Project 4

点击翻译按钮获取中文摘要

Project 4 ABSTRACT Project 4 aims to develop a translational in vitro-to-in vivo testing strategy for evaluating the inter-tissue and inter- individual variability in responses to complex environmental exposures. This goal is a critical part of the overall strategy of the Texas A&M University Superfund Research Center to characterize and manage the human health risks associated with exposure to environmental emergency-mobilized hazardous substances through the development of tools that can be used by first responders, the impacted communities, and the government bodies involved in site management and cleanup. In the past funding period, we not only developed a multi- tissue “biological read-across” approach for complex environmental exposures in high-content/high-throughput assays using human induced pluripotent stem cells (iPSC), but also demonstrated its utility for quantitative estimation of hazard of complex environmental exposures through a number of case studies that spanned community, national and international scales. These studies show how new approach methodologies (NAMs) can be applied for assessment of risks from real-life exposures. Our central hypothesis remains that a tiered risk-based strategy for safety evaluation utilizing human organotypic in vitro cultures, combined with population- based reverse toxicokinetics, can be used to accurately characterize the risks posed by combined exposures to hazardous substances during environmental emergencies. First, we will develop a population-based human in vitro approach to characterize inter-tissue and inter-individual variability in responses to complex environmental exposures. We will test the hypothesis that human population-based in vitro models can refine hazard predictions and characterize the molecular underpinnings and extent of inter-tissue and inter-individual variability. Second, we will develop a high-throughput reverse toxicokinetics (RTK) modeling approach for complex exposures to enable in vitro-to-in vivo extrapolation (IVIVE) of environmental samples. Because IVIVE is critical for interpretation of in vitro NAMs data in the context of human health, we hypothesize that novel exposomic analyses and new organ-on-a-chip models can provide concentration- and combined exposure-dependent RTK parameters needed for IVIVE, ultimately enabling more accurate predictions of effects in vivo. Third, as art of Center’s Disaster Research Response (DR2) approach, we will demonstrate the application of human multi- tissue and population-wide high-throughput in vitro models to disaster research response. We will show how the “biological read-across” method developed in the past funding period can be applied to DR2 by testing the hypothesis that in vitro toxicity data can be used to quantitatively predict and characterize health hazard of environmental samples. We will partner with all Projects to use their samples or collaborate on analytical, molecular and biomedical engineering methods and techniques. We will work with all Cores for data analysis and management, geospatial analysis, and translation of our research to the impacted communities and other stakeholders. The data and methods from this project will be of critical importance in responses to disasters.