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Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment
its assessment of immunotoxicity produced by TCDD, other dioxins, and DLCs.
The assessment of changes in immune competence, regardless of the cause, is complex, as the immune system is composed of a large and diverse group of cellular and soluble components. In addition, compensatory and overlapping mechanisms in host immunity can make it difficult to identify subtle or modest changes within the immune system.
Because of the many different cell types and soluble factors, which alone or cooperatively mediate a wide variety of evocable immunological responses, there is no one test or assay that can measure all the different elements. Therefore, the approaches used to identify changes in immune status are multifaceted, including pathological examination of lymphoid organs, enumeration of leukocyte subpopulations, quantification of soluble mediators, and measurement of immune function responses, such as susceptibility to infection or reduced immunological responses to vaccines. Standard assays are available for all the above determinations; however, because of the sheer enormity of the task to measure them all, immune competence is typically assessed by using a small number of immunological end points, often quantifying various aspects of innate, humoral, and cell-mediated immunity. Therefore, the EPA review draws on a large but diverse database of studies that are often difficult to compare because different assays, model systems, responses, and animal species were used.
EPA draws several important conclusions about the immunotoxicity of TCDD, other dioxins, and DLCs that are summarized in the Reassessment, Part III, Integrated Summary and Risk Characterization. The first is that “there appears to be too little information to suggest definitively that 2,3,7,8-TCDD at levels observed (in the reported studies) causes long-term adverse effects on the immune system in adult humans” (p. 2-34; lines 19 to 21). The second is that “cumulative evidence from a number of studies indicates that the immune system of various animal species is a target for toxicity of TCDD and structurally-related compounds, including PCDDs, PCDFs [polychlorinated dibenzofurans] and PCBs [polychlorinated biphenyls]” (p. 2-34; lines 24 to 26). Third, animal studies show that TCDD suppresses both “cell-mediated and humoral immune responses, suggesting that there are multiple cellular targets within the immune system that are altered by TCDD” (p. 2-34; lines 26 to 28). EPA goes on to state that “it can be inferred from the available data that dioxin-like congeners are immunosuppressive” in animals. Fourth, the weight of evidence from animal studies in vivo and in vitro “supports a role for Ah-mediated immune suppression” by DLCs (p. 2-35, lines 27 to 28); “other in vivo and in vitro data, however, suggest that non-AHR (aromatic hydrocarbon receptor)-mediated mechanisms may also play