Project 3

"Inter-tissue and –individual variability in response to mixtures"

Ivan Rusyn and David Threadgill will establish rapid and informative laboratory tests that aim to determine the types of human health and environmental hazards to which people may be exposed; these tests then can be used during or after an environmental disaster emergency. This project also will focus on the health risks associated with an exposure to chemical mixtures from the Galveston Bay/Houston Ship Channel sites that might be swept ashore or otherwise moved in a way that would increase the likelihood of human exposure during an environmental emergency such as hurricanes, floods, or chemical spills. Researchers will address several critical challenges in the area of environmental risk assessment by characterizing and managing the human health risks associated with an exposure to these hazardous substances by developing of tools that can be used by first responders, the impacted communities, and the government bodies involved in site management and cleanup.

Relevance

By providing officials with the scientific tools that can rapidly identify tissue-specific health hazards and classify unknown composition mixtures, officials in areas where an environmental disaster has struck will be able to make timely decisions using evidence-based methods that can mitigate the risks to human health posed by hazardous substances redistributed during a disaster emergency.

Principal Investigators:




The overall objective of this project is to develop a translational cell-to-animal-to-human testing strategy for evaluating the inter-tissue and inter-individual variability in responses to environmental mixtures.


Specific aims:

  1. Develop a novel “biological read-across” approach—a compendium of human organ-specific cell lines that can be used to rapidly evaluate similarity in the effects of unknown chemical mixtures to known environmental hazards. This approach will allow the team to categorize the effects of mixtures from Galveston Bay/Houston Ship Channel sites with respect to the magnitude and tissue-specificity of hazard.
  2. Develop a model using cells from different people and different mouse strains to test population variability in toxic effects of chemicals and mixtures. The team will use real-life mixtures from Galveston Bay/Houston Ship Channel collected by Project 1. Researchers also will test known toxic chemicals and mixtures in mice of the same strains to determine if the effects seen in cultured cells are concordant with effects in whole animals.
  3. 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. IVIVE using reverse toxicokinetics approaches has been critical for interpretation of in vitro ToxCast/Tox21 data in the context of human health risk. Such methods are well established for individual chemicals, but no work has been done yet on mixtures.
  4. Test the utility of the “biological read-across” for quantitative estimation of hazard for complex environmental mixtures. The researchers’ recent work extended traditional chemical structure-based read-across to infer a compound’s toxicity from both chemical and biological analogues, but no research has been done to consider mixtures or biological data alone.