Project 2: An Integrated Experimental and Computational Approach to Understand t

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PROJECT SUMMARY (See Instructions); A recent report released by the National Research Council (NRC) entitled "Science and Decisions" has suggested that in cases where there is a background incidence of a dysfunction which is augmented by a toxicant, human variability would effectively linearize the population dose-response curve even if the dose response curve in an individual person was non-linear or showed a threshold. The arguments for linearization of the dose-response curve due to human variability are largely theoretical with a limited amount of experimental data and the use of a threshold approach for non-cancer endpoints has been standard practice in chemical risk assessment for decades. Changing to a linear, no threshold approach would have a major impact on clean up levels at Superfund sites and any decision to replace the traditional threshold approach for non-cancer endpoints should be based on sound science with adequate experimental data 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is widely accepted to act through a receptor-mediated mode-of action with an associated non-linear dose response. We propose to use TCDD as a model chemical to experimentally evaluate the ideas laid out in the NRC report. The primary hypothesis of the project is that characterization of the dose-response curves for the immunosuppression and embryotoxicity of TCDD will demonstrate that the response is consistent with a non-linear model and the incorporation of population variability will not linearize the population-based dose-response curve in the manner proposed by the NRC. This hypothesis will be tested using a panel of inbred mice that provides an In vivo model of the genetic heterogeneity in the human population and an in vitro human model. The specific aims of this proposal are: (1) evaluate the effects of genetic heterogeneity on the population dose-response curve for TCDD-mediated embryotoxicity and serum hormone alterations using the Mouse Phenome Diversity Panel of inbred mice as a model; (2) evaluate the effects of human inter-individual variability on the population dose-response curve for TCDD-mediated suppression of B-cell IgM secretion; (3) Identify and characterize the genes and pathways associated with the inter-strain differences in TCDD-mediated embryotoxicity to understand the mode-of-action. Computational models of TCDD-mediated embryotoxicity and B-cell suppression will be constructed and used to understand behavior of the system at low, environmentally-relevant doses. Through these specific aims, a substantial amount of scientific data and analysis will be generated across multiple non-cancer endpoints (early embryotoxicity, steroid hormone alterations, and B-cell immunosuppression), in two different species (mice and humans), and using both in vivo and in vitro models to evaluate the assumption underlying the NRC report.