Industry experience in the identification of the immunotoxic potential of agrochemicals

During recent years immunotoxicity has been increasingly recognized as an i mportant endpoint in rodent short-time studies. This has been documented by FDA, OECD, and just recently in a new EPA guideline. This guideline is con fined 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 d etecting immunotoxic effects has been demonstrated to different degrees. Ou r experience with some of these parameters is reported here. Due to the rec ommendation of the guideline, it is necessary to differentiate from the con text of the study data between primary and secondary immunotoxicity, the la tter 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, altho ugh primary effects, on the whole, occur relatively seldom during toxicolog ical screening. In both cases, we found a good correlation between cell ana lysis and functional parameters on one hand and pathology on the other, thu s warranting that overt immunotoxicity would not remain undetected in routi ne studies with high dose levels. However, the higher predictivity of funct ional parameters and the analysis of special subpopulations is necessary fo r the determination of the no-effect level and for fine differentiation dur ing 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 o f immune competent cells and a functional assay, is able to discriminate be tween primary and secondary effects as well as immunosuppression and immuno stimulation, and thus to identify an immunotoxic hazard. (C) 2001 Elsevier Science B.V. All rights reserved.