NCTR Research Highlights

Periodic report on research activities and special events at NCTR

2024 Research Highlights

NCTR Uncovers Drug Interaction with UGT Enzymes as an Indicator of Drug-Induced Liver Injury
NCTR Summer Student Success
NCTR Hosts the 14^th Annual Global Summit on Regulatory Science
Building a Strategy to Assess Safety of Botanicals
Anaerobic and Aerobic Bacteria Detected in Commercial Tattoo and Permanent Makeup Inks
NCTR Staff Present at International Veterinary Medicine Conference
FDA Grand Rounds, July 2024: Salmonella and Escherichia coli: Challenges along the One Health Continuum
NCTR Artificial Intelligence Initiative Proposes General Framework for Adopting LLMs in Regulatory Application
FDA Grand Rounds, March 2024: Evaluating Mutagenicity by Error-Corrected Sequencing
NCTR Researcher Serves as Chair for Women in Cancer Research During its 25th Year
FDA/NCTR Highlighted at 2024 Arkansas Bioinformatics Consortium
NCTR Publishes 2023 Annual Report

December 4, 2024

NCTR Uncovers Drug Interaction with UGT Enzymes as an Indicator of Drug-Induced Liver Injury

Researchers at FDA’s National Center for Toxicological Research (NCTR), collaborating with scientists from Elsevier’s Life Sciences, conducted a study to explore how interactions between drugs and non-cytochrome P450 (non-CYP) enzymes might lead to drug-induced liver injury (DILI). Their findings, published in Hepatology on July 17, 2024, will be featured on the cover of the journal’s May 2025 issue.

This research is part of the Liver Toxicity Knowledge Base project, an initiative by NCTR to pinpoint risk factors for DILI and develop models to predict DILI accurately. The study used a dataset on drug interactions with non-CYP enzymes generated from in vitro studies stored within the PharmaPendium database. This dataset included DILI data of 317 drugs and their interactions with 42 non-CYP enzymes.

Authors report that drugs acting as pure inhibitors of a UDP-glucuronosyltransferases (UGT) enzyme are three times more likely to have high DILI risk than non-inhibitors. Drugs that are both substrates and inhibitors of a UGT enzyme have an even higher risk — 13 times more likely to raise DILI concerns. However, high DILI concern was neither associated with pure UGT substrates nor other non-CYP enzyme families.

The study concluded that drug interactions with UGT enzymes are a strong predictor of DILI risk across different drug types, complementing another DILI predictor, the Rule-of-Two (RO2). This insight adds to current DILI prediction methods, offering a valuable tool for drug development.

October 22, 2024

NCTR Summer Student Success

Each summer, NCTR hosts a ten-week summer program for undergraduate and graduate students that provides hands-on research and laboratory experience mentored by FDA scientists. NCTR’s Summer Student Research Program (SSRP) is administered by the Oak Ridge Institute for Science and Education (ORISE) and is designed for science and mathematics students preparing for future careers in toxicology, regulatory science, medical sciences or related scientific disciplines.

This summer, the students had several opportunities to submit abstracts and present their research in a public forum.

Central Arkansas Undergraduate Summer Research Symposium – July 24, 2024

The Central Arkansas Undergraduate Summer Research Symposium took place on July 24, 2024, at the University of Arkansas for Medical Sciences campus in Little Rock, Arkansas. The symposium provided a venue to celebrate the achievements of undergraduates pursuing research projects at colleges, universities, and research institutions across Arkansas, including presentations and posters from participants in NCTR’s SSRP. Of the 13 submitted abstracts, one NCTR student, Neil Dogra (mentored by Dr. Timothy Flanigan, Division of Neurotoxicology), was chosen to give an oral presentation, and another student, Reha Nunna (mentored by Dr. Youngbeom Ahn, Division of Microbiology), received an award for her poster presentation.

The presentations and posters shared at the Undergraduate Summer Research Symposium covered a broad range of disciplines including biology, chemistry, physics, engineering, and computational science.

FDA Annual Student Scientific Research Day – August 1, 2024

The 2024 FDA Annual Student Scientific Research Day was held on August 1, 2024, for virtual presenters. This event showcased student research at FDA and provided a forum for some of NCTR’s SSRP participants to prepare written abstracts that summarized their projects. The Program goals are to:

Recognize FDA student research and contributions to FDA.
Present FDA student research on a public website annually.
Support STEM education for students in FDA scientific priority areas.

