Toxicology in the 21st century – Working our way towards a visionary reality

Berg, Ninna; Wever, Bart De; Fuchs, Horst W.; Gaça, Marianna; Krul, Cyrille; Roggen, Erwin L.

doi:10.1016/j.tiv.2011.02.008

Cited by 55 publications

(42 citation statements)

References 15 publications

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“…Advances in the field of in vitro toxicological testing are motivated by the principle of the Three Rs (Balls, 2010) and the Tox21 framework (Krewski et al 2010), both demanding that animal use should be minimized and mechanistic data should be acquired using human cellular-based in vitro systems (Sheldon and Cohen Hubal, 2009;Berg et al, 2011;Rovida et al, 2015). Owing to the increasing concern about the toxicity impact of particle exposure via inhalation, non-animal alternative methods that are appropriate for predicting respiratory toxicity effects in humans are needed.…”

Section: Discussionmentioning

confidence: 99%

“…The repetitions would allow a more reliable observation and further understanding of the cellular and molecular changes following CS exposure. Aligned with Toxicity Testing in the 21 st Century -a Vision and a Strategy (Krewski et al, 2010), according to which animal use should be minimized and mechanistic data should be acquired using human cell-based in vitro systems (Sheldon and Cohen Hubal, 2009;Berg et al, 2011;Rovida et al, 2015), the present study implements a systems toxicological approach where computational biology analyses (i.e., a global analysis of mRNA and miRNA changes using a network-based approach) were used to complement various functional cell-based assays (i.e., cytotoxicity assay, cytochrome P450 activity assay, measurement of secreted pro-inflammatory factors, histological analysis, and cilia beating analysis).…”

Section: -D Nasal Cultures: Systems Toxicological Assessment Of a Camentioning

confidence: 99%

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3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

Iskandar

Mathis

Martin

et al. 2017

ALTEX

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ratory animals -to reduce the number of animals, to refine the design of procedures such that pain and distress are minimized, and to replace animal models with alternative methods and lower organisms when possible (Doke and Dhawale, 2015). In this regard, the capability to preserve human respiratory cells in culture provides a tool not only to generate mechanistic data, but also to improve the predicted effects of exposure hazard through inhalation in humans. An emphasis on assessment studies using human-derived in vitro culture systems will reduce the problems that are inherent to interspecies translatability (Manuppello and Sullivan, 2015).In vitro toxicology approaches have evolved from focusing on the molecular changes within a cell to understanding the toxicity-related mechanisms (cell-cell interactions) in models IntroductionMechanistic investigation of the impact of exposure on the lower airway remains challenging because access to lung tissues is limited. Although biopsy samples can be obtained from patients/donors for mechanistic studies of exposure-induced injury, a biopsy procedure is invasive and there are related ethical concerns (Peppercorn, 2013). Alternatively, animal studies allow the collection of biological samples from various animal models of human diseases. However, biological responses can vary among animal species, and findings obtained from animal studies may not apply to humans. Alternatives to animal testing have been proposed to overcome these drawbacks, including the 3Rs strategy -reduction, refinement, and replacement of labo- Research SummaryIn vitro toxicology approaches have evolved from a focus on molecular changes within a cell to understanding of toxicity-related mechanisms in systems that can mimic the in vivo environment. The recent development of three dimensional (3-D) organotypic nasal epithelial culture models offers a physiologically robust system for studying the effects of exposure through inhalation. Exposure to cigarette smoke (CS) is associated with nasal inflammation; thus, the nasal epithelium is relevant for evaluating the pathophysiological impact of CS exposure. The present study investigated further the application of in vitro human 3-D nasal epithelial culture models for toxicological assessment of inhalation exposure. Aligned with 3Rs strategy, this study aimed to explore the relevance of a human 3-D nasal culture model to assess the toxicological impact of aerosols generated from a candidate modified risk tobacco product (cMRTP), the Tobacco Heating System (THS) 2.2, as compared with smoke generated from reference cigarette 3R4F. A series of experimental repetitions, where multiple concentrations of THS2.2 aerosol and 3R4F smoke were applied, were conducted to obtain reproducible measurements to understand the cellular/molecular changes that occur following exposure. In agreement with "Toxicity Testing in the 21 st Century -a Vision and a Strategy", this study implemented a systems toxicology approach and found that for all tested concentrations the impa...

