Annual Report for Fiscal Year 2017
The National Center for Toxicological Research (NCTR) partners with researchers from elsewhere in FDA, other government agencies, academia, and industry to provide innovative technology, methods development, vital scientific training, and technical expertise. The unique scientific expertise of NCTR is critical in supporting FDA product centers and their regulatory roles. NCTR research for NTP is funded by both voluntary allocations and an interagency agreement.
NCTR/NTP Staff
NCTR studies funded by voluntary allocations are listed below. Click the project title for a brief summary.
Study Scientist: Jeffrey Fisher
Creation of PBPK models for BPA in mouse, rat, and rhesus monkey for multiple life stages: adult; neonate; pregnant, mother and fetus; and lactating, mother and neonate. These PBPK models will be used to calculate internal measures of dose for both aglycone (i.e., active) and conjugated (i.e., inactive) forms of BPA. Human PBPK models for BPA (adult, neonate, pregnant mother and fetus, and lactating mother and infant) will be created using information obtained from the monkey, mouse, and rat models and from the limited human information published in the literature. The human suite of PBPK models will be used to extrapolate the internal doses of BPA associated with toxicity in laboratory animals to human doses. They will also be used to better characterize internal dosimetry of BPA. This simulation protocol will help reduce the uncertainty in assessment of health risks BPA poses to human populations.
Study Scientist: Jeffrey Fisher
(1) Creation of biologically based dose-response models for the hypothalamic-pituitary-thyroid axis in the developing rat and human as a function of iodide status.
(2) Interfacing of the models with physiologically based pharmacokinetic or toxicokinetic models for thyroid active chemicals with predicted conditions, such as iodide status and chemical exposure, for which brain thyroid hormone homeostasis cannot be maintained in the fetus and neonate.
(3) Use of the models to evaluate the possible influence of population exposures to thyroid active chemicals on fetal and neonatal thyroid status as a function of iodide intake.
Study Scientist: Igor Pogribny
(1) Determination of the role of epigenetic dysregulation in the etiology and pathogenesis of dietary NASH-induced hepatocarcinogenesis in mice.
(2) Determination of whether interstrain-specific susceptibility of mice to NASH-induced hepatocarcinogenesis is associated with differences in individual hepatic epigenetic phenotypes.
(3) Determination of the role of epigenetic dysregulation in the etiology and pathogenesis of NASH-induced hepatocarcinogenesis in mice induced by tamoxifen administration.
(4) Determination of whether aberrant epigenetic markers can be used as targets for preventing NASH- induced hepatocarcinogenesis in mice.
Study Scientist: Li Pang
(1) Establishment of the in vitro model and positive control.
(2) Evaluation of model sensitivity and specificity and tests of the possibility of high-throughput screening and ranking of QT-prolonging drugs for the risk of torsade de pointes.
Study Scientist: Peter Fu
(1) Validation of the proposed mechanism by which pyrrolizidine alkaloids induce tumors in rodents.
(2) Development of an LC-ES/MS/MS method for detecting and quantifying dehaloperoxidase-derived DNA adducts in rodents.
(3) Development of an LC-ES/MS/MS method for detecting and quantifying genotoxic pyrrolizidine alkaloids in herbal plants and herbal dietary supplements.
(4) Development of an LC-ES/MS/MS method for detecting and quantifying dehaloperoxidase-derived hemoglobin adducts in rodents.
Study Scientist: Daniel Doerge
(1) Development and implementation of a sensitive and selective analytical methodology to measure BPA in human blood and urine.
(2) Integration of animal exposure data and human biomonitoring data into a PBPK model for BPA.
Study Scientist: Amy Inselman
Determination of the effects of risedronate and black cohosh (alone or combined) on bone density, bone turnover, and bone histology in a postmenopausal rat model.
Study Scientist: Igor Pogribny
(1) Determination of the dose-dependent, in vitro genetic and epigenetic effects of compounds FDA regulates.
(2) Characterization of the specific epigenetic changes induced in vitro by genotoxic and nongenotoxic compounds.
(3) Characterization of the specific genetic and epigenetic effects of compounds FDA regulates using an in vitro three-dimensional organotypic liver culture model system.
