Toxicity testing typically involves studying adverse health outcomes in animals subjected to high doses of toxicants with subsequent extrapolation to expected human responses at lower doses. The system relies on the use of a 40+year-old patchwork of animal tests that are expensive (costing more than $3B per year), time-consuming, low-throughput and often provide results of limited predictive value for human health effects. The low-throughput of current toxicity testing approaches (which are largely the same for industrial chemicals, pesticides and drugs) has led to a backlog of more than 80,000 chemicals to which humans are potentially exposed whose potential toxicity remains largely unknown. In 2007, the National Research Council (NRC) released the report "Toxicity Testing in the 21st Century: A Vision and a Strategy", that charted a long-range strategic plan for transforming toxicity testing. The major components of the plan include the use of predictive, high-throughput cell-based assays (of human origin) to evaluate perturbations in key toxicity pathways, and to conduct targeted testing against those pathways. This approach will greatly accelerate our ability to test the vast "storehouses" of chemical compounds using a rational, risk-based approach to chemical prioritization, and provide test results that are far more predictive of human toxicity than current methods. Although a number of toxicity pathways have already been identified, most are only partially known and no common annotation exists. Mapping the entirety of these pathways (i.e. the Human Toxome) will be a large-scale effort, perhaps on the order of the Human Genome Project. In this project, we propose to comprehensively map pathways of endocrine disruption, representing a first step towards mapping the human toxome. We will leverage our rapidly evolving scientific understanding of how genes, proteins, and small molecules interact to form molecular pathways that maintain cell function, applying orthogonal "omics" approaches (transcriptomics, metabolomics) to map and annotate toxicity pathways for a defined set of endocrine disruptors. Following the identification of toxicity pathways, we will conduct a series of stakeholder workshops to enable development of a consensus-driven process for pathway annotation, validation, sharing and risk assessment, and develop a public database on toxicity pathways, providing a common, community-accessible framework that will enable the toxicology community at large to comprehensively and cooperatively map the human toxome using integrated testing strategies. Finally we will validate the identified pathways of toxicity extend the concepts to additional toxicants, cell systems and endocrine disruptor hazards as well as to additional omics platforms and to dose response modeling.

Public Health Relevance

Toxicity testing typically involves studying adverse health outcomes in animals subjected to high doses of toxicants with subsequent extrapolation to expected human responses at lower doses. The low-throughput of current toxicity testing approaches (which are largely the same for industrial chemicals, pesticides and drugs) has led to a backlog of more than 80,000 chemicals to which humans are potentially exposed whose potential toxicity remains largely unknown. Employing new testing strategies that employ the use of predictive, high-throughput cell-based assays (of human origin) to evaluate perturbations in key toxicity pathways, and to conduct targeted testing against those pathways, we can begin to greatly accelerate our ability to test the vast storehouses of chemical compounds using a rational, risk-based approach to chemical prioritization, and provide test results that are far more predictive of human toxicity than current methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES020750-03S2
Application #
8727162
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Balshaw, David M
Project Start
2011-09-20
Project End
2016-03-31
Budget Start
2013-09-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$34,009
Indirect Cost
$9,022
Name
Johns Hopkins University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kleensang, Andre; Maertens, Alexandra; Rosenberg, Michael et al. (2014) t4 workshop report: Pathways of Toxicity. ALTEX 31:53-61
Krug, A K; Gutbier, S; Zhao, L et al. (2014) Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+). Cell Death Dis 5:e1222
Bouhifd, Mounir; Hogberg, Helena T; Kleensang, Andre et al. (2014) Mapping the human toxome by systems toxicology. Basic Clin Pharmacol Toxicol 115:24-31
Smirnova, Lena; Hogberg, Helena T; Leist, Marcel et al. (2014) Developmental neurotoxicity - challenges in the 21st century and in vitro opportunities. ALTEX 31:129-56
Hartung, Thomas; Corsini, Emanuela (2013) Immunotoxicology: challenges in the 21st century and in vitro opportunities. ALTEX 30:411-26
Ramirez, Tzutzuy; Daneshian, Mardas; Kamp, Hennicke et al. (2013) Metabolomics in toxicology and preclinical research. ALTEX 30:209-25
Hartung, Thomas; Hoffmann, Sebastian; Stephens, Martin (2013) Mechanistic validation. ALTEX 30:119-30
Hartung, Thomas (2013) Look back in anger - what clinical studies tell us about preclinical work. ALTEX 30:275-91
Hartung, Thomas; Luechtefeld, Tom; Maertens, Alexandra et al. (2013) Integrated testing strategies for safety assessments. ALTEX 30:3-18
Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E (2013) Ultrasensitive response motifs: basic amplifiers in molecular signalling networks. Open Biol 3:130031