Assessment of cytotoxicity assays as predictors of ocular irritation of pharmaceuticals.
We have evaluated the use of cytotoxicity assays in vitro as an alternative to predicting ocular irritation potential in animals. Three different measures of cytotoxicity--leucine incorporation into protein, MTT dye reduction, and neutral red uptake--were measured in a presumed target cell, corneal epithelial cells from rabbit, as well as in a nontarget cell, V79 (Chinese hamster lung fibroblasts). An IC50 value was determined for each endpoint in one or both target cells for a series of 27 commercially available compounds and 56 in-house materials from a variety of chemical classes (carbonitriles, imidazoles, substituted benzenes, aromatic acids, peptides, phenols, esters, etc.). Analysis of the data by Spearman rho rank correlation and Pearson's correlation indicated that none of the endpoint-target cell combinations used here accurately predicts in vivo irritation potential for this group of compounds. The MTT dye reduction endpoint gave the best overall correlation, regardless of target cell, but still had a correlation coefficient below -0.5. We conclude that the measurement of cytotoxicity is of limited value as an alternative assay for the classes of materials studied here.
Sina
J F
JF
Merck Sharp and Dohme Research Laboratories, West Point, PA.
Ward
G J
GJ
Laszek
M A
MA
Gautheron
P D
PD
D000818:Animals; D002478:Cells, Cultured; D003315:Cornea / Q000166:cytology / Q000187:drug effects*; D064420:Drug-Related Side Effects and Adverse Reactions; D004848:Epithelium / Q000187:drug effects; D007930:Leucine / Q000378:metabolism; D009499:Neutral Red / Q000378:metabolism; D011817:Rabbits; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014116:Toxicology / Q000379:methods
D013778:Tetrazolium Salts; D013844:Thiazoles; D009499:Neutral Red; C022616:thiazolyl blue; D007930:Leucine