title: Critical appraisal of alternative irritation models: three decades of testing ophthalmic pharmaceuticals.
abstract: BACKGROUND
  Testing ocular tolerability of ocular pharmaceuticals is an essential regulatory requirement. The current approved reference model (gold standard) for ocular irritation testing is the Draize test. However this method is subjective and involves using live animals, hence the need to develop alternative in vitro and ex vivo testing strategies.
  
  
  METHODS
  Pubmed, Science Direct, Scopus, Google Scholar, Medline, Current Content, Web of Science and validation reports from international regulatory bodies; The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and European Centre for the Validation of Alternative Methods (ECVAM) were searched for in vitro alternatives.
  
  
  RESULTS
  Whilst no single in vitro test can effectively replace the Draize eye irritation test, regulatory bodies and cosmetic/pharmaceutical industries agree that there is a need for in vitro alternatives with validated endpoints to evaluate pharmaceutical ingredients and finished eye products.
  
  
  RESULTS
  There is no single in vitro test / assay that can predict the ocular irritation potential of mild to moderate test substances.
  This review provides a critical appraisal of the selected in vitro and ex vivo ocular toxicity models recommended by international regulatory bodies. These include cytotoxicity methods, biochemical systems and ex vivo assays. The latter are approved by ECVAM as in vitro alternatives for the well-known Draize test. Hen's egg test-chorioallantoic membrane and the isolated rabbit eye test are also accepted by regulatory agencies in France, Germany, the Netherlands and the UK. A combination of ex vivo assays along with histological examination of excised bovine cornea can predict the conjunctival and corneal tolerability and cover a wider range of ocular pharmaceutical substances.
authors: Faculty of Science, Engineering and Computing, Kingston University London, Kingston upon Thames, UK Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, Egypt.
authors: Hamdy
authors: H
authors: Abdelkader
authors: Faculty of Science, Engineering and Computing, Kingston University London, Kingston upon Thames, UK.
authors: Barbara
authors: B
authors: Pierscionek
authors: Faculty of Science, Engineering and Computing, Kingston University London, Kingston upon Thames, UK.
authors: Mark
authors: M
authors: Carew
authors: School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
authors: Zimei
authors: Z
authors: Wu
authors: Faculty of Science, Engineering and Computing, Kingston University London, Kingston upon Thames, UK School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand r.alany@kingston.ac.uk r.alany@auckland.ac.nz.
authors: Raid G
authors: RG
authors: Alany
mesh_terms: D060433:Administration, Ophthalmic; D000826:Animal Testing Alternatives / Q000639:trends*; D000818:Animals; D002417:Cattle; D003315:Cornea / Q000187:drug effects*; D065306:Corneal Injuries / Q000139:chemically induced*; D004345:Drug Industry / Q000639:trends; D005126:Eye Burns / Q000139:chemically induced*; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000009:adverse effects*; D011817:Rabbits; D015203:Reproducibility of Results
chemical_list: D009883:Ophthalmic Solutions
keywords: Draize test; bovine cornea; cornea; hen's egg chorioallantoic membrane; irritation; ocular toxicity; opacity and permeability