A global initiative to refine acute inhalation studies through the use of ‘evident toxicity’ as an endpoint: Towards adoption of the fixed concentration procedure

Sewell, Fiona; Ragan, Ian; Marczylo, Tim; Anderson, Brian J.; Braun, Anne; Casey, Warren; Dennison, Ngaire; Griffiths, David; Guest, Robert; Holmes, Tom; Huygevoort, Ton van; Indans, Ian; Kenny, Terry A.; Kojima, Hajime; Lee, Kyuhong; Prieto, Pilar; Smith, Paul; Smedley, Jason; Stokes, William S.; Wnorowski, Gary; Horgan, Graham

doi:10.1016/j.yrtph.2015.10.018

Cited by 21 publications

(22 citation statements)

References 4 publications

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“…The working group carried out a largescale analysis of inhalation toxicity data from 188 substances, and developed guidelines to support the recognition and use of "evident toxicity." Such guidelines are described in Sewell et al (2015). The scientific evidence provided by these two studies, supported the approval of the FCP method as OECD method in 1 REACH.…”

Section: Current Regulatory Test Guidelines For Acute Inhalation Toxicitymentioning

confidence: 83%

In vitro Alternatives to Acute Inhalation Toxicity Studies in Animal Models—A Perspective

Movia

Bruni-Favier

Prina‐Mello

2020

Front. Bioeng. Biotechnol.

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When assessing the risk and hazard of a non-pharmaceutical compound, the first step is determining acute toxicity, including toxicity following inhalation. Inhalation is a major exposure route for humans, and the respiratory epithelium is the first tissue that inhaled substances directly interact with. Acute inhalation toxicity testing for regulatory purposes is currently performed only in rats and/or mice according to OECD TG403, TG436, and TG433 test guidelines. Such tests are biased by the differences in the respiratory tract architecture and function across species, making it difficult to draw conclusions on the potential hazard of inhaled compounds in humans. Research efforts have been therefore focused on developing alternative, human-relevant models, with emphasis on the creation of advanced In vitro models. To date, there is no In vitro model that has been accepted by regulatory agencies as a stand-alone replacement for inhalation toxicity testing in animals. Here, we provide a brief introduction to current OECD test guidelines for acute inhalation toxicity, the interspecies differences affecting the predictive value of such tests, and the current regulatory efforts to advance alternative approaches to animal-based inhalation toxicity studies. We then list the steps that should allow overcoming the current challenges in validating In vitro alternatives for the successful replacement of animal-based inhalation toxicity studies. These steps are inclusive and descriptive, and should be detailed when adopting in house-produced 3D cell models for inhalation tests. Hence, we provide a checklist of key parameters that should be reported in any future scientific publications for reproducibility and transparency.

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Section: Current Regulatory Test Guidelines For Acute Inhalation Toxicitymentioning

confidence: 83%

In vitro Alternatives to Acute Inhalation Toxicity Studies in Animal Models—A Perspective

Movia

Bruni-Favier

Prina‐Mello

2020

Front. Bioeng. Biotechnol.

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“…It may also be considered more environmentally relevant and indicative of “ecological death”—in the wild these fish would not survive (e.g., because of predation). There is already a precedent in mammalian acute toxicity testing where “evident toxicity” is used as the endpoint in place of death (e.g., Organisation for Economic Co‐operation and Development 2002, 2017b, 2018; Sewell et al 2015). “Evident toxicity” is defined as clear signs of toxicity without causing severe toxic effects or mortality, which predict that exposure to the next highest concentration will cause severe toxicity or death/moribundity in most animals.…”

Section: Current State Of the Science Testing Framework And Key 3rmentioning

confidence: 99%

“…In 2019, a bold move was made by the USEPA—the body responsible for regulating industrial chemicals and PPPs in the United States—by announcing its plan to eliminate requests for mammalian safety tests by 2035 (US Environment Protection Agency 2019). Efforts have already started to reduce and refine mammalian acute toxicity tests where they remain mandatory, for example, through activities to modernize the USEPA's PPP data requirements (US Environment Protection Agency 2017; Prior et al 2019), deletion of the OECD's acute oral toxicity test (test guideline 401; Organisation for Economic Co‐operation and Development 1987) in 2002 specifically because of animal welfare concerns, and the recent adoption of OECD test guideline 433 (Organisation for Economic Co‐operation and Development 2018) to increase the use of more humane endpoints in place of death in acute inhalation studies (Sewell et al 2015, 2018). In nonmammalian toxicology there have been similar efforts to improve the welfare implications of avian acute toxicity testing, through introduction and adoption of OECD test guideline 223 (avian acute oral toxicity test) (Organisation for Economic Co‐operation and Development 2016a).…”

