Contact sensitivity by diisocyanates: potencies and cross-reactivities

The dermal sensitizing potencies of four diisocyanates were investigated using the mouse ear-swelling test (MEST) with BALB/cBy mice. Mice were administered topical doses of diisocyanates to the abdomen and were challenged on the ear 4 days later with a nonirritating dose of chemical. The increase in ear thickness at 24 hr postchallenge indicated the extent of contact sensitivity. Ear thickness increase plotted against the log of the dose of diisocyanate indicated three regions of effects: a no-effect region, a dose-response region, and a region of reduced response at highest dosages. The potencies of the diisocyanates expressed as the SD50 (dose required to sensitize 50% of the animals in each group) were hexamethylene diisocyanate, 0.088 mg/kg; diphenylmethane-4,4'-diisocyanate, 0.73 mg/kg; and toluene diisocyanate, 5.3 mg/kg. For dicyclohexylmethane diisocyanate, the steep dose-response curve suggested a threshold-type response occurring at 0.24 mg/kg. The specificity of sensitization was evaluated by challenging sensitized animals with heterologous diisocyanates. The homologous reactions were always the most extensive. However, cross-reactions were noted between aryl and alkyl diisocyanates. Toluene diisocyanate, the weakest sensitizer, elicited the fewest cross-reactions. The MEST proved to be a simple and effective method for assessing delayed-type hypersensitivity without need of adjuvants, occlusive patches, abrasions, or other procedures which fail to mimic industrial exposures. The observation that very high exposures resulted in reduced response indicates that protocols which generate dose-response data must be utilized to accurately assess the sensitizing potencies of industrial chemicals.