Pretent status and problems with the methods for testing immunotoxicity.

Abstract

Immunotoxicology has become a very important field because of the immunological adverse effects of various cytokines (IL-2 and IFNα, etc.) and biological response modifiers in addition to the immunosuppression caused by steroid hormones and anticancer agents and drug (antibiotic)-induced allergies. The adverse effects include the development of infectious diseases or various cancers due to immunosuppression and the occurrence of allergies or autoimmunity due to immunopotentiation. Studies to establish testing guidelines were done worldwide using immunosuppressants (azathioprine and cyclosporin A), and the most suitable marker or test system to detect immunotoxicity of xenobiotics was explored. Moreover, the necessity of immunotoxicity studies is stressed in “Redbood II” (FDA, draft; 1993). In experiments on thymus toxicity in the rat, the following data were obtained. The weight of the thymus increased from birth until 8 weeks of age and then decreased gradually. The weight was also decreased by stress induced by factors such as fasting, the attachment of an Elizabeth collar, etc. and the administration of cyclophosphamide (immunosuppressant). This drug caused degenerative changes in the thymus, spleen, and bone marrow and inhibited the plaque forming cell response to sheep red blood cells in rats. TGP-3 (human recombinant interleukin 2) caused fever via the production of interleukin 1β and increased the number of eosinophils. When the immune system was suppressed by exposure to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) or chronic administration of an immunosuppressant (cyclophosphamide), the susceptibility to infectious diseases and tumor formation was increased. On the other hand, when the action of the immune system was potentiated by the repeated administration of an immunomodulator (antirheumatic agent), autoimmune diseases rarely occurred. The importance of immunotoxicology and future directions for immunotoxicity testing are discussed in this paper.