Ten public abstracts were submitted by NCTR SSRP participants. Please visit FDA’s 2024 Student Scientific Research Day webpage for more information on the event and to read the student abstracts.

October 18, 2024

NCTR Hosts the 14^th Annual Global Summit on Regulatory Science

The Global Coalition for Regulatory Science Research (GCRSR), established under the leadership of the former FDA Commissioner, Dr. Margaret A. Hamburg, was created to enhance international partnerships and collaborations that focus on adapting emerging technologies and big data science to improve regulatory science research on the safety and efficacy of foods and drugs. Today, GCRSR comprises over 20 regulatory agencies from 12 countries. One of its flagship initiatives is the annual Global Summit on Regulatory Science (GSRS), which brings together regulators, industry, and academia to discuss emerging technologies poised for regulatory implementation. This year, the 14th GSRS was hosted by the FDA’s National Center for Toxicological Research (NCTR), with a focus on Digital Transformation in Regulatory Science.

Group of GSRS24 attendees standing in front of the Arkansas River in Little Rock, AR — *GSRS24 attendees in Little Rock, Arkansas*

As outlined in the program at-a-glance, GSRS24 was a three-day event which opened with a pre-conference workshop, followed by the main program that spanned two full days. Current FDA Commissioner, Dr. Robert M. Califf, kicked off the conference with his welcome remarks and emphasized the importance of advancing digital technologies within regulatory science. The event featured a diverse lineup of speakers from across the globe, including the United States, Brazil, Canada, China, Germany, Italy, Japan, Saudi Arabia, Singapore, Switzerland, and the United Kingdom. Additionally, a poster session showcased 35 posters addressing a broad range of topics beyond digital technology. The conference concluded with closing remarks from the FDA’s Acting Chief Scientist, Dr. David Strauss, who reflected on the future of artificial intelligence (AI) and machine learning in regulatory science.

The main program included seven sessions, starting with a global overview of digital technologies in regulatory science. Two sessions were particularly notable—a dialogue on the readiness of regulatory science for AI and a showcase of current tools supporting regulatory applications. Other sessions explored AI, machine learning, and the application of digital technologies in regulated products, public health, and novel applications. Around 200 participants attended the conference, including more than 50 international participants from 15 countries. Local participation was robust, with strong representation from FDA. More than a third of the 200 attendees were from the local community. Swissmedic also announced their plans to host next year’s GSRS25 in Lausanne, Switzerland.

For more information about this year's summit, visit the GSRS24 page or the GCRSR external site.

September 30, 2024

Building a Strategy to Assess Safety of Botanicals

Two principal investigators with FDA’s National Center for Toxicological Research (NCTR) contributed their expertise to a review paper titled “Screening Tools to Evaluate the Neurotoxic Potential of Botanicals: Building a Strategy to Assess Safety,” that was published in Expert Opinion on Drug Metabolism & Toxicology1 . Jyotshna Kanungo, Ph.D., and Fang Liu, Ph.D., are researchers within NCTR’s Division of Neurotoxicology and members of the multi-agency and international Botanical Safety Consortium’s (BSC) Neurotoxicity Working Group.

The Botanical Safety Consortium (BSC) is a collaboration established by the FDA, the National Institute of Environmental Health Sciences (NIEHS), and the Health and Environmental Sciences Institute (HESI). BSC’s mission is to “provide a forum for scientists from government, academia, consumer health groups, industry, and non-profit organizations to work collaboratively to generate a sound scientific basis for integrating existing safety data and the latest toxicology tools to evaluate botanical safety in dietary supplements.”2 BSC’s immediate goal is to evaluate the suitability of assays for botanicals as complex mixtures.

Researchers provided their insights at BSC’s monthly meetings on in vitro stem cells in culture and zebrafish models used in neurotoxicity assessments. The paper—which discusses the efforts of BSC’s Neurotoxicity Working Group to develop new alternative methods (NAMs) for screening the neurotoxic potential of botanical extracts—outlines the use of NAMs to assess neurotoxic endpoints such as neuronal activity and behavior. The paper also details the selection of botanical case studies and aims to establish a comprehensive framework for neurotoxicity screening, which emphasizes the need for multiple NAMs to account for the complexity of neurotoxicity.

