Our previous research has established that the genetic makeup of the host plays a key role in metabolism and its biological effects of trichloroethylene (TCE) in mouse liver. Genetic polymorphisms have a profound effect on differences between individuals who may have developed disease after exposure to environmental agents, yet these factors are not being fully considered in risk assessment. Indeed, the need to account for differences among humans in cancer susceptibility other than from possible early-life susceptibility is becoming ever more evident to both the scientific community and the regulatory agencies. A hypothesis that apparent species- and organ-specific metabolism and toxicity of TCE are genetically controlled and that the mechanisms of susceptibility can be successfully elucidated using a panel of inbred mice will be addressed here. First, we will elucidate genetic determinants of inter-individual differences in TCE metabolism by collecting time course, dose-response, and repeat dose data on TCE metabolites in blood and tissues from a large panel of genetically diverse inbred mouse strains. The data will be used to investigate the genetic causes of variation in the metabolism of TCE, a step crucial for understanding the potential for TCE-induced adverse health effects in a heterogeneous human population. Second, we will build population-wide pharmacokinetic models for TCE metabolism, which will account for inter-individual variability in metabolism from the genetics point of view by using the time-course and dose-response data obtained on the genetically-diverse animals. Third, we will determine the effects of inter-individual genetic variability on strain-specific responses to TCE through dose-response modeling of gene expression and metabolomic data. Collectively, this project is timely in proposing a paradigm that will not only offer valuable insights into the molecular basis for genetically-determined variability in response to TCE, and develop PBPK and statistical models, but also will provide necessary science-based underpinnings and tools for the new paradigms being incorporated into the risk assessment and decision-making on TCE and related chlorinated solvents, as well as other environmental agents.
This proposal will advance the science of toxicology and the practice of risk assessment by (1) integrating traditional dose- and time-response toxicology research approaches with the knowledge of genetic variation using trichloroethylene as a model environmental contaminant and (2) dissecting complex mechanisms of action of an environmental agent by constructing kinetic models of individual-to-population risk of toxicity.
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