Integrated Systems Toxicology Division

The Integrated Systems Toxicology Division applies a systems biology approach to describe normal biological, homeostatic processes and to identify key events that signal departure from those processes leading to adverse health outcomes. Research seeks to develop an integrated framework across health endpoints through the identification of toxicological pathways. This approach is accomplished by:

• the use of computational and molecular approaches to identify "key events" for biologically based dose-response and mode-of-action-based models;
• the development of physiologically based pharmacokinetic models for linkage to biologically based dose-response models;
• the application of genetic/epigenetic approaches for understanding differential life-stage sensitivities;
• and working with the Toxicity Assessment Division and the Environmental Public Health Division to generate data to reduce model uncertainties, including the identification of biomarkers/bioindicators for key events.
  
  
• SYSTEMS BIOLOGY BRANCH
  The Systems Biology Branch provides expertise in developing primary data and analyzing available data in the context of biological systems (i.e., cells, tissues, organs, organisms). The emphasis will be on examining how the molecular machinery executes biological functions, identifying the role of biological networks capturing, transmitting, integrating and dispersing biological information normally and in the presence of stressors (e.g., chemical, biologic). This approach also will be applied in developing species extrapolation models.
  
  
• GENETIC AND CELLULAR TOXICOLOGY BRANCH
  The Genetic and Cellular Toxicology Branch provides expertise in using high-throughput in vitro cellular models to investigate toxicity pathways. The emphasis will be on approaches for developing key events along the path from the normal condition to an adverse health outcome. This will require the development of a knowledge of the genetics and epigenetics that underlie adverse outcomes. Such research will include developing an understanding of differential life stage sensitivities. In addition, there will be an emphasis on how cells can mitigate responses by selective DNA and cellular repair processes and gene expression changes.
  
  
• CARCINOGENESIS BRANCH
  The Carcinogenesis Branch provides expertise for the conduct of research that is focused on the characterization of tumors at the tissue, cellular and molecular levels. The emphasis will be on those tumors that are known or suspected to have a significant environmental component in their etiology. In addition, there will be approaches developed for investigating the biology underlying possible nonlinear responses for key events leading to cancer.
  
  
• PHARMACOKINETICS BRANCH
  The Pharmacokinetics Branch provides expertise in developing the dosimetric underpinnings for the overall research on toxic effects of environmental chemicals. The emphasis will be on close coordination with the research of the whole laboratory to develop pharmacokinetic models that are essential for tissue dose determinations as a necessary component for dose-response characterization.

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