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Division Director: Frederick A. Beland, Ph.D.

Meet the Principal Investigators — Biochemical Toxicology

Bisphenol A: Toxicology and Pharmacokenetic Data to Inform Ongoing Safety Assessments
Presented by K. Barry Delclos, Ph.D.

Watch the Recorded Presentation

The Division of Biochemical Toxicology conducts fundamental and applied research specifically designed to define the biological mechanisms of action underlying the toxicity of products regulated by, or of interest to, the centers of the FDA. This research is focused on measuring the toxicities and risk of cancer related to specific chemicals and the introduction of new techniques to enable regulatory agencies to evaluate better the risks associated with exposure to chemicals. The risk-assessment research is firmly rooted in mechanistic and exposure studies focused on the understanding of toxicological endpoints. This approach allows greater confidence in the subsequent risk assessments. 

Research Theme

Research within the division is centered on quantifying the toxicities and carcinogenic risks associated with specific chemicals and introducing new risk-assessment techniques to enable regulatory agencies to evaluate the risks associated with exposure to chemicals. The Division of Biochemical Toxicology capitalizes on scientific knowledge in the areas of biochemistry, organic and analytical chemistry, cellular and molecular biology, nutritional biochemistry, toxicology, phototoxicology, computational modeling and simulation-based risk assessment methods, and pharmacology. 

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2020 Select Accomplishments

Analyzing Arsenic Toxicity 

To address questions regarding arsenic toxicity, NCTR scientists performed mode-of-action analysis, investigating ways that glutathione affects the metabolism and disposition of arsenic, beginning with transport from the intestine and liver to other organs like lung, kidney, and bladder, and then oxidation to the excreted arsenic metabolite. Studies of arsenic metabolism and disposition such as this emphasize the link between A) metabolic activation vs. excretion of arsenic and B) the disruption of critical cellular thiol-based regulatory processes that define the human and animal dose-response characteristics of disease which are the basis for risk assessment. This study links the reductive potential of  glutathione with the metabolic activation, transport, and elimination of various forms of arsenic in the body to further define the associations between dietary exposure to various forms of arsenic and the development of important human diseases. Publication is available in Environment International.

Examining PFAS-Based Compounds in Various Foods, a 2020 PHCE-Funded Study 

Scientists from NCTR and Center for Food Safety and Nutrition (CFSAN) performed Pharmacokinetic (PK) evaluation of 6:2 fluorotelomer alcohol (6:2 FTOH)-based per- and polyfluorinated alkyl substance (PFAS), which is a degradation product of polymers used as stain-, water-, and greaseproof coatings that can migrate to foods, to examine the potential for its metabolites to persist in rat plasma, liver, and fat. Results of this PK analysis are the first to characterize the potential for persistence of the 5:3 acid metabolite in rat tissues after 90 days of repeated oral exposure to the parent compound 6:2 FTOH based on steady state PK parameters, and therefore, may inform future toxicity assay study designs to evaluate these and similar compounds. Results also showed that the time to steady state of the metabolite 5:3 acid in plasma, liver, and fat was approximately 1 year which is significantly longer than the 90-day toxicity studies currently available, suggesting that toxicity studies of at least 1-year duration are needed to evaluate any long-term systemic effects due to persistence of the 5:3 acid metabolite following repeated oral exposure to the 6:2 FTOH parent compound. This PHCE-funded study was published in Toxicological and Applied Pharmacology and informed this regulatory action by CFSAN.

PBPK Modeling Used to Study Depression Drug in Pregnant Women 

NCTR and CDER scientists developed a comprehensive physiologically-based pharmacokinetic (PBPK) modeling framework with a user-friendly interface using sertraline, a drug commonly used to treat depression in pregnant women. PBPK modeling has been a valuable asset for regulatory science and can become a powerful tool in the hands of clinicians. It is especially helpful for drugs used in pregnancy since these drugs cannot be tested for safety and efficacy during pregnancy due to ethical concerns. The approach that was followed can be adapted to predict the change in plasma concentrations of other drugs across increasing gestational age, allowing dose adjustments as the pregnancy progresses. Although the model has limitations, it lays a foundation to encourage prediction-based approaches to dosing in pregnancy in a user-friendly and real-time manner. The PBPK model was converted to a prototype web-based interactive dosing tool to demonstrate how the output of a PBPK model may translate into optimal sertraline dosing in pregnancy. Quantitative prediction of drug exposure using PBPK modeling in pregnancy will support clinically appropriate dosing and increase the therapeutic benefit for pregnant women. Publication available in npj Systems Biology and Applications.

Investigating Role of Precision Medicine in Triple-Negative Breast Cancer 

Researchers at NCTR collaborated with CDER, University of Tennessee Health Science Center (Memphis, TN), and University of Port-Harcourt (Port Harcourt, Nigeria) to investigate the role of vorinostat and indole-3-carbinol (I3C) on regulating critical receptors that are not normally expressed in triple negative breast cancer (TNBC), which is one of the most aggressive sub-types of breast cancer often with poor prognosis. Understanding whether ER, PR, or HER2 receptors can be reactivated in specific subtypes will greatly enhance understanding of epigenetic regulation in these highly deadly cancers and can, thus, expand the treatment potential of the currently approved targeted therapies for these subtypes of TNBC. The effect of treatments using vorinostat as an epigenetic drug and indole-3-carbinol as a dietary agent were assessed alone or in combination in cells representing different TNBC subtypes to determine if re-expressing critical receptors could increase the cells’ sensitivity to targeted therapies. Precision medicine is extremely important, and molecular profiling of patients’ tumors may prove in the future to be one of the most effective ways for handling aggressive cancers, such as TNBC. Paper was published in Anticancer Research.

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Resources for You

• NCTR Grand Rounds: "Bisphenol A: Toxicology and Pharmacokenetic Data to Inform Ongoing Safety Assessments (Presentation recorded in Adobe Connect on September 13, 2018)
• Annual Reports
• Meet the Principal Investigators

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