Title

Immunomodulatory effects of organochlorine mixtures

Date of Completion

January 2005

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

The immunotoxic effects of organochlorines (OCs) have been demonstrated in laboratory animals. However, the immunotoxicity of mixtures, rather than single OC compounds, has rarely been evaluated. Since environmental contaminants are found in mixtures in "real life," the present study investigated the effects of exposure to OC compounds (PCB IUPAC# 138, 153, 169, 180 and 2,3,7,8-tetrachlorodibenzo-p-dioxin), individually and in mixtures, on the acquired immune system, upon in vitro exposure, in B6C3F1 mice (the common model in immunotoxicology), marine mammals and humans. T and B lymphocyte proliferation and immunophenotyping were significantly modulated by OCs in most species tested, mostly by non-coplanar PCBs. This is a concern because the non-coplanar PCBs have little or no affinity to the AhR and do not exert their toxicity through the AhR pathway, they have been considered relatively non-toxic. Additionally, the effects of OCs in mixture were not simply additive in most species and were hard to predict from the effects of the components due to the complexity of the OC interactions in mixture, such as synergistic and antagonistic effects. Immunophenotyping demonstrated that the most likely target of OCs appeared to be T cells in mice and both T and B cells in humans upon Con A and LPS stimulation, respectively. Clustering the data from lymphocyte proliferation results suggested that phylogeny does not predict the toxicity of OCs. Our results also clearly demonstrated that the current methods to estimate the toxicity of OC mixtures, the toxic equivalency (TEQ approach, and the mouse model did not accurately predict the effects of OCs in marine mammals or humans. Our data suggests the presence of species-specific sensitivities to different mixtures, in which OC interactions are complex, and that OCs exert their effects through dioxin-independent pathways. A better understanding of the comparative immunotoxic potential of mixtures of OCs may provide a more accurate and better approach for the evaluation of impacts of these ubiquitous contaminants on health, and the assessment of the risk associated with environmental exposure for wildlife, domestic animals and humans. ^