes in a small subset of the biological cascade. Therefore, although applying single-omics analyses can lead to the identification of biomarkers for certain exposures, they cannot provide a systemic understanding of toxicity pathways or adverse outcome pathways. Integration of multiple omics data sets promises a substantial improvement in detecting this pathway response to a toxicant, by an increase of information as such and especially by a systemic understanding. Here, we report the findings of a thorough evaluation of the prospects and challenges of multi-omics data integration in toxicological research. We review the availability of such data, discuss options for experimental design, evaluate methods for integration and analysis of multi-omics data, discuss best practices, and identify knowledge gaps. Re-analyzing published data, we demonstrate that multi-omics data integration can considerably improve the confidence in detecting a pathway response. Finally, we argue that more data need to be generated from studies with a multi-omics-focused design, to define which omics layers contribute most to the identification of a pathway response to a toxicant.

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Prospects and challenges of multi-omics data integration in toxicology

The advent of new testing systems and "omics"-technologies has left regulatory toxicology facing one of the biggest challenges for decades. That is the question whether and how these methods can be used for regulatory purposes. The new methods undoubtedly enable regulators to address important open questions of toxicology such as species-specific toxicity, mixture toxicity, low-dose effects, endocrine effects or nanotoxicology, while promising faster and more efficient toxicity testing with the use of less animals. Consequently, the respective assays, methods and testing strategies are subject of several research programs worldwide. On the other hand, the practical application of such tests for regulatory purposes is a matter of ongoing debate. This document summarizes key aspects of this debate in the light of the European "regulatory status quo", while elucidating new perspectives for regulatory toxicity testing.

Regulatory toxicology in the twenty-first century: challenges, perspectives and possible solutions.

Dietary risks for the German population owing to pesticide residues in foods were assessed based on food monitoring data, consumption surveys for children and adults and compound specific toxicological reference values or general thresholds of toxicological concern. A tiered probabilistic modelling was conducted to screen 700 pesticides for significant long- and short-term dietary exposures. Especially for the short-term dietary exposure, the probabilistic methodology used allows simultaneous consideration of the complete daily consumption, whereas most regulatory bodies still rely on single commodity approaches. After screening, refined exposure assessments were conducted for 19 compounds under consideration of conversion factors for toxicologically relevant metabolites, processing information, experimentally derived variability factors and the edible portion for each food item. In total, for 693 compounds the dietary exposure was unlikely to present a chronic or acute public health concern for the German population. In contrast, the refined assessments indicate that the short-term dietary exposure for chlorpyrifos and the cumulative short-term dietary exposure for dimethoate and omethoate may present a public health concern. For copper, owing to exposure assessment limitations, as well as for dimethylvinphos, halfenprox and tricyclazole, which exceeded the thresholds of toxicological concern, the dietary risk assessment remained inconclusive.

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Thomas Kuhl

Papers

Regulatory toxicology in the twenty-first century: challenges, perspectives and possible solutions.

Probabilistic dietary risk assessment of pesticide residues in foods for the German population based on food monitoring data from 2009 to 2014.

Transfer kinetics of fipronil into chicken (Gallus gallus domesticus) eggs