A global initiative to refine acute inhalation studies through the use of ‘evident toxicity’ as an endpoint : Towards adoption of the fixed concentration procedure - Ineris - Institut national de l'environnement industriel et des risques Access content directly
Journal Articles Regulatory Toxicology and Pharmacology Year : 2015

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
  • Function : Author
Ian Ragan
  • Function : Author
Tim Marczylo
  • Function : Author
Brian Anderson
  • Function : Author
Warren Casey
  • Function : Author
Ngaire Dennison
  • Function : Author
David Griffiths
  • Function : Author
Robert Guest
  • Function : Author
Tom Holmes
  • Function : Author
Ton van Huygevoort
  • Function : Author
Ian Indans
  • Function : Author
Terry Kenny
  • Function : Author
Hajime Kojima
  • Function : Author
Kyuhong Lee
  • Function : Author
Paul Smith
  • Function : Author
Jason Smedley
  • Function : Author
William S. Stokes
  • Function : Author
Gary Wnorowski
  • Function : Author
Graham Horgan
  • Function : Author

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.

Dates and versions

ineris-01855133 , version 1 (07-08-2018)

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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, 2015, 73 (3), pp.770-779. ⟨10.1016/j.yrtph.2015.10.018⟩. ⟨ineris-01855133⟩

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