Study Scientist: Gonçalo Gamboa da Costa
Development of methods for analyzing the food additive, brominated vegetable oil, in rat feed and rat tissues.
Study Scientist: William Tolleson
Use of high-throughput profiling approaches to identify microRNAs that regulate genes involved in PA carcinogenicity in hepatic cell systems and investigation of the functions of microRNAs by bioinformatics tools and in vitro functional assays. These results will identify microRNA species for use as biomarkers for PA-induced carcinogenicity, with added benefits derived from mechanistic knowledge of how these microRNAs might function in the biological effects of PAs. The discovery and characterization of microRNAs associated with the hepatocarcinogenic activity of PAs will benefit food safety and human health by providing simple tools for assessing exposure to foodborne toxins.
Study Scientist: John Talpos
(1) Determination of the dose-response effects of gaseous anesthetics nitrous oxide and isoflurane (individual or combined) on neuronal cell death in the developing nonhuman primate using magnetic resonance imaging (MRI) and positron emission tomography (MicroPET).
(2) Determination of the effects of dose and duration of gaseous anesthetics on nonhuman primate long-term behavior and pathology using MRI and MicroPET.
(3) Evaluation of antioxidants in the amelioration of toxicity associated with gaseous anesthetics.
Study Scientist: Jyotshnabala Kanungo
(1) Study of wildtype zebrafish embryos exposed to NMDA receptor antagonists (MK-801, dextromethorphan, ketamine, and sevoflurane) to assess their effects on Rohon-Beard sensory neurons. The effects on the primary and secondary motor neurons and their axons are being assessed using hb9:GFP transgenic embryos. Postexposure washout experiments are being pursued to determine the effects of these drugs on the nervous system.
(2) Determination of estradiol-17β levels in control and treated embryos and quantification of changes in gene expression for the two CYP aromatases/estrogen synthases (brain aromatase cyp19a1b and gonadal aromatase cyp19a1a) using quantitative polymerase chain reaction (qPCR).
(3) Assessment of phenotype-based cell signaling mechanisms, such as MAPK (mitogen-activated protein kinases) and neuron development-specific gene expression.
(4) Examination of reversal of noted adverse effects of these compounds on neurons, particularly by treatment with acetyl L-carnitine.
Study Scientist: Syed Ali
(1) Evaluation of the toxicity of graphene sheets using in vitro primary cultures of embryonic day 14 primary rat striatal neurons.
(2) Determination of pathways involved in graphene toxicity using embryonic day 14 primary rat striatal neurons.
Study Scientist: Qiang Gu
(1) Examination of proteomic changes at the expression and phosphorylation levels using five established in vivo models of neurotoxicity.
(2) Identification of common changes in protein expression and phosphorylation status in these animal model systems.
(3) Confirmation of the observed alterations in protein expression and phosphorylation status by independent methods.
(4) Application of the proteomic findings to a global ischemic animal model to verify the utility of protein biomarkers for use in neurotoxicity assessments.
Study Scientist: John Chelonis
(1) Examination of the effects of early developmental sevoflurane exposure on neurodegeneration and complex operant learning.
(2) Determination of whether pretreatment with acetyl-L-carnitine can attenuate impairments in these measures.
(3) Examination of the time course of acetyl-L-carnitine pretreatment on sevoflurane-induced neuroapoptosis.
Study Scientist: Syed Ali
(1) Use of soft lithograph and microfabrication techniques to engineer a multilayered blood-brain-barrier-on-a-chip model that can be subjected to different magnitudes and durations of mechanical stress that mimic mild and repetitive traumatic brain injury.
(2) Characterization of the effects of traumatic brain injury on blood-brain-barrier integrity using the chip model.
Study Scientist: Syed Imam
Assessment of the utility of high-throughput neurotoxicity screening of metallic nanoparticles for detecting neurochemical and neurophysiological alterations in vitro for use in developing reference standards for metallic nanoparticles. Once developed and validated, these techniques can be optimized for analyzing other FDA-regulated nanomaterials.
