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

Fiona Sewell Ian Ragan Tim Marczylo Brian Anderson Anne Braun 1 Warren Casey Ngaire Dennison David Griffiths Robert Guest Tom Holmes Ton van Huygevoort Ian Indans Terry Kenny Hajime Kojima Kyuhong Lee Pilar Prieto 2 Paul Smith Jason Smedley William S. Stokes Gary Wnorowski Graham Horgan
1 INERIS - Institut National de l'Environnement Industriel et des Risques
2 IHCP - JRC Institute for Health and Consumer Protection
Abstract : Acute inhalation studies are conducted in animals as part of chemical hazard identification and characterisation, including for classification and labelling purposes. Current accepted methods use death as an endpoint (OECD TG403 and TG436), whereas the fixed concentration procedure (FCP) (draft OECD TG433) uses fewer animals and replaces lethality as an endpoint with ‘evident toxicity.’ Evident toxicity is defined as clear signs of toxicity that predict exposure to the next highest concentration will cause severe toxicity or death in most animals. A global initiative including 20 organisations, led by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) has shared data on the clinical signs recorded during acute inhalation studies for 172 substances (primarily dusts or mists) with the aim of making evident toxicity more objective and transferable between laboratories. Pairs of studies (5 male or 5 female rats) with at least a two-fold change in concentration were analysed to determine if there are any signs at the lower dose that could have predicted severe toxicity or death at the higher concentration. The results show that signs such as body weight loss (>10% pre-dosing weight), irregular respiration, tremors and hypoactivity, seen at least once in at least one animal after the day of dosing are highly predictive (positive predictive value > 90%) of severe toxicity or death at the next highest concentration. The working group has used these data to propose changes to TG433 that incorporate a clear indication of the clinical signs that define evident toxicity.
Keywords : ACUTE INHALATION STUDIES 3RS EVIDENT TOXICITY FIXED CONCENTRATION PROCEDURE (FCP) REFINEMENT REGULATORY TOXICOLOGY TG4303 TG436 TG433
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Journal articles
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Submitted on : Tuesday, August 7, 2018 - 2:24:47 PM
Last modification on : Tuesday, August 7, 2018 - 2:24:48 PM

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Fiona Sewell, Ian Ragan, Tim Marczylo, Brian Anderson, Anne Braun, et al.. A global initiative to refine acute inhalation studies through the use of ‘evident toxicity’ as an endpoint : Towards adoption of the fixed concentration procedure. Regulatory Toxicology and Pharmacology, Elsevier, 2015, 73 (3), pp.770-779. ⟨10.1016/j.yrtph.2015.10.018⟩. ⟨ineris-01855133⟩

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