; 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.

Public Health Relevance

; The research addresses whether human variability linearizes 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. Changing to a linear, no-threshold approach would have a major impact on clean up levels at Superfund sites. Experimentally addressing this issue has significant economic and public health implications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES004911-24
Application #
8829252
Study Section
Special Emphasis Panel (ZES1-LWJ-D)
Project Start
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
24
Fiscal Year
2015
Total Cost
$313,288
Indirect Cost
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Nault, Rance; Doskey, Claire M; Fader, Kelly A et al. (2018) Comparison of Hepatic NRF2 and Aryl Hydrocarbon Receptor Binding in 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Treated Mice Demonstrates NRF2-Independent PKM2 Induction. Mol Pharmacol 94:876-884
Dornbos, Peter; LaPres, John J (2018) Incorporating population-level genetic variability within laboratory models in toxicology: From the individual to the population. Toxicology 395:1-8
Zhang, Shuai; Liu, Qinfu; Gao, Feng et al. (2018) Interfacial Structure and Interaction of Kaolinite Intercalated with N-methylformamide Insight from Molecular Dynamics Modeling. Appl Clay Sci 158:204-210
Fader, Kelly A; Nault, Rance; Raehtz, Sandi et al. (2018) 2,3,7,8-Tetrachlorodibenzo-p-dioxin dose-dependently increases bone mass and decreases marrow adiposity in juvenile mice. Toxicol Appl Pharmacol 348:85-98
Zhang, Shuai; Liu, Qinfu; Cheng, Hongfei et al. (2018) Mechanism Responsible for Intercalation of Dimethyl Sulfoxide in Kaolinite: Molecular Dynamics Simulations. Appl Clay Sci 151:46-53
Zhang, Qiang; Li, Jin; Middleton, Alistair et al. (2018) Bridging the Data Gap From in vitro Toxicity Testing to Chemical Safety Assessment Through Computational Modeling. Front Public Health 6:261
Fader, K A; Nault, R; Kirby, M P et al. (2018) Corrigendum to ""Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERB?/? activation in aryl hydrocarbon receptor-elicited hepatotoxicity"" [Toxicol. Appl. Pharmacol. 321 (2017) 1-17]. Toxicol Appl Pharmacol 344:74
Konganti, Kranti; Ehrlich, Andre; Rusyn, Ivan et al. (2018) gQTL: A Web Application for QTL Analysis Using the Collaborative Cross Mouse Genetic Reference Population. G3 (Bethesda) 8:2559-2562
Zhang, Shuai; Liu, Qinfu; Gao, Feng et al. (2018) Molecular Dynamics Simulation of Basal Spacing, Energetics, and Structure Evolution of a Kaolinite-Formamide Intercalation Complex and Their Interfacial Interaction. J Phys Chem C Nanomater Interfaces 122:3341-3349
Fader, Kelly A; Zacharewski, Timothy R (2017) Beyond the Aryl Hydrocarbon Receptor: Pathway Interactions in the Hepatotoxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Related Compounds. Curr Opin Toxicol 2:36-41

Showing the most recent 10 out of 417 publications