Methodologies for developmental immunotoxicity (DIT) testing.

ABSTRACT

Developmental immunotoxicity has gained increasing recognition as a significant factor influencing the risk of later life disease. Based on the data collected thus far on different chemicals and drugs, the developing immune system can be significantly more sensitive than the adult immune system to xenobiotic-induced insult. There are distinct differences between the immune system surrounding birth and that in the mature adult as well as differences in the nature of immunotoxic changes based on age. Immunosuppresssion is not the only concern. Immunotoxic changes that increase the risk for allergic or autoimmune responses should also be considered. Therefore, one should not assume that immunotoxicity assays validated for adult exposure assessment are inherently the most predictive for developmental immunotoxicology (DIT) evaluation. Many of those adult-based protocols were developed solely to detect immunosuppression, whereas DIT concerns include shifts in immune balance. For this reason, it is useful to examine the various immune endpoints that have been employed in recent perinatal immunotoxicity studies, compare those against routine adult immunotoxicity evaluation protocols, and consider the options that are available for effective DIT testing. The results published on several chemicals and drugs in recent years suggest that functional tests are a front-line priority for perinatal immunotoxicity detection and that a combination of at least two functional tests (such as a multi-isotype T-dependent antibody response (TDARs), and a cell-mediated immune response assay such as the delayed-type hypersensitivity assay and/or T cell or NK cytotoxicity assays) should be paired with immune cell populations and histopathological analysis. Cytokine production measurements offer outstanding promise and may eventually be able to be substituted for other more laborious procedures. However, multi-cytokine analysis needs to be standardized in terms of optimum source for analysis and protocol.