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Section: Discussionmentioning

confidence: 99%

Section: -D Nasal Cultures: Systems Toxicological Assessment Of a Camentioning

confidence: 99%

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

Iskandar

Mathis

Martin

et al. 2017

ALTEX

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“…With the current focus of toxicology on the understanding of toxicity pathways in (human) cell systems and mechanistic safety assessment, the role of HCI technologies is likely to increase further (leist et al, 2008;Andersen and Krewski, 2009;Krewski et al, 2010;Berg et al, 2011;van Vliet, 2011). to fully exploit the potential of HCI, there are still some remaining gaps and challenges to be overcome (Box 2).…”

Section: Discussionmentioning

confidence: 99%

“…the modeling of these dynamic responses across dose and time allows the identification of signaling pathways underlying cellular defense, adaptation, toxicity and death (Mohamed et al, 2011;Herpers and van de Water, 2013;Wink et al, 2014). therefore, HCI is considered a promising technology to address the challenges laid out in Toxicity Testing in the 21 st Century: A Vision and a Strategy (NRC, 2007;leist et al, 2008;Andersen and Krewski, 2009;Berg et al, 2011;van Vliet et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Current approaches and future role of high content imaging in safety sciences and drug discovery

Vliet

Daneshian

Beilmann

et al. 2014

ALTEX

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* a report of t 4 -the transatlantic think tank for toxicology, a collaboration of the toxicologically oriented chairs in Baltimore, Konstanz and Utrecht sponsored by the Doerenkamp-Zbinden Foundation; participants do not represent their institutions and do not necessarily endorse all recommendations made.Disclaimer: This document has been reviewed by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. Summary High content imaging combines automated microscopy with image analysis approaches to simultaneously quantify multiple phenotypic and/or functional parameters in biological systems. The technology has become an important tool in the fields of safety sciences and drug discovery, because it can be used for mode-of-action identification, determination of hazard potency and the discovery of toxicity targets and biomarkers. In contrast to conventional biochemical endpoints, high content imaging provides insight into the spatial distribution and dynamics of responses in biological systems

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“…Due to the vast number of chemicals and/or their mixtures to be assessed for safety, there is an increasing need to evaluate toxic effects at the cellular level as described e.g. in the term "21 st century toxicology" (Berg et al 2011). One of the challenges is to design appropriate tests which rely on a molecular and cellular mechanistic understanding of toxicants mode of action using in vitro methods based on human cells.…”

Section: Introductionmentioning

confidence: 99%

A novel micronucleus in vitro assay utilizing human hematopoietic stem cells

Kotova

Hebert

Härnwall

et al. 2015

Toxicology in Vitro

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The induction of micronucleated reticulocytes in the bone marrow is a sensitive indicator of chromosomal damage. Therefore, the micronucleus assay in rodents is widely used in genotoxicity and carcinogenicity testing. A test system based on cultured human primary cells could potentially provide better prediction compared to animal tests, increasing patient safety while also implementing the 3Rs principle, i.e. replace, reduce and refine. Hereby, we describe the development of an in vitro micronucleus assay based on animal-free ex vivo culture of human red blood cells from hematopoietic stem cells. To validate the method, five clastogens with direct action, three clastogens requiring metabolic activation, four aneugenic and three non-genotoxic compounds have been tested. Also, different metabolic systems have been applied. Flow cytometry was used for detection and enumeration of micronuclei. Altogether, the results were in agreement with the published data and indicated that a sensitive and cost effective in vitro assay to assess genotoxicity with a potential to high-throughput screening has been developed.

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Toxicology in the 21st century – Working our way towards a visionary reality

Cited by 55 publications

References 15 publications

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

3-D nasal cultures: Systems toxicological assessment of a candidate modified-risk tobacco product

Current approaches and future role of high content imaging in safety sciences and drug discovery

A novel micronucleus in vitro assay utilizing human hematopoietic stem cells

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