Importance of immunotoxicity in safety assessment: a medical toxicologist's perspective.

The clinical data accumulated so far unequivocally demonstrate that immunotoxicity is associated with significant morbidity. Immunotoxic effects are divided into four categories: immunosuppression, immunostimulation, hypersensitivity and autoimmunity. Each category is associated with distinct adverse effects. Even though concern primarily focused on immunosuppression, hypersensitivity and immunostimulation are also key issues, especially with pharmaceuticals. Histology of the lymphoid organs is not sufficient to reliably predict immunosuppression and at least one immune function assay is recommended. It is not known whether function assays used to predict immunosuppression are applicable to the prediction of immunostimulation. Specific assays can be helpful. Most available animal models and assays are not valid to assess the potential for hypersensitivity, and autoimmunity is not predictable at all. Conflicting guidelines and the lack of human data contribute further to this situation. Several critical factors deserve consideration. Dose-response relationships are often atypical and this should impact on the study design. Due to the redundancy of the immune system, a single change is not necessarily sufficient evidence for immunotoxicity so that a global assessment of all preclinical findings is advisable. Genetic factors play a major role in immune responses. As wide inter-individual variability is unavoidable, sufficient numbers of animals, a cautious comparison with both study and historical controls, and the possible use of inbred or genetically modified animals are to be considered. Marked interspecies differences in the immune system should lead to use more than one animal species and to confirm animal data during clinical trials. The inclusion of certain immune endpoints applicable to animals and man is therefore essential. The optimal timing of immunotoxicity studies is debated, but early studies are recommended. Despite significant progress, quite a few issues are still pending. Nevertheless, due to the many adverse effects reported in man, the immunotoxicity potential of every new molecular entity should be systematically and specifically evaluated.