Industry experience in the identification of the immunotoxic potential of agrochemicals

During recent years immunotoxicity has been increasingly recognized as an important endpoint in rodent short-time studies. This has been documented by FDA, OECD, and just recently in a new EPA guideline. This guideline is confined to the immunosuppressive effects of chemicals. Various parameters to detect immunotoxic effects exist, including cell counts, cell subpopulation analysis, functional tests, and/or advanced pathology. Their validity in detecting immunotoxic effects has been demonstrated to different degrees. Our experience with some of these parameters is reported here. Due to the recommendation of the guideline, it is necessary to differentiate from the context of the study data between primary and secondary immunotoxicity, the latter being an unspecific sequel of toxicity to other organs. In our studies, we found examples for both mechanisms. For primary immunotoxic substances, immunosuppression is markedly more frequent than immunostimulation, although primary effects, on the whole, occur relatively seldom during toxicological screening. In both cases, we found a good correlation between cell analysis and functional parameters on one hand and pathology on the other, thus warranting that overt immunotoxicity would not remain undetected in routine studies with high dose levels. However, the higher predictivity of functional parameters and the analysis of special subpopulations is necessary for the determination of the no-effect level and for fine differentiation during the screening of comparable immunotoxic compounds. Cyclosporin A is an example for the former, and the screening of different agrochemicals is an example for the latter aspect. As verified by the collaboration studies, an advanced histopathology of lymphoid organs, combined with flow cytometry of immune competent cells and a functional assay, is able to discriminate between primary and secondary effects as well as immunosuppression and immunostimulation, and thus to identify an immunotoxic hazard.