Model for Assessment of Immunotoxicity of Environmental Pollutants

A panel of tests have been developed based on laboratory exposure of dogs to levels of PCB (Aroclor 1248) commonly found around superfund sites. Many of the immune and non-immune aberrations described appear unusual. <P> For this reason, we propose to: <OL> <LI> evaluate the sensitivity of the panel by exposing dogs to varying levels of dietary PCB (100 microg 2 mg/kg); <LI> evaluate the contribution of PCB-induced hypothyroidism to immunologic changes, delayed wound healing, weight loss and behavioral changes by comparing PCB fed, control and thyroidectomized dogs before and after oral supplementation with triiodothyronine (T3). To evaluate the efficacy of T3 therapy on immune system restoration and evaluate the metabolism of thyroxine (T4) by measuring T4 half-life in control and PCB fed dogs; <LI> to probe the fundamental mechanisms responsible for PCB-induced hypogammaglobulinemia A and M. Studies will focus on the appropriateness of B-cell Ig class switching in PCB and normal dogs, circulating half-life of canine IgA and IgM in PCB fed and control dogs and the use of in vitro techniques to study B-cell de-novo antibody synthesis and its relationship to cell proliferation, cytokine synthesis, response to cytokines and response to alternative signal transduction. Increased cellular proliferation was documented in PCB fed dogs by blastogenesis testing, histology and measuring p34cdc-2 kinase. The latter was elevated in all PCB fed dogs and is a major regulator of cell cycle induction and progression. We will evaluate levels of p34cdc-2 kinase in lymphoid tissues of dogs fed PCB to determine if activation is present, dose dependent and associated with hyper- and hypoproliferation states. <LI> Dogs will be evaluated in households selected on the basis of known exposure risk (Akwesasne Nation Community) using the field test panel. Of the seven tests conducted in dogs, five will be quantitated in humans sharing the household (by N.Y.S.D.O.H.). We will compare results of our panel in dogs with other household occupants and attempt to correlate physiological changes with. PCB levels and exposure risk. Two tests will be conducted in wild caught shrews from the same geographic site. Through these studies we hope to have a greater understanding of the basic mechanisms involved in PCB toxicity. The dog model will provide immunologic and endocrine targets for PCB activity. We shall determine the lowest concentration of PCB which can pose a toxic risk to dogs (and humans) and we shall validate or panel of biomarkers in dogs by cross-comparison to humans and wildlife which share the environment with dogs.