Study Scientist: Qiang Gu
Study Scientist: Julian Leakey
Study Scientist: Julian Leakey
Study Scientist: Sangeeta Khare
Study Scientist: Sangeeta Khare
Study Scientist: Nan Mei
Study Scientist: Anil Kumar Patri
Study Scientist: Tao Chen
Study Scientist: Peter Fu
Study Scientist: George Hammons
(1) Determination of the effect of two types of nanoparticles, silver and titanium dioxide, at various particle sizes, surface coatings, dosages, and durations of exposure on global methylation and genome-wide DNA methylation using array profiling in four types of human cells (liver, lung, skin, and colorectal).
(2) Determination of the effect of these nanoparticles on the pattern of global histone modifications and on genome-wide profiles of histone modifications in the four types of human cells. The analysis includes comparisons with disease-associated histone modifications.
(3) Correlation of the nanoparticle effect on DNA methylation with its effect on DNA methyltransferase expression.
(4) Correlation of the nanoparticle effect on global histone modifications with its effect on expression of histone-modifying enzymes as potential underlying mechanisms of the alteration in DNA methylation or histone modification patterns.
Study Scientist: Wei Ding
Assessment of the immunotoxicity of different categories of nanoparticles using biomarkers of innate immunity measured in vitro in human immune cells (monocytes, human peripheral blood mononuclear cells).
Study Scientist: Tao Chen
(1) Examination of human skin microbiota cell viability in the presence of nanoscale materials in cosmetics.
(2) Determination of the effect of nanomaterials in cosmetics on human skin microbial ecology.
(3) Demonstration of the mechanisms of toxicity of nanoscale materials in cosmetics to skin microbiota using the human skin tissue model EpiDerm and reverse transcription polymerase chain reaction (RT-PCR) and whole genome microarray technologies.
(4) Elucidation of the dose-response relationship of nanoscale materials in cosmetics on skin bacterial cell toxicity.
(5) Assessment of the potential health risk of human skin exposure to nanomaterials in cosmetics.
Study Scientist: Anil Patri
(1) Use of established qualitative methods to characterize different species of nanoscale Ag contained in five types of dry and five types of liquid feminine hygiene products.
(2) Evaluation of the migration/uptake and toxicity of Ag nanoparticles and ions used in feminine hygiene products using a human cell-based in vitro three-dimensional culture model that has many of the structural and functional features of the human vaginal mucosal layer.
(3) Evaluation of the effects of Ag nanoparticles and ions contained in feminine hygiene products on human vaginal microbiota using culture techniques and semiquantitative molecular methods.
Study Scientist: Sangeeta Khare
(1) Determination of the effect of nanomaterials on the permeability of epithelial cells and establishment of immune correlates.
(2) Delineation of the interaction of nanomaterials with gastrointestinal tract and gut-associated microbiota using an ex-vivo model (intestinal explants).
(3) Establishment of the effect of nanoparticles on the developmental stage of the intestine and assessment of the biodistribution of nanoparticles using the zebrafish model.
Study Scientist: John Sutherland
(1) Comparison of the relative efficacy of FDA-regulated nanomaterials used in dentistry for inhibition of bacterial adhesion to surfaces and biofilm formation.
(2) Evaluation of the effect of nanomaterials on growth and antimicrobial susceptibility profiles of typical species from the oral microbiota.
Study Scientist: Anil Patri
(1) Establishment of the human stem cell model for nanotoxicity testing.
(2) Exploitation of the preliminary observation that titanium dioxide inhibits mesenchymal stem cell differentiation into adipocytes while other nanomaterials have no effect on the cells.
(3) Establishment of a novel sensitive model for nanotoxicity testing and provision of that information to FDA regulators on effects of titanium dioxide and other nanomaterials used in food, drugs, cosmetics, and medical products.
Study Scientist: Page McKinzie
(1) Understanding of the distribution and range of spontaneous oncogene mutant frequencies in the major organs of rats and mice.
(2) Provision of important basic information for the validation of these oncogene mutant frequencies as biomarkers of chemically induced carcinogenesis.
