Center awarded a new grant by US EPA


The Center has been awarded a new EPA STAR grant entitled "Toxicogenetics of tetrachloroethylene metabolism and toxicity: Using Collaborative Cross mouse population approach to address remaining gaps in human health assessments (RD 83561201). The long-term objective of this research proposal is to uncover the mechanistic linkages between the genome (e.g., variation in DNA sequence among individuals), metabolism (e.g., formation of organ-specific toxic intermediates), and adverse molecular events (e.g., transcriptional changes associated with toxicity) in response to a widely used chemical tetrachloroethylene. Tetrachloroethylene (Perchloroethylene, PERC) is a high-production chemical of great concern to both risk assessors and public health officials worldwide. It has long been assumed that PERC metabolism and toxicity closely mimic those of trichloroethylene (TCE), a structurally similar chlorinated solvent. However, recent human health assessments of these chemicals by the International Agency for Cancer Research and the US Environmental Protection Agency determined that major differences in toxicokinetics and toxicodynamics exist between TCE and PERC. Furthermore, it was concluded that critical gaps remain in understanding of the human health hazard of PERC, including toxicokinetics, toxicodynamics and population variability.

The work on this project will focus on characterization of the variability in toxicokinetics of tetrachloroethylene by using the Collaborative Cross mouse model of the human population; characterizing variability in toxicodynamics by evaluating inter-strain differences in dose-dependent effects on the liver and kidney in a sub-acute study; and evaluating the effects of inter-strain variability in its metabolism on liver and kidney effects in a sub-chronic study.

July 01, 2014