Superfund Research Program
An Integrated Experimental and Computational Approach to Understand the Effects of Population Variability on the Shape of the Dose-Response Curve
Project Leader: John J. LaPres
Grant Number: P42ES004911
Funding Period: 2006-2020
Project Summary (2013-2020)
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 use of a threshold approach for non-cancer endpoints has been standard practice in chemical risk assessment for decades, while the arguments for linearization of the population dose-response curve are largely theoretical with a limited amount of experimental data. Changing to a linear, no threshold approach would have a major impact on clean up levels at Superfund sites. 2,3,7,8-Tetrachlerodibenze-p-dioxin (TCDD) is widely accepted to act through a receptor-mediated mode-of-action with an associated non-linear dose response.
The research team is using TCDD as a model chemical to experimentally evaluate the ideas laid out in the NRC report. The primary hypothesis of this 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 is being 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 goals of this proposal are:
- To 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
- To evaluate the effects of human inter-individual variability on the population dose-response curve for TCDD-mediated suppression of B-cell IgM secretion
- To 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 are being constructed and used to understand behavior of the system at low, environmentally relevant doses. Through these goals, 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 assumptions underlying the NRC report.