Evaluation ofthe Immune System

Choice of Experimental Animal. The choice for experimental animal is the species that absorbs, metabolizes, distributes, and excretes (ADME) the test chemical in a manner similar to humans. Often, the ADME ofthe test chemical is unknown before testing. Here, mice, rats, or dogs are used because there are methods available to detect effects on the immune response. Regulatory agencies require testing in both the rat and the mouse because validated testing methods are available.

Route and Duration. It seems obvious that xenobiotics should be tested in protocols in which the route of administration and duration are similar to the human situation. For example, animal studies on dioxin have used acute highdose protocols inducing adverse effects whereas the human experience is chronic low-dose exposure with no effects on the immune system.

For target organ toxicity studies, the study duration may be much shorter. When antigen is used to stimulate the immune system in the presence of maximal test chemical levels, changes can be detected in 14- or 28-day studies. This is related to the rapid turnover of immunocompetent cells during the elicitation of an immune response (Munson et al., 1991). Both the EPAand the FDA use either 14- or 28-day testing paradigms. Exposures of 90 days or longer are necessary to define induction of tolerance and compensatory mechanisms that may allow biotransformation of test material.

Sample Source. The ultimate goal of the immunotoxicologist is to compare effects of the test chemical in human and animal systems. This is often difficult because of differences in the sample sources. In humans, peripheral blood is used as the sample source. Lymphocytes in blood represent cells in transit and constitute only 2% of the total lymphocyte pool. Therefore, peripheral blood may not be representative of effects in lymphoid organs. In contrast, animal studies use splenic or lymph node cells from secondary lymphoid organs. Effects on lymphoid organs may predate effects observed in the peripheral blood.

Test Methods. The choice of test methods depends on whether a study's purpose is screening or mechanistic. In screening studies it is important to use holistic assays that measure the function of either the antibody- or cell-mediated immune effector mechanisms. The sheep red blood cell plaque-forming assay is the method of choice for a screening assay of inductive immune responses. It requires the interaction of several cell types (e.g., T and B cells and macrophages), the production of cytokines, and the synthesis of antibodies. Moreover, the assay can be used to detect the effect of xenobiotics on isotypic switching from IgM to IgG antibodies. In contrast, natural killer cell function may be a screening assay for innate immunity to viruses and metastatic tumors. There are no good screening assays for cell-mediated immunity. Delayed hypersensitivity and cytotoxic T cell function have been used for screening, but they suffer from inherent assay variability. Mechanistic studies are, of course, hypothesis driven and specific ex vivo or in vitro tests can be used.

Interpretation of Results. Data from an immunotoxicity test cannot be interpreted without consideration of other changes occurring in the test animal. Decrements in immune function are only relevant if they occur at dose levels at which there is no other toxicity and there is a clear dose-response relationship. Changes in body weight, organ weights, food consumption, or hematology are often associated with exposure to chemicals.

It is necessary to take into consideration the normal range or control values of the assay in data interpretation. Significant differences between treated and control animals are biologically relevant when they exceed the expected variability of the assay, the normal control range, or historical controls.

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