Chemically-induced immunopathology and immune functional changes

Toxicological pathology of lymphoid organs plays an important role in the risk assessment process of immunotoxicants. Identification of chemicals that have the potential to cause injury to the immune system is of considerable public health significance because of the role of the immune system in infectious diseases, hypersensitivity reactions and autoimmune diseases. In assessing immunotoxicity, a two-tier testing system is usually employed in rodents in which the first tier is a general screen for (immuno)toxicity including enhanced histopathology of lymphoid organs and the second tier consists of more specific immune function studies including host resistance tests or mechanistic studies. Studies with the potent immunotoxicants TCDD, TBTO, HCB, azathioprine and cyclosporin A are discussed, which provide data correlating histopathology with immune function changes. This is followed by a discussion of the outcomes of enhanced histopathology investigation in the interlaboratory validation studies with azathioprine, cyclosporin A and HCB in the rat, as well as the results of a recent evaluation of enhanced histopathology in the mouse as an indicator of immunotoxicity. From these studies, that have been the basis for a number of regulatory activities, the following conclusions can be drawn: i) the consistency between histopathology and functional tests, ii) the complimentary information of pathology and immunology observations, and iii) the dependence on standardised protocols and trained toxicologic pathologists to accurately identify and grade microscopical changes in lymphoid organs and tissues