August 13, 2024

Anaerobic and Aerobic Bacteria Detected in Commercial Tattoo and Permanent Makeup Inks

Researchers from FDA’s Office of the Chief Scientist/National Center for Toxicological Research (NCTR) collaborated with scientists from FDA’s Center for Food Safety and Applied Nutrition/Office of Cosmetics and Colors on a study to investigate the presence of anaerobic and aerobic bacteria in commercial tattoo and permanent makeup (PMU) inks. The manuscript “Detection of anaerobic and aerobic bacteria from commercial tattoo and permanent makeup inks” was published in Applied and Environmental Microbiology, a journal of the American Society for Microbiology (ASM) on July 2, 2024. The findings demonstrated that nearly half of the PMU ink samples and close to one-quarter of the tattoo ink samples tested contained bacterial contamination, even if the products were labeled “sterile”.

Overall, the current study findings are within the broader context of ongoing research into microbial contamination of tattoo and PMU inks, confirming persistent contamination risks and emphasizing the need for stringent quality control and effective sterilization methods. The specific focus on anaerobic bacteria adds a new dimension to understanding microbial risks associated with tattoo and PMU inks. While improvements by industry have been noted, ongoing vigilance is needed to ensure the safety of tattoo and PMU inks, contributing to developing better standards and practices to protect public health.

“Our findings reveal that unopened and sealed tattoo inks can harbor anaerobic bacteria, known to thrive in low-oxygen environments like the dermal layer of the skin, alongside aerobic bacteria,” said corresponding author Seong-Jae (Peter) Kim, Ph.D., a microbiologist with the Division of Microbiology at NCTR. “This suggests that contaminated tattoo inks could be a source of infection from both types of bacteria. There was no clear link between a product label claiming sterility and the actual absence of bacterial contamination,” said Dr. Kim.

The study found lower bacterial counts compared to previous research, with most contaminated samples showing counts less than 250 colony forming units (CFU)/g, and a few samples exceeding 800 CFU/g up to 10⁵. However, these levels are not significantly different from those reported in previous studies, indicating that contamination of tattoo and PMU inks remains an ongoing issue.

In June 2023, FDA issued draft guidance to help tattoo ink manufacturers and distributors recognize situations in which a tattoo ink may become contaminated with microorganisms, and thus, be potentially injurious to health. This guidance also recommends certain steps that manufacturers and distributors could take to help prevent the occurrence of these conditions, or to identify and remediate insanitary conditions that already exist during manufacturing and distribution.

August 1, 2024

NCTR Staff Present at International Veterinary Medicine Conference

Delegates from NCTR attended the Twelfth International Conference on Antimicrobial Agents in Veterinary Medicine (AAVM), held in Athens, Greece, June 16-19, 2024. Antimicrobials are medications—antibiotics, antivirals, antifungals, and antiparasitics—which are used to prevent and treat infectious diseases in humans, animals, and plants. Antimicrobial resistance can occur when these medications are no longer effective—due to misuse or overuse—causing disease or even death. While there has been increased effort to promote an overall reduced and more responsible use of antimicrobials, they are still crucial in farm- and companion-animal therapy. There is a well-known risk of spreading bacterial resistance when antimicrobials are used, and as animal and human antimicrobial use increases, so do animal- and human-health concerns. Although antimicrobial drug alternatives are being produced, they are often not readily available.

Important topics covered at this conference included:

Antimicrobial resistance overview
One-Health approach to antimicrobials
Antimicrobial drug use in food-producing animals
Environmental impact of antimicrobials
Antivirulence challenges
Advances in diagnostics
Antimicrobial stewardship
Pharmacokinetic-pharmacodynamic modeling

Researchers from NCTR’s Division of Microbiology, attendees from FDA’s Center for Veterinary Medicine, and stakeholders from South America and Europe were able to participate in an exchange of scientific ideas. The following scientific topics were presented by NCTR staff:

"Characterization of the Virulence and Antimicrobial Resistance of APEC Associated with Poultry Disease Versus those Isolated from Healthy Birds" (Jing Han, Ph.D., presentation)
"Salmonella enterica Serovar Agona: Assessment of Their Distribution, Antimicrobial Resistance, Virulence Potential, and Plasmid Biology" (Rajesh Nayak, Ph.D., plenary presentation)
"Novel Mechanism of Action of the Gentamicin-Resistance Protein, GrdA" (Ashraf Khan, Ph.D., poster)

