The overall aim of this Challenge is to develop a QSAR-based tool that reliably predicts human respiratory irritancy potential of chemicals. The tool should fulfill the five OECD principles for QSAR validation to demonstrate the statistical and mechanistic reliability of the model. This will endorse the model's use under regulatory context (e.g. REACH, Environmental Protection Agency (EPA)).
Inhalation of certain chemicals may potentially cause irritation to the respiratory tract resulting in inflammation, which if unresolved can lead to irreversible fibrosis of the lungs (Cometto-Muñiz JE and Cain WS, 1995). Examples of respiratory irritants include acetic acid, benzoyl chloride and formic acid.
Currently there are limited in silico, in vitro and in vivo models to determine the respiratory irritation potential of new or existing substances. Assessing whether a chemical will cause respiratory irritation in humans is often determined by observations in rodent acute (single) and repeat dose inhalation toxicology studies. However, there are no specific test protocols in place to determine the irritancy potential of respiratory toxicants or allergens. In the absence of specific or well defined guidelines, respiratory irritation results are extrapolated from the acute inhalation toxicity studies (the Organisation for Economic Co-operation and Development (OECD) test guidelines (TG) 403 and 436) performed on rats (OECD, 2009a, OECD 2009b). This involves the modification of protocols to include endpoints for respiratory irritation and requires additional dose groups. For example, RD50 data (concentration producing a 50% respiratory rate decrease as determined by the Alarie test (Alarie Y, 1966)) in rodents is often used as a surrogate for irritation potency of respiratory irritants. However, it is difficult to extrapolate the rodent respiratory hazard data to human respiratory irritation.
Under the REACH (Registration, Evaluation, Authorisation and Restriction of chemicals) regulations, the registrant may be able to demonstrate that a substance poses no respiratory risk if exposure via the inhalation route is not expected. However, for most substances exposure via the inhalation route is likely to be common, and if the substance is a skin or eye irritant then it may be difficult to justify a waiver for acute inhalation studies. Without robust models for respiratory irritation, it is possible that chemicals may pass through the R&D pipeline and reach the market place with the potential liability of being respiratory irritants. The goal of this Challenge is to develop an accurate in silico tool that is capable of predicting human respiratory irritation potential.
The respiratory irritancy potential of chemicals is typically assessed and extrapolated from modified rodent acute inhalation toxicity studies (OECD TGs 403 and 436 (OECD, 2009a, OECD, 2009b)). These in vivo toxicity studies are classified as severe under the UK’s Animals (Scientific Procedures) Act and require additional dose groups. A typical modified acute inhalation toxicity study uses approximately 42 animals/study.
Development of a QSAR tool that reliably predicts the respiratory irritancy potential of chemicals in humans will allow for the early identification of potential toxicities in candidate chemicals without having to use in vivo studies, and contribute to the scientific justification to waive the in vivo studies for respiratory irritation for those taken forward to registration.
Single Phase Challenge winner
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Full Challenge information
The following Challenge Panel considered applications submitted to this Challenge:
|Dr Malcolm Skingle (Chair)||GlaxoSmithKline|
|Dr Satinder Sarang (Sponsor)||Shell|
|Dr Martijn Rooseboom (Sponsor)||Shell|
|Dr Uday Phadke||Cartezia|
|Dr Scott Boyer||Karolinska Institute, Swedish Toxicology Sciences Research Centre|
|Dr Steven Webb||Liverpool John Moores University|
|Dr David Lovell||St George's University of London|
|Professsor Andrew Smith||MRC Toxicology Unit|