A collaborative evaluation of seven alternatives to the Draize eye irritation test using pharmaceutical intermediates.
Much of the data which have been generated on in vitro alternatives to the Draize eye irritation test have dealt with compounds within a specific chemical class or product category. However, in the pharmaceutical industry, it is often necessary to evaluate materials which are not related in structure or properties. It was thus decided to evaluate a diverse series of chemicals in seven in vitro methods for estimating ocular irritation. Thirty-seven test materials were chosen to represent a broad range of pH, solubility, and in vivo irritation potential. Assays were chosen to include as many different types of end points as practical. The group of assays was composed of TOPKAT (assessing structure-activity relationships), bovine corneal opacity-permeability (BCO-P; corneal opacity/toxicity), Eytex (protein coagulation), neutral red uptake (cytotoxicity), MTT in living dermal equivalent (cytotoxicity), Microtox (cytotoxicity in bacteria), and CAMVA (inflammation/toxicity). The results of the study indicated that, in general, the cytotoxicity end points did not correlate well with the in vivo data. The BCO-P, CAMVA, and Eytex assays had the best overall concordance (88.9, 75.8, and 75.0%, respectively) with this set of compounds. Estimation of irritation potential based on structure-activity (TOPKAT) was possible for only approximately 50% of the compounds; however, the assay showed 100% sensitivity (i.e., no false negatives), but low specificity (i.e., negatives correctly identified only 54.5% of the time). These data suggest that for screening of chemicals of diverse structure and properties, the more mechanism-based assays, as opposed to general cytotoxicity assays, hold more promise and should be further evaluated.
Sina
J F
JF
Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Galer
D M
DM
Sussman
R G
RG
Gautheron
P D
PD
Sargent
E V
EV
Leong
B
B
Shah
P V
PV
Curren
R D
RD
Miller
K
K
D000826:Animal Testing Alternatives; D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D005069:Evaluation Studies as Topic; D005123:Eye / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007509:Irritants / Q000633:toxicity*; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
D007509:Irritants