July 26, 2024

FDA Grand Rounds, July 2024: Salmonella and Escherichia coli: Challenges along the One Health Continuum

Steven Foley, Ph.D., director of NCTR’s Division of Microbiology and Senior Biomedical Research and Biomedical Product Assessment Service Expert (SBRBPAS), presented at the virtual FDA Grand Rounds on July 11, 2024. The key One Health areas of exploration in Dr. Foley’s presentation—"Salmonella and Escherichia coli: Challenges along the One Health Continuum"—were to:

Describe the importance of the One Health concept and how it applies to public health.
Discuss the importance of Salmonella enterica (Salmonella) and Escherichia coli (E. coli) as One Health-related pathogens.
Discuss the challenges with antimicrobial resistance spread among Salmonella and E. coli.

Salmonella and E. coli are bacterial pathogens that infect humans and a wide range of other animal hosts. They have the potential to spread across species, creating One Health concerns. Many of these strains are also resistant to multiple antibiotics which leads to increased treatment challenges, making antimicrobial resistance a significant public health threat. Some types of E. coli which cause disease in animals, can potentially be a source for infections in humans as demonstrated by carrying common groups of genes associated with disease development. These shared virulence factors may also be targets for disease control. Similarly, many Salmonella bacteria that are isolated from food animals—such as cattle, pigs, and poultry—and the environment share characteristics (virulence and antimicrobial resistance genes, plasmid content, and genome sequences) with those that cause human disease. These challenges were highlighted by exploring serotype Agona, a globally distributed Salmonella serotype that is common among food animals and human patients.

A virulence factor database, developed by NCTR in collaboration with FDA’s Center for Veterinary Medicine, covers both the Salmonella and E. coli species. This database is assisting FDA in its goals of addressing One Health concerns related to antimicrobial resistance and the spread of disease-causing pathogens.

Learn more about Dr. Foley in his principal investigator bio-sketch.

May 7, 2024

NCTR Artificial Intelligence Initiative Proposes General Framework for Adopting LLMs in Regulatory Application

Are you curious about how the FDA uses large language models (LLMs) and artificial intelligence (AI) in its regulatory work? Scientists in NCTR’s Division of Bioinformatics and Biostatistics (DBB)—led by Dr. Leihong Wu—proposed a general framework for adopting LLMs and demonstrated the framework through AskFDALabel, a system customized to assist with drug labeling review. The findings were shared in Regulatory Toxicology and Pharmacology and show how AskFDALabel provides a more efficient, accurate, and reliable solution for extracting relevant information from drug labeling documents.

More importantly, AskFDALabel showcases the development of a localized, transparent LLM fine-tuned to assist with labeling review by asking questions and retrieving information in the labeling documents. It can be readily extended to other documents under regulatory review to address an usually difficult and labor-intensive aspect of the review process. This framework represents a significant, secure, and inexpensive example of using AI to advance regulatory needs.

The NCTR-developed AI4TOX is an AI toxicology program under the leadership of DBB Director, Dr. Weida Tong, that aims to apply the most advanced AI methods to develop new tools to support FDA regulatory science and strengthen the safety review of FDA-regulated products. AI4TOX consists of four initiatives—BERTox (which is also led by Dr. Leihong Wu), AnimalGAN, SafetAI, and PathologAI.

Visit NCTR's Research Focus Area: Artificial Intelligence section to learn about these initiatives or contact Dr. Weida Tong for additional information.

March 26, 2024

FDA Grand Rounds, March 2024: Evaluating Mutagenicity by Error-Corrected Sequencing

Javier Revollo, Ph.D., research biologist and principal investigator in NCTR’s Division of Genetic and Molecular Toxicology, presented at the virtual FDA Grand Rounds public event on March 14, 2024. The goals of Dr. Revollo’s presentation—"Evaluating Mutagenicity by Error-Corrected Sequencing"—were to:

Compare and contrast germline and somatic mutations.
Discuss the importance of identifying somatic mutations.
Describe how DNA sequencing can be used to identify somatic mutations.

