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Michigan State University

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
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

Learn More About the Grantee

Visit the grantee's eNewsletter page Visit the grantee's eNewsletter page

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:

  1. 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
  2. To evaluate the effects of human inter-individual variability on the population dose-response curve for TCDD-mediated suppression of B-cell IgM secretion
  3. 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.

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