is always a problem. Moreover, this problem is compounded in that the end points (infection and neoplasia) of immune-system deficiency are secondary to other confounding factors. To use immunotoxicity data from animal studies in the quantitative assessment of risk (the prediction of the incidence of disease at a given human dose), we would have to be able to predict the disease incidence that results from a given degree of immunodeficiency. However, animal immunotoxicology is now at a point where it should be used in identification of pollutants that have the potential to induce immunodeficiency and in the estimation of the degree of hazard that environmental agents have, according to their immunosuppressive potency. Because of the potential for tragic outcomes associated with exposure to immunosuppressive environmental pollutants, prudent public health concerns indicate the need for a remedy. The following discussion concerns some of the environmental toxicants shown to alter immune function at doses at which toxicity in other organ systems is not readily apparent.

Probably the most extensively studied class of environmental pollutants are halogenated aromatic hydrocarbons (HAHs), including dibenzo-p-dioxins, dibenzofurans, polychlorinated biphenyls (PCBs), and polybrominated biphenyls (PBBs) (Vos and Luster, 1989). These compounds, many of which are widespread in the environment, are primarily used in commercial production of industrial chemicals, pesticides, flame retardants, and heat conductors. Dioxins and PCBs produce myelosuppression, immunosuppression, thymic atrophy, and inhibition of immune complement system components in almost all species tested, including primates. The most potent dioxin, TCDD, is an extremely potent immunosuppressant in mice. A dose of 1-2 µg/kg of body weight is all that is required to reduce immune function by 50%. As probably occurs with a number of immunosuppressive HAHs, the specific effects of TCDD on the immune system can vary, depending on the age of the animal at the time of chemical exposure. For example, the primary effect of perinatal TCDD exposure is persistent suppression of cellular immunity, a condition that mimics neonatal thymectomy. In contrast to perinatal exposure, TCDD exposure in adult mice, while still inducing deterioration of thymic tissue (predominantly cortical lymphoid depletion), causes a transient antiproliferative response in rapidly dividing cell populations, including hematopoietic cells and B cells. The marked and persistent suppression of T-cell function seen in neonates is not manifested in adults, although suppression of cytotoxic T-cell response and altered members of regulatory T cells have been reported.

Regardless of age at the time of exposure or the target tissue examined, immunosuppression by TCDD, as well as by PCBs, is believed to be mediated through stereospecific and irreversible binding to an intracellular receptor protein (the Ah genotype) found in the cellular targets for TCDD, including lymphoid tissue, bone marrow cells, and the thymic epithelium (Thomas and Faith, 1985). The Ah genotype was determined primarily in immune studies comparing inbred strains of Ah-responsive and nonresponsive mice in which the ability of TCDD to cause immunotoxicity correlated with the presence of the Ah locus (Vecchi et al., 1983; Tucker et al., 1986). In addition, a good correlation exists between the binding affinities of various HAHs and their ability to induce immunotoxicity (Silkworth et al., 1984; Tucker et al., 1986).

The role, if any, of microsomal enzyme induction in the cellular mechanisms responsible for immunotoxicity after TCDD binds to its receptor is unknown. The observation that the thymic epithelium contains a high concentration of receptor has led to the