Novel toxicity assessment strategies highlighted at DNTP board meeting
Spurring innovation in toxicological research is the main driver behind two new programs from the NIEHS Division of the National Toxicology Program (DNTP), presented at the June 8 National Toxicology Program (NTP) Board of Scientific Counselors meeting. Vicki Sutherland, Ph.D., and Julie Foley outlined the Consumer Products and Therapeutics(https://ntp.niehs.nih.gov/ntp/about_ntp/bsc/2021/june/meeting_materials/cpt_bsc_508.pdf) (CPT) program, and David Crizer, Ph.D., described the Novel Tools and Approaches(https://ntp.niehs.nih.gov/ntp/about_ntp/bsc/2021/june/meeting_materials/nta_bsc_508.pdf) (NTA) program.
Predicting toxicity of consumer products
Consumer products represent a ubiquitous source of chemicals — often, mixtures of chemicals — that by direct use or through migration to the environment create chronic, low-level human exposures. The vast number of chemicals in this group makes assessing their toxicity one chemical at a time both time- and cost-prohibitive. The CPT program aims to identify, evaluate, and adopt more efficient strategies for toxicology assessment that can be applied to this research area.
One such strategy involves class-based assessments, where high-throughput — that is, high-volume — methods are used to predict toxicity based on similarity to previously characterized compounds. Substances are usually grouped based on similarities in chemical structure or biological function, but other criteria can also be used for classification.
To determine whether class-based approaches can be effectively applied to chemicals in consumer products, the program will use organohalogen flame retardants (OFRs) as a model. OFRs are found in numerous everyday items, such as upholstered furniture and plastic electronic casings, and have been extensively researched at DNTP.
Examining data on OFR toxicity generated by both traditional and class-based methodologies will help establish whether class-based strategies live up to their promise, and whether the approach can be expanded to other chemical classes in consumer products.
According to Foley, the CPT program is partnering with the Consumer Product Safety Commission, which will work to prevent human exposure to OFRs.
Therapeutics — the other half of CPT
“Consumer products and therapeutics toxicity assessment are combined under the CPT program, but we consider them separate categories with separate research goals, to allow us to better address potential health effects,” Foley noted.
Funding from the National Institutes of Health Office of AIDS Research supports AIDS drug-related studies at DNTP. The therapeutics component of the CPT program is centered around addressing potential long-term effects of exposure to HIV combination antiretroviral therapies (cARTs).
Combination therapies are often used by HIV-positive individuals during pregnancy to prevent transmission of the virus to the developing fetus.
“Drug makers have evaluated the reproductive and developmental toxicity of individual antiretroviral therapies, but the different combinations used have not necessarily been tested,” explained Sutherland.
Current DNTP research examines the effects of in utero exposure to various cARTs as well as what occurs biologically in offspring. The CPT team seeks to foster a group of experts at NIEHS and elsewhere to inform ongoing research initiatives, provide more in-depth analyses, and potentially combine different data streams.
“One of the most rewarding parts of the work here at DNTP has been the ability to leverage NIEHS and DNTP capabilities and expertise to help identify areas of concern so that physicians can proactively work to improve people’s lives,” Sutherland said.
New tools to solve new problems
As the field of toxicology grows, the need to develop and validate new high-quality research capabilities becomes increasingly important.
“The toxicology field has reached a pivotal point where the need for more rapid, predictive, and human-relevant data can no longer be met by the tools and approaches that currently exist,” said DNTP chemist Crizer, who described the NTA program.
Ensuring that new research capabilities align with