Toxicity testing in the 21st century: progress in the past decade and future perspectives

Krewski, Daniel; Andersen, Melvin E.; Tyshenko, Michael G.; Krishnan, Kannan; Hartung, Thomas; Boekelheide, Kim; Wambaugh, John F.; Jones, Dean P.; Whelan, Maurice; Thomas, Russell S.; Yauk, Carole; Barton-Maclaren, Tara S.; Cote, Ila

doi:10.1007/s00204-019-02613-4

Cited by 241 publications

(162 citation statements)

References 399 publications

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“…The important parts of this strategy are the increased use of high-throughput in vitro test systems and methods in computational toxicology for the purpose of reducing the reliance on time-consuming and costly toxicological studies using experimental animals. This vision has received international support and has provided a blueprint for implementing change in toxicological science [9,23]. In 2011, the European Union launched SEURAT-1, the first execution phase of "Safety Evaluation Ultimately Replacing Animal Testing (SEURAT)", with the ultimate goals of the future implementation of mechanism-based, integrated toxicity testing strategies into modern safety assessment approaches [24].…”

Section: Approach Towards the Use Of Alternatives To Testing On Animalsmentioning

confidence: 99%

“…In addition, promotion of non-animal approaches is also among the objectives of the REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals), CLP (Classification, Labeling, and Packaging) and BPR (Biocidal Products Regulations) initiatives, which are based on the 3Rs principle of animal use for testing [25]. Through the abovementioned efforts, many government agencies within the United States, European Union, and other international bodies are beginning to incorporate the new approach methodologies envisioned in the original TT21C vision into regulatory practice [23].…”

Section: Approach Towards the Use Of Alternatives To Testing On Animalsmentioning

confidence: 99%

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The Current Understanding of Autophagy in Nanomaterial Toxicity and Its Implementation in Safety Assessment-Related Alternative Testing Strategies

Chen

Liao

et al. 2020

IJMS

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Nanotechnology has rapidly promoted the development of a new generation of industrial and commercial products; however, it has also raised some concerns about human health and safety. To evaluate the toxicity of the great diversity of nanomaterials (NMs) in the traditional manner, a tremendous number of safety assessments and a very large number of animals would be required. For this reason, it is necessary to consider the use of alternative testing strategies or methods that reduce, refine, or replace (3Rs) the use of animals for assessing the toxicity of NMs. Autophagy is considered an early indicator of NM interactions with cells and has been recently recognized as an important form of cell death in nanoparticle-induced toxicity. Impairment of autophagy is related to the accelerated pathogenesis of diseases. By using mechanism-based high-throughput screening in vitro, we can predict the NMs that may lead to the generation of disease outcomes in vivo. Thus, a tiered testing strategy is suggested that includes a set of standardized assays in relevant human cell lines followed by critical validation studies carried out in animals or whole organism models such as C. elegans (Caenorhabditis elegans), zebrafish (Danio rerio), and Drosophila (Drosophila melanogaster)for improved screening of NM safety. A thorough understanding of the mechanisms by which NMs perturb biological systems, including autophagy induction, is critical for a more comprehensive elucidation of nanotoxicity. A more profound understanding of toxicity mechanisms will also facilitate the development of prevention and intervention policies against adverse outcomes induced by NMs. The development of a tiered testing strategy for NM hazard assessment not only promotes a more widespread adoption of non-rodent or 3R principles but also makes nanotoxicology testing more ethical, relevant, and cost- and time-efficient.

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Section: Approach Towards the Use Of Alternatives To Testing On Animalsmentioning

confidence: 99%

Section: Approach Towards the Use Of Alternatives To Testing On Animalsmentioning

confidence: 99%

The Current Understanding of Autophagy in Nanomaterial Toxicity and Its Implementation in Safety Assessment-Related Alternative Testing Strategies

Chen

Liao

et al. 2020

IJMS

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“…61,62 3. 20,34,[59][60][61][62][63][64] In addition, animals are not always appropriate for predicting human toxicity correctly. 33,65,66 Hence, alternative test method accuracy is limited by animal test reproducibility.…”

