Systems Toxicology

Director:  Donna L. Mendrick, Ph.D.

The Division of Systems Toxicology supports the development of new technologies and works to facilitate integration of data from multiple technology platforms for scientific application to questions that are in direct support of the FDA mission. Six Centers of Excellence comprise the Division of Systems Toxicology: Functional Genomics, Hepatotoxicity, Innovative Technologies, Metabolomics, Proteomics, and Toxicoinformatics. The goals of this Division include: 

1. to provide technical expertise and guidance for the inclusion of omics and in silico data into the review process and within the drug-development process
2. to identify new, more predictive biomarkers of toxicity, prognosis, diagnosis, and disease that will aid in the development and approval of safer and more effective medicines, foods, and medical devices
3. to identify new approaches to improve food safety, cancer treatment, and medical imaging for less invasive diagnoses 

When appropriate, biomarkers will be submitted for official qualification and new approaches patented if significant outside investment for their development is required.

The Center for Functional Genomics uses high-information content microarrays in the development of mechanistic and biomarker data for improved safety assessments. Whole-genome commercial arrays, as well as in-house fabricated custom microarrays, show great promise in drug-safety evaluation, and FDA is actively encouraging this new technology. Major efforts include the development of preclinical predictive toxicology biomarkers and continuing to serve as an FDA resource for genomics issues.

The Center for Hepatotoxicology addresses critical liver-injury issues by applying a systems-toxicology approach. The goal is to improve the identification of hepatotoxic compounds prior to human exposure and to augment the detection of early signs of injury in humans induced by drugs, chemicals, and disease processes. Biomarkers will be identified using integrated genomics, metabolomics, proteomics, and bioinformatics approaches.

The Center for Innovative Technologies uses multi-faceted approaches to address important issues of human health. Examples include a program in mass spectrometry-based analyses in counterterrorism, the use of flow cytometry for rapid detection of bacteria in food, and significant efforts in sensors and nanotube technology. In addition, the group provides computational approaches to predictive toxicology and efficacy.

The Center for Metabolomics aids in the assessment of preclinical and clinical safety issues as part of an FDA-wide biomarkers-development effort. This Center has initiated active collaborations within NCTR, across FDA, and with academic and pharmaceutical-research groups to identify biomarkers of toxicity and disease.

The Center for Proteomics continues to develop and evaluate novel proteomic technologies with the aim of facilitating the translation of basic science to medical products, and facilitating proteomic research through collaboration with investigators to address FDA critical issues related to drug safety and efficacy.

The Center for Toxicoinformatics conducts research in bioinformatics and chemoinformatics and develops and coordinates informatics capabilities within NCTR, across FDA Centers, and in the larger toxicology community. A goal of the toxicoinformatics group is to develop methods for the analysis and integration of omics (genomics, proteomics, and metabolomics) datasets with classical in-life parameters. This group is taking an active role in supporting FDA’s bioinformatics modernization plan, including the e-submission process.

Ongoing Research Projects

• Analysis of Blood Pyruvate and Valproic Acid Toxicity in Wistar Han Rats in Response to Dietary Carbohydrate and Calorie Restriction with a High-Fat, Moderate, and Low-Carbohydrate Diet (P00709)
• Analysis of Proton-MRS Data Using a Distributed Artificial Neural Network (E0719501)
• Assessment of the Global Gene Expression Changes During the Life Cycle of Rats (E0712201)
• Baseline Practices for Analyzing Genome-Wide Association Study (GWAS) Data (E0729701)
• Clinical Metabonomic Biomarkers of Disease and Toxicity (S00643)
• Development and Optimization of Quantitative LC/MS Metabolic Profiles for Amino Acids, Vitamins,and Other Important Metabolites (P00725)
• Development and Refinement of the FDA Genomic Tool, ArrayTrack™ for Advancing Pharmacogenomics and Personalized Medicine in the Context of the FDA's Critical Path Initiative (S00671)
• Development of an FDA Resource and Knowledge Base for Sex Difference in Drug Induced Liver Injury (DILI) (E0733801)
• Development of ArrayTrack™ Modules to Link Functionality of ArrayTrack with SAS Scientific Discovery Solutions (SDS) (E0721401)
• Development of Liver Toxicity Knowledge Base (LTKB) to Empower the FDA Review Process (E0721501)
• Development of MitoChip, a Glass-Based Oligonucleotide Microarray Containing Mitochondrial and Nuclear Genes Associated with Mitochondrial Function (E0718601)
• Differential Gene Expression in Rodent and Human Primary Hepatocytes Exposed to the Peroxisome Proliferators-Activated Receptor (PPAR)-Alpha Agonists (E0721301)
• Empowering the FDA Review Process on Clinical and Preclinical Data Through Electronic Data Submission (S00699)
• Evaluation of Glycolysis and TCA Fluxes in MPTP Treated C57BL Mouse Model of Parkinson's Disease (E0732601)
• FERN Level One Validation Study of a Mobile, Field-Rugged Rapid Detection and Enumeration System for Salmonella in Foods (E0731601)
• Interagency Collaboration on Identification of In Vitro and Omics Biomarkers for Liver Toxicity (E0734401)
• Metabolomic Signatures of Bacterial Contamination in Milk as a Model System (E0732501)
• Methods for Support of a Functional Proteomics Facility at NCTR (E0713501)
• MicroArray Quality Control (MAQC) Project Database (S00691)
• Molecular Mechanisms Underlying Gender-Associated Differences in the Adverse Reactions to the Antiretroviral Agent, Zidovudine (AZT): Role of Mitochondrial Toxicity (E0725601)
• Phase II of the MicroArray Quality Contol Project (MAQC-II) Toward Personalized Medicine (S00705)
• Preclinical Metabolomic investigation of drug pharmacokinetics in Multiple Drug Toxicity Studies (E0732401)
• Rapid Bacterial Identification with Subspecies-Level Specificity (E0714701)
• Study of Drug-Induced Liver Toxicity using Primary Rat and Mouse Hepatocytes (E0732101)
• Systems-Biology Approach to Evaluate Sex Differences in the Heart of a Rat Model (E0723001)
• The Development of Novel Nanotube-Based Technologies That Benefit Public Health, Protect the Public, Produce High-Efficiency Separations and Filtration, and Improve Energetic-Material Therapeutics (E0720501)
• The Development of Rapid Spectral-Based Pathogen Identification Methods for Food Defense and Counter-Bioterrorism (E0714601)

The NCTR Annual Report contains information on the latest accomplishments and plans for the Division of Biochemical Toxicology as well as project and publication listings.