SUMMARY OF AN INTERNATIONAL METHODS VALIDATION-STUDY, CARRIED OUT IN 9 LABORATORIES, ON THE IMMUNOLOGICAL ASSESSMENT OF CYCLOSPORINE-A IN THE FISCHER-344 RAT

In evaluating the adverse effects of chemicals on the immune response, the mouse has been the predominant animal species of choice. The acce ptance of the mouse as a validated animal model has been the result, i n part, of the studies conducted by the US National Toxicology Program (NTP). In these studies functional and host-resistance assays were de veloped and validated using five compounds and four testing laboratori es. In toxicological evaluations of drugs and chemicals, the rat has b een the rodent species of choice of the worldwide toxicology community . The current study was designed to begin the validation of the rat as a model for immunotoxicology assessment. Nine laboratories participat ed in the study, including laboratories from Canada, France, the Unite d States and The Netherlands. Before the study began a detailed protoc ol was prepared and standard operating procedures were developed. Cycl osporin A was selected as the prototype immunosuppressive compound, an d was administered orally to male Fischer 344 rats. Data were collecte d on standardized forms and submitted to a central laboratory for stat istical analysis. Similar dose-response trends were observed between t he various laboratories. In the natural killer cell assay and concanav alin A mitogen assay similar results were observed in at least 63% of the laboratories. In the T-dependent antibody-plaque forming cell assa y, and the mixed leucocyte response, 100% of the laboratories that con ducted the assays had statistically similar results. The results from this study support the usefulness of the rat as a model species for im munotoxicity assessment and represent a beginning for international in terlaboratory validation of immunotoxicology assays in this species.