JANUARY: NCTR HIGHLIGHTS
Towards Toxicology In Silico
NCTR scientists have developed a predictive model for dioxin isomer toxicity using Quantitative Spectral Data Activity Relationships (QSDAR), Pat. 6,898,533. Different Quantitative Structure Activity Relationship (QSAR) models have been used for years to predict properties of chemicals including toxicity and to design more effective drugs.
QSDAR takes advantage of the fact that computer programs can easily and accurately predict the carbon-13 NMR spectra of chemicals, and these spectra are direct measures of the structure’s quantum mechanical properties. By comparison, QSAR models rely on a series of classical mechanical calculations or laboratory measurements that approximate the quantum mechanical properties, thereby consuming resources and accumulating errors with each approximation.
The QSDAR model predicted high toxicity for four dioxin isomers not thought to be important. Dr. Stephen Safe, Texas A&M, was able to provide authentic samples of two isomers, and ORA scientists at the Arkansas Regional Laboratory demonstrated:
- the purity of each authentic isomer
- each isomer had commensurately high values in the AH-receptor assay, a traditional model for evaluating potential dioxin isomer toxicity
- mass spectrometry peaks for these same two isomers were indeed present in the historical dioxin assay program database. (Accepted for publication: Wilkes et al., Toxicological Sciences, Advance Access published December 7, 2007; DOI: 10.1093/toxsci/kfm294)
QSDAR has been used previously to create accurate prediction models for estrogenicity, corticosteroid binding, and aromatase binding. Future projects will evaluate the effectiveness of QSDAR models measuring the biological action of a series of drugs within a structural class.
Arkansas Congressional Delegation Meet at NCTR
On January 15, Jeffrey Shuren, M.D., J.D., Assistant Commissioner for Policy; Stephen Mason, Assistant Commissioner for Legislation; and Norris Alderson, D.V.M., Director, Office of Science, met with Arkansas U.S. Senators Blanche Lincoln and Mark Pryor; U.S. Representative Mike Ross; NCTR senior staff; and collaborators from within Arkansas at NCTR. The Congressional delegates had a keen interest in discussing nanotechnology safety assessment; the role of FDA research in supporting the safety of food and medical devices; and, leveraging opportunities among the government, education, and private sector to support these goals. Dr. Shuren and Mr. Mason also were briefed on major Center research initiatives by the research directors. Later they met with the combined staff of the Jefferson Laboratories in an all-hands meeting that highlighted the importance of science in FDA regulatory decisions.
FEBRUARY: NCTR HIGHLIGHTS
Arkansas State Representative David Rainey is Keynote Speaker at Dr. Martin Luther King, Jr. Commemorative Luncheon On Thursday, January 24, 2008, the Jefferson Laboratories and the Central Arkansas Chapter of Blacks in Government (BIG) co-sponsored a commemorative luncheon and program celebrating the life and legacy of Dr. Martin Luther King, Jr. The program included a presentation by the Honorable David Rainey, the state representative for Arkansas District 11 that includes Jefferson County. Dr. Paul Norris, Director, Arkansas Regional Laboratory, and Dr. William Slikker, Director, National Center for Toxicological Research, each paid tribute to the theme of love, hope, and a commitment to continue to work in unity for the public good that was presented by Representative Rainey in recognizing Dr. King.
Critical Path – Automated Assays
The in vivo rodent erythrocyte micronucleus test is used in regulatory safety assessment to evaluate the potential of agents to cause chromosomal damage. The use of nonhuman primates (NHPs) also may have value in the genotoxicity testing of regulated products, especially human pharmaceuticals. Conducting the micronucleus test in NHPs, however, is extraordinarily resource intensive, often requiring the sacrifice of the animal to obtain bone marrow and the manual scoring of thousands of cells with a microscope.
NCTR led a collaborative study that found that flow cytometry evaluation of micronuclei in peripheral blood was both more efficient and precise than the traditional methods. The flow cytometry method uses only a small amount of blood allowing multiple samples to be taken from the same animal, which also provides its own baseline values. This improved procedure for evaluating genetic toxicology in NHPs is not only faster and more precise than the traditional microscopic analysis but also lends itself to analyzing micronuclei in conjunction with other toxicological endpoints, thus improving the preclinical safety assessment.
These findings recently were published by C. E. Hotchkiss et al. in Toxicological Sciences (e-publication in advance of print). For further information, contact Dr. Martha Moore, NCTR.
PET Imaging at NCTR
PET (or positron emission tomography) is an established clinical imaging tool used to detect and follow the biological course of several diseases at the molecular level before anatomical changes may be apparent; e.g., several cancers, heart disease including coronary artery disease, neurological disorders including Alzheimer’s, Parkinson’s, and epilepsy.
