; 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 #
5P42ES004911-23
Application #
8695352
Study Section
Special Emphasis Panel (ZES1-LWJ-D)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
23
Fiscal Year
2014
Total Cost
$274,745
Indirect Cost
Name
Michigan State University
Department
Type
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Stedtfeld, Robert D; Stedtfeld, Tiffany M; Waseem, Hassen et al. (2017) Isothermal assay targeting class 1 integrase gene for environmental surveillance of antibiotic resistance markers. J Environ Manage 198:213-220
Fader, Kelly A; Nault, Rance; Zhang, Chen et al. (2017) 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-elicited effects on bile acid homeostasis: Alterations in biosynthesis, enterohepatic circulation, and microbial metabolism. Sci Rep 7:5921
Waseem, Hassan; Williams, Maggie R; Stedtfeld, Tiffany et al. (2017) Virulence factor activity relationships (VFARs): a bioinformatics perspective. Environ Sci Process Impacts 19:247-260
Fader, Kelly A; Nault, Rance; Kirby, Mathew P et al. (2017) Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERB?/? activation in aryl hydrocarbon receptor-elicited hepatotoxicity. Toxicol Appl Pharmacol 321:1-17
Kovalova, Natalia; Nault, Rance; Crawford, Robert et al. (2017) Comparative analysis of TCDD-induced AhR-mediated gene expression in human, mouse and rat primary B cells. Toxicol Appl Pharmacol 316:95-106
Samhan, Farag A; Stedtfeld, Tiffany M; Waseem, Hassan et al. (2017) On-filter direct amplification of Legionella pneumophila for rapid assessment of its abundance and viability. Water Res 121:162-170
Li, Jinpeng; Bhattacharya, Sudin; Zhou, Jiajun et al. (2017) Aryl Hydrocarbon Receptor Activation Suppresses EBF1 and PAX5 and Impairs Human B Lymphopoiesis. J Immunol 199:3504-3515
Stedtfeld, Robert D; Brett Sallach, J; Crawford, Robert B et al. (2017) TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal. Appl Microbiol Biotechnol 101:7409-7415
Dornbos, Peter; LaPres, John J (2017) Incorporating population-level genetic variability within laboratory models in toxicology: From the individual to the population. Toxicology 395:1-8
Ahmad, Farhan; Stedtfeld, Robert D; Waseem, Hassan et al. (2017) Most probable number - loop mediated isothermal amplification (MPN-LAMP) for quantifying waterborne pathogens in <25min. J Microbiol Methods 132:27-33

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