Study Scientist: Manju Manjanatha
Evaluation of a newly developed transgenic, hairless, albino mouse bearing a gpt-delta reporter construct (THA) for responsiveness of the construct (gpt and spi- red/gam genes) to UVB (ultraviolet B radiation). The animal will be used to examine kinetics of induction of UVB-induced mutations in a reporter construct in the dermis and epidermis and to correlate activity with UVB induction of skin tumors.
Study Scientist: Yuping Wang
Conduct of a comprehensive survey of microRNAs using the next generation sequencing technology. Findings will elucidate the molecular pathways and processes modulated by RNAs (including messenger RNAs, microRNAs, and other noncoding RNAs) and their importance in drug-induced liver injury risk and phenotypes.
Study Scientist: Li Pang
(1) Development of standard baseline criteria for high-throughput readouts of drug-induced arrhythmia in human iPSC-CMs from different suppliers.
(2) Assessment of individual variance and possible sex differences in drug-induced cardiotoxic responses across a panel of nongenetically modified iPSC lines.
Study Scientist: Vasily Dobrovolsky
Development of a method that could routinely identify Pig-a mutations in individual Pig-a mutant phenotype cells.
Study Scientist: Lei Guo
Development and utilization of in vitro assays for assessing drug-induced liver toxicity by evaluating cytotoxicity and quantifying representative endpoints for assessing clinical-related outcomes such as apoptosis/necrosis, steatosis, and cholestasis.
Study Scientist: Tao Chen
(1) Determination of microRNAs in blood and carcinogenic target tissues that respond to carcinogen exposures and the best time for sampling of their expression after treatments in rats.
(2) Determination of microRNA profiles from the blood and target tissue samples of rats treated with different mode-of-action carcinogens, such as alkylating agents, aneugens, clastogens, and nongenotoxic carcinogens at the appropriate sampling time.
(3) Determination of the functions and pathways of the dysregulated microRNAs by the carcinogen treatments and examine whether the microRNA changes can be anchored to the carcinogens with the known mode-of-actions and whether the changes in blood are related to those in the target tissues.
(4) Establishment of specific microRNA biomarkers in blood for assessing different types of carcinogens.
Study Scientist: Vijayalakshmi Varma
Development of a B6C3F1 mouse model of obesity to investigate the impact of obesity on anthracycline-induced cardiotoxicity and the model’s suitability to investigate other potential drug-induced toxicities under conditions of obesity.
Study Scientist: Carol Guo
Establishment and demonstration of the feasibility of novel high-throughput and high-content in vitro genotoxicity assays conducted using human liver cells in conjunction with quantitative dose-response approaches for assessing and distinguishing the genotoxicity of FDA-regulated products.
Study Scientist: Huixiao Hong
(1) Augmentation of different endocrine-related endpoint data and development of prediction models for screening chemicals with endocrine activity potential by integrating the augmented multiple types of endocrine-related endpoint data.
(2) Building of an androgenic activity database and construction of integration-based prediction models.
Study Scientist: Noriko Nakamura
Evaluation of the in vitro testis organ system as an alternative model to assess male reproductive toxicology and establishment of a standardized protocol for the assay.
Study Scientist: Svetoslav Slavov
Testing of the feasibility and implementation of software code for enhancements to the three-dimensional quantitative spectral data-activity relationship (3D-QSDAR) technique and demonstration of the potential beneficial effect on the performance of 3D-QSDAR models for various data sets and endpoints.
Study Scientist: Jeffery Fisher
Assistance to other FDA Centers and research organizations outside of FDA with their requests for support from staff scientists within NCTR and other scientists on safety and risk assessment issues of interest to FDA.
Study Scientist: Annie Lumen
(1) Demonstration of a proof of concept for using emerging computational techniques in understanding pregnancy-related alterations in drug pharmacokinetics.
(2) Assistance in developing recommendations for dose adjustments and drug labeling in the pregnant population, thus promoting women’s health during this crucial period.
Study Scientist: Weida Tong
Assembly of a comprehensive list of herbal and dietary supplements that have potential to cause drug-induced liver injury in humans into a web-based database that can be used for reference in regulatory processes when hepatotoxicity issues arise.
