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About FDA

July-September 2006


Critical Path — Safety Evaluation
In vitro and in vivo assays are used in regulatory test batteries to predict the carcinogenic potential of chemical agents. Several compounds test as weak, or negative, using in vitro genotoxin assays, but they test positive in the in vivo assays. The reasons for these differences include metabolism; influence of gut microflora; effects on pharmacology, in particular, folate metabolism, etc.

An international team of scientists, including NCTR and CDER, reviewed primarily unpublished data from company archives to produce a decision-tree guide for the evaluation of compounds that appear to be genotoxins in vivo but not in vitro. Of note, the compounds identified for this review interfere with the cell cycle, and this can result in atypical chromosome separation (aneugenicity) or chromosome breakage. The regulatory implications of this class of compounds also were discussed in this review.

For more information, contact Dr. Robert Heflich, Division of Genetic and Reproductive Toxicology, NCTR.


Critical Path — Decisional Tools: Computer-Assisted Pathology Software System (CAPS™)
NCTR met with officials of Systems Pathology Company, LLC, to discuss a joint initiative for continued development and testing of a computer-assisted pathology software system (CAPS™). The completed system will include a comprehensive library of “smart imaging” programs to assist pathologists in conducting microscopic evaluation of tissues. The programs are designed to differentiate normal versus non-normal tissues. Computerized advancement will be expected to increase pathologic evaluation throughput thereby speeding the process of new drug development. This will help alleviate the shortage of toxicological pathologists.

For further information, contact Dr. Thomas Flammang, NCTR.

Critical Path — Decisional Tools: New ArrayTrack™ Module

NCTR scientists, the inventors of ArrayTrack™ software that is used to warehouse and analyze microarray data in regulatory analysis, have released a new module named GOFFA (Gene Ontology for Functional Analysis). Gene Ontology (GO) that characterizes and categorizes the functions of genes and their products according to biological processes, molecular functions, and cellular components, has been emerging as a common practice for interpreting differentially expressed gene data from genomics and proteomics technologies.

GOFFA provides five interactive functions (Tree View, Terms View, Genes View, GO Path and GO TreePrune) to analyze the gene ontology data, including two unique functions, GO Path and GO TreePrune. The GO Path function displays the statistically most probable GOFFA Tree paths in order, and GO TreePrune provides a visual display of the GO based on user-specified statistical cut-offs of the data. The visual display represents the intuitive depiction of the most likely relevant biological functions.

For further information, contact Dr. Weida Tong, Division of Systems Toxicology, NCTR.

Critical Path — Clinical Tools
Epigenetic changes are stable and heritable alterations in gene expression that do not involve gene mutation and are increasingly recognized to be involved in the origins and progression of disease including cancers. Thusly the ability to track epigenetic changes, such as changes in methylation patterns of DNA, have implications as markers for the early detection, treatment and prevention of disease.

A team of scientists from NCTR and the University of Lethbridge in Canada have overcome common problems with known protocols for identifying changes in DNA methylation patterns. They have demonstrated a new laboratory procedure that was able to differentiate clearly, identify, and characterize a number of novel unique DNA sequences with differentially methylated (increased and decreased) sites in normal and human breast cancer cell lines and in normal and rat tumor liver tissues.

For further information, contact Dr. Igor Pogribny, Division of Biochemical Toxicology, NCTR.


Critical Path Initiative — MicroArray Quality Control (MAQC)
The MicroArray Quality Control (MAQC) project was initiated by the FDA’s National Center for Toxicological Research (NCTR), Jefferson, Arkansas, on February 11, 2005, in order to address reliability concerns as well as other performance, quality, and data analysis issues. One hundred and thirty-seven scientists from 51 organizations including government agencies, manufacturers of microarray platforms and RNA samples, microarray service providers, academic laboratories, and other stakeholders designed a study plan. Two distinct, commercially available reference RNA samples were generated and analyzed at multiple test sites using a variety of microarray-based and alternative technology platforms, resulting in a rich dataset with over 1,300 microarray hybridizations.

The MAQC project observed intraplatform consistency across test sites as well as high interplatform concordance in terms of genes identified as differentially expressed. Findings of the MAQC project were published in a series of articles in Nature Biotechnology, September 8, 2006. Data are available through GEO (series accession number: GSE5350), ArrayExpress (accession number: E-TABM-132), ArrayTrack™, and the MAQC website.

For further information, contact Dr. William Slikker, Jr., Acting Director, NCTR/FDA.

NCTR Hosts Acting Commissioner von Eschenbach
On Thursday, September 21, 2006, NCTR was privileged to have the Acting Commissioner, Food and Drugs, spend the day at the FDA Jefferson Laboratories. The Acting Commissioner enjoyed a walking tour and discussions with the NCTR senior scientific staff that focused on the value and evolution of science that will bridge discovery with intervention to make a difference in patients’ lives. During an All Hands meeting, Dr. von Eschenbach charged the Jefferson Labs staff to anticipate future public health needs and engage in facilitating a collegial and integrated scientific agenda. He applauded the extraordinary expertise at NCTR and said that the work here is at the core of the metamorphosis of the FDA. NCTR science provides a base infrastructure that is a critical component of the FDA. Dr. von Eschenbach stated “FDA must not only be science based, but a science led organization.” He is committed to the success of the NCTR.

For further information, contact Dr. William Slikker, Jr., Acting Director, NCTR/FDA.

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