As explained on the FDA Grand Rounds page, somatic mutations are permanent and heritable genetic alterations that increase cancer risk. They can occur spontaneously but most often result from DNA damage induced by the environment (e.g., sunlight) or genotoxic compounds (e.g., chemical mutagens). Conventional mutation detection assays can only indirectly estimate somatic mutation frequencies through reporter genes, which can limit the implementation of such assays. To overcome this challenge, error-corrected sequencing methods and bioinformatic algorithms capable of directly identifying somatic mutations from any DNA samples are being developed and refined.

Learn more about Dr. Revollo in his Principal Investigator Bio-sketch.

March 25, 2024

NCTR Researcher Serves as Chair for Women in Cancer Research During its 25th Year

Dr. Beverly Lyn-Cook, senior research biologist within NCTR’s Division of Biochemical Toxicology, serves as the chairperson for the American Association for Cancer Research (AACR) professional group, Women in Cancer Research, which celebrates its 25th anniversary this year. According to its website, Women in Cancer Research supports women scientists, provides critical mentorship and funding opportunities, and advocates for equality in cancer research.

Dr. Lyn-Cook was recently profiled in the AACR blogpost, “Women in Cancer Research: 25 Years of Progress.” Learn more about Dr. Lyn-Cook in her "Researcher Spotlight."

March 11, 2024

FDA/NCTR Highlighted at 2024 Arkansas Bioinformatics Consortium

The 10^th annual Arkansas Bioinformatics Consortium (AR-BIC) meeting was held February 26-27, 2024, in Little Rock, Arkansas with the theme, “Real World Impact of AI.” The AR-BIC annual meeting has become the largest bioinformatics gathering in the State and provides a platform for networking, collaborating, and sharing ideas with meetings of 200+ attendees.

Participation of Senior Leadership from FDA and NIEHS

The FDA Principal Deputy Commissioner, Dr. Namandjé Bumpus, and Director of the National Institute of Environmental Health Sciences (NIEHS), Dr. Rich Woychick, shared their vision on the promises and challenges of utilizing artificial intelligence and data informatics in the regulatory science space. In addition, this year’s AR-BIC agenda (*PDF download) featured plenary sessions, workshops, roundtable discussions, breakout sessions, and a poster session/contest. Many of these events featured NCTR researchers.

NCTR Postdoctoral Fellows Awarded in AR-BIC Poster Contest

During the two-day event, AR-BIC featured a competitive poster session for postdoctoral fellows and students. Two of NCTR’s postdoctoral fellows were winners in the poster contest which recognized the research contributions of trainees.

Dr. Chandra Mohan Reddy Muthumula’s (Division of Microbiology, NCTR) poster titled, “Impacts of In Utero Antiretrovirals on Offspring Intestinal Microbiome and Metabolites” won second place.
Dr. Shivangi Shrimali (Division of Bioinformatics and Biostatistics, NCTR) won third place with a poster titled, “Assessment of Challenges Towards Implementing New Approach Methods for Predicting Drug Induced Liver Injury.”

NCTR Contributions to AR-BIC

In 2011, a Memorandum of Understanding (MOU) between FDA and the state of Arkansas established a framework for cooperation between NCTR and Arkansas research universities and institutions, which eventually led to the creation of AR-BIC. Since the inception of AR-BIC in 2013, NCTR has continued to be an influential and active partner, with researchers and leaders from NCTR currently serving on AR-BIC’s Advisory Council and Scientific Program Committee.

NCTR Representation on the AR-BIC Advisory Council:

Tucker Patterson, Ph.D., NCTR Center Director
Weida Tong, Ph.D., Director, Division of Bioinformatics and Biostatistics (DBB)

NCTR Representation on the AR-BIC Scientific Program Committee:

Steve Foley, Ph.D., Director, Division of Microbiology
Huixiao Hong, Ph.D., Bioinformatics Branch Chief, DBB
Dongying Li, Ph.D., Staff Fellow, DBB
Weida Tong, Ph.D., Director, DBB
Joshua Xu, Ph.D., Review-to-Research and Return Branch Chief, DBB

The 2025 AR-BIC annual meeting is scheduled for February 27-28, 2025, in Fayetteville, Arkansas. Visit the AR-BIC website for more information about the Consortium.

March 1, 2024

NCTR Publishes 2023 Annual Report

Check out NCTR's 2023 Annual Report. The report includes research project information, collaboration highlights, and ongoing initiatives for each of NCTR's research divisions as well as key accomplishments from the calendar year.