# Inter-tissue and -individual variability in responses to mixtures

> **NIH NIH P42** · TEXAS A&M UNIVERSITY · 2020 · $222,486

## Abstract

Project 3 ABSTRACT
Project 3 aims to develop a tiered translational in vitro-to-in vivo experimental testing strategy for evaluating the
inter-tissue and inter-individual variability in responses to complex environmental mixtures. 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. We have recently demonstrated that
organotypic and population-based experimental models for toxicology can enable not only a more rapid
identification of chemical hazards, but also serve as the opportunity to test real-life exposures. Our overall
hypothesis is that a tiered, risk-based strategy for safety evaluation consisting of human and mouse
organotypic in vitro cultures and Collaborative Cross mouse strains, combined with a population-based reverse
toxicokinetics, is a sensible “fit-for-purpose” approach to characterizing hazards of complex mixtures from
contamination events during environmental emergencies. First, we will develop a multi-tissue “biological read-
across” approach for complex environmental mixtures using high-content/-throughput assays with human
induced pluripotent stem cells (iPSC). Data from high-content screening and high-throughput genomic
analyses with human iPSC-derived organotypic cultures (hepatocytes, cardiomyocytes, endothelial cells,
macrophages, neurons, etc.) will be used to categorize the effects of mixtures with respect to the magnitude
and tissue-specificity of the hazard. Second, we will develop a population-based in vitro-in vivo approach in
mice to characterize inter-tissue and inter-individual variability in responses to complex environmental
mixtures, including the Galveston Bay/Houston Ship Channel site samples that will be collected in Project 1.
We will use the Collaborative Cross, a panel of genetically diverse mouse strains that model human population
variability, to establish a library of mouse iPSC-derived embryoid bodies that encompass diverse cell lineages.
This population-based in vitro model will be used in toxicity screening of chemicals and mixtures. Third, we will
develop a high-throughput reverse toxicokinetics modeling approach for in vitro-to-in vivo extrapolation (IVIVE)
of quantitative estimates of hazard for complex environmental mixtures. In partnership with the Exposure
Science Core, we will utilize modern untargeted metabolomics methods to deconvolute complex mixtures into
toxicokinetically-similar components on which high-throughput IVIVE can be performed. Finally, we will
demonstrate the utility of our biological read-across approach for quantitative estimation of hazard for complex
environmental mixtures. We will partner with the Data Science and Decision ...

## Key facts

- **NIH application ID:** 9903371
- **Project number:** 5P42ES027704-04
- **Recipient organization:** TEXAS A&M UNIVERSITY
- **Principal Investigator:** Ivan Rusyn
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $222,486
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903371

## Citation

> US National Institutes of Health, RePORTER application 9903371, Inter-tissue and -individual variability in responses to mixtures (5P42ES027704-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9903371. Licensed CC0.

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