Section: Introductionmentioning

confidence: 99%

Key Opportunities to Replace, Reduce, and Refine Regulatory Fish Acute Toxicity Tests

Burden

Benstead

Benyon

et al. 2020

Enviro Toxic and Chemistry

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Fish acute toxicity tests are conducted as part of regulatory hazard identification and risk-assessment packages for industrial chemicals and plant protection products. The aim of these tests is to determine the concentration which would be lethal to 50% of the animals treated. These tests are therefore associated with suffering in the test animals, and Organisation for Economic Cooperation and Development test guideline 203 (fish, acute toxicity) studies are the most widely conducted regulatory vertebrate ecotoxicology tests for prospective chemical safety assessment. There is great scope to apply the 3Rs principles-the reduction, refinement, and replacement of animals-in this area of testing. An expert ecotoxicology working group, led by the UK National Centre for the Replacement, Refinement and Reduction of Animals in Research, including members from government, academia, and industry, reviewed global fish acute test data requirements for the major chemical sectors. The present study highlights ongoing initiatives and provides an overview of the key challenges and opportunities associated with replacing, reducing, and/or refining fish acute toxicity studies-without compromising environmental protection.

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“…BWL as an objective indicator of MTD is supported by a similar cross-company initiative within the chemicals industry (mainly agrochemicals), led by the NC3Rs, where data on clinical signs observed during acute inhalation toxicity studies in rats was shared. Statistical analyses showed that BWL >10% is highly predictive (positive predictive value of 94%) of death or severe toxicity at higher doses, showing that the MTD had already been reached or exceeded ( Sewell et al 2015 ). More data sharing is required to establish criteria for longer study durations.…”

Section: Maximum Tolerated Dose (Mtd) Studiesmentioning

confidence: 99%

Opportunities to Apply the 3Rs in Safety Assessment Programs

Sewell

Edwards

Prior

et al. 2016

ILAR J

Self Cite

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Before a potential new medicine can be administered to humans it is essential that its safety is adequately assessed. Safety assessment in animals forms an integral part of this process, from early drug discovery and initial candidate selection to the program of recommended regulatory tests in animals. The 3Rs (replacement, reduction, and refinement of animals in research) are integrated in the current regulatory requirements and expectations and, in the EU, provide a legal and ethical framework for in vivo research to ensure the scientific objectives are met whilst minimizing animal use and maintaining high animal welfare standards. Though the regulations are designed to uncover potential risks, they are intended to be flexible, so that the most appropriate approach can be taken for an individual product. This article outlines current and future opportunities to apply the 3Rs in safety assessment programs for pharmaceuticals, and the potential (scientific, financial, and ethical) benefits to the industry, across the drug discovery and development process. For example, improvements to, or the development of, novel, early screens (e.g., in vitro, in silico, or nonmammalian screens) designed to identify compounds with undesirable characteristics earlier in development have the potential to reduce late-stage attrition by improving the selection of compounds that require regulatory testing in animals. Opportunities also exist within the current regulatory framework to simultaneously reduce and/or refine animal use and improve scientific outcomes through improvements to technical procedures and/or adjustments to study designs. It is important that approaches to safety assessment are continuously reviewed and challenged to ensure they are science-driven and predictive of relevant effects in humans.

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A global initiative to refine acute inhalation studies through the use of ‘evident toxicity’ as an endpoint: Towards adoption of the fixed concentration procedure

Cited by 21 publications

References 4 publications

In vitro Alternatives to Acute Inhalation Toxicity Studies in Animal Models—A Perspective

In vitro Alternatives to Acute Inhalation Toxicity Studies in Animal Models—A Perspective

Key Opportunities to Replace, Reduce, and Refine Regulatory Fish Acute Toxicity Tests

Opportunities to Apply the 3Rs in Safety Assessment Programs

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