Section: The Clp Calculation Methodsmentioning

confidence: 99%

Towards a tiered test strategy for plant protection products to address mixture toxicity by alternative approaches in human health assessment

Bloch

Marx‐Stoelting

Martin

2020

Pest Management Science

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Plant protection products (PPPs) consist of pesticide active substances and co‐formulants. Generally, active substance effects are assumed to dominate in PPP toxicity. Nevertheless, co‐formulants may well affect the toxicity of PPPs via toxicodynamic and toxicokinetic interaction. To account for potential mixture effects and improve PPP data requirements for application in risk assessment, a tiered test strategy is proposed. The strategy is based on a comparison of PPP and active substance toxicity, which enables the prioritisation of PPPs for further testing, adaptation of the toxicological threshold value or removal of toxic co‐formulants from the PPP. Moreover, it focuses on the integrative assessment of existing information and newly generated data using alternative test methods. The proposed strategy will improve PPP toxicological assessment by accounting for mixture toxicity, providing a set of regulatory options for risk assessment and the necessary data for hazard assessment. The predictivity of alternative methods for PPPs will improve by evaluation of their reliability and uncertainty. © 2020 The Authors. Pest Management Science published by JohnWiley & Sons Ltd on behalf of Society of Chemical Industry.

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“…Legislation in the EU, such as the ban of animal testing for cosmetics, has been a strong incentive for industry to launch their own (and very successful) research programs on NAM safety and quality control (Beilmann et al 2019). In the US, the National Academy of Sciences (NAS) 2007 report on the future of toxicity testing in the twenty-first century (NRC 2007;Leist et al 2008Leist et al , 2014Krewski et al 2010Krewski et al , 2020 was pivotal, triggering a chain of events culminating with roadmaps from major agencies (EPA, FDA) to reduce and ultimately abandon animal testing (Collins et al 2008;Tice et al 2013;Bouhifd et al 2015;FDA 2017;Thomas et al 2018;EPA 2019). A second notable report from a committee of the NAS addressed drug efficacy for countermeasures to terrorism (biological weapons) (NRC 2011; Hartung and Zurlo 2012).…”

Section: Introductionmentioning

confidence: 99%

Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines

et al. 2020

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The COVID-19-inducing virus, SARS-CoV2, is likely to remain a threat to human health unless efficient drugs or vaccines become available. Given the extent of the current pandemic (people in over one hundred countries infected) and its disastrous effect on world economy (associated with limitations of human rights), speedy drug discovery is critical. In this situation, past investments into the development of new (animal-free) approach methods (NAM) for drug safety, efficacy, and quality evaluation can be leveraged. For this, we provide an overview of repurposing ideas to shortcut drug development times. Animal-based testing would be too lengthy, and it largely fails, when a pathogen is species-specific or if the desired drug is based on specific features of human biology. Fortunately, industry has already largely shifted to NAM, and some public funding programs have advanced the development of animal-free technologies. For instance, NAM can predict genotoxicity (a major aspect of carcinogenicity) within days, human antibodies targeting virus epitopes can be generated in molecular biology laboratories within weeks, and various human cell-based organoids are available to test virus infectivity and the biological processes controlling them. The European Medicines Agency (EMA) has formed an expert group to pave the way for the use of such approaches for accelerated drug development. This situation illustrates the importance of diversification in drug discovery strategies and clearly shows the shortcomings of an approach that invests 95% of resources into a single technology (animal experimentation) in the face of challenges that require alternative approaches.

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Toxicity testing in the 21st century: progress in the past decade and future perspectives

Cited by 241 publications

References 399 publications

The Current Understanding of Autophagy in Nanomaterial Toxicity and Its Implementation in Safety Assessment-Related Alternative Testing Strategies

The Current Understanding of Autophagy in Nanomaterial Toxicity and Its Implementation in Safety Assessment-Related Alternative Testing Strategies

Towards a tiered test strategy for plant protection products to address mixture toxicity by alternative approaches in human health assessment

Harnessing the power of novel animal-free test methods for the development of COVID-19 drugs and vaccines

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