NCTR’s high-resolution microPET installation has been completed and will be used in preclinical studies to evaluate the emergence and development of toxicity. The first NCTR protocol, “Methods Development for High Resolution micro-Positron Emission Tomography (microPET) to Assess Rodent Neuroplasticity and Toxicity during Development,” will be used to evaluate system performance. High-resolution microPET will dramatically increase the level and sophistication of data that can be obtained from animal models of toxicity and disease and provide direct links to clinical applications.
For more information, contact Dr. Merle Paule, Director, Division of Neurotoxicology, NCTR or Dr. William Slikker, Director, NCTR.
A collaboration between NCTR and the University of Southern California has shown that circulating levels of tamoxifen and its therapeutically active metabolites in Asian women (n=380) undergoing therapy for breast cancer was not affected by dietary soy intake. By comparison, this study also showed that age/menopausal status, body weight, and use of hypertensive medications, particularly diuretics, significantly influenced the circulating levels of tamoxifen and its metabolites.
However, approximately one-third of patients with estrogen-receptor positive tumors do not ever respond to tamoxifen therapy, and patients eventually can become resistant to the therapeutic benefits of tamoxifen treatment. Future studies that include breast cancer survival and relapse assessments will be needed to determine whether soy isoflavones can affect the overall efficacy of tamoxifen chemotherapy.
These findings recently were published by Wu et al. in Journal of Clinical Oncology published 2007; Vol 25; 3024-3030. For further information, contact Dr. Tom Flammang or Dr. Dan Doerge at NCTR.
A woman’s lifetime exposure to estrogen is a factor for increased risk of breast cancer; estrogen stimulates the growth of estrogen-dependent breast cancer. Collaborative studies between scientists at NCTR and the University of Arkansas for Medical Sciences have shown that a specific member of the UDP-glucuronosyltransferase family of genes, UGT1A10, is a novel, estrogen-regulated gene involved in the estrogen removal process. Increasing concentrations of estrogen increased (induced) the expression of UGT1A10 in a breast-cancer cell culture system, plateaued, and then decreased (down-regulated) UGT1A10. UGT1A10 was also identified in human breast tissues and was shown to be down-regulated in breast carcinomas compared to adjacent normal breast specimensa. These studies provide evidence that decreased UGT gene expression and resulting decreased estrogen removal could result in the promotion of carcinogenesis. (Starlard-Davenport et al., Steroids Vol. 73 (2008) and aSteroids (In Press).
For more information, contact Dr. William Slikker, Director, NCTR.
MARCH: NCTR HIGHLIGHTS
Safety Evaluation of Cosmetic Preparation
The National Toxicology Program (NTP) Board of Scientific Counselors Technical Reports Subcommittee met February 27, 2008, to review NCTR’s comprehensive assessment for the topical application of the cosmetic ingredient Aloe vera (plant leaf extract). The subcommittee concluded that, at dose levels above human exposure, the plant fractions had no, to marginal, effects on the carcinogenicity of simulated sunlight in mice. The cream doses contained aloe gel, whole leaf, decolorized whole leaf extracts, or aloe-emodin. CFSAN scientists will use this data to determine what risk, if any, Aloe preparations may pose for humans. Aloe vera preparations have found widespread use in skincare products; however, published reports suggest that these preparations may synergize with UV radiation and enhance skin cancer. The one-year studies were conducted in the NTP/FDA Phototoxicology Center at NCTR using the hairless (SKH-1) mouse model to evaluate the potential of the typical standardized aloe preparations to enhance the photocarcinogenicity of simulated sunlight.
For further information, contact Dr. William Slikker, Jr., at NCTR.
NCTR, CDC, ATSDR, EPA, NIOSH, and NIH scientists met February 14, 2008, in Atlanta, Georgia, for the inaugural meeting of the Inter-Agency Computational Toxicology Colloquium. The conferees discussed formation of inter-agency computational toxicology projects in areas of mutual interest, including: identification and qualification of biomarkers, development of prediction algorithms, chemical-testing prioritization using high throughput screening methodology, quantitative-structure activity relationships, integrative systems biology, utilization of omics data in risk assessments, and computer-based approaches to safety and risk assessment. Subgroups were identified to outline research proposals to be discussed at the second Colloquium that will be hosted by NCTR.
For further information contact Drs. James C. Fuscoe, Division of Systems Toxicology or William Slikker, Director, NCTR.
The Virtual Pathology Environment
NCTR has established a secure digital-imaging and software system to be used by Pathology Working Groups (PAGs) in the formal peer review of GLP studies. Although digital imaging has been used informally by pathologists to share information for a long time, advances in technologies have allowed these applications to be incorporated into the formal pathology peer-review environment. This virtual-pathology environment significantly reduces procedural costs and facilitates the organization of global professionals producing the most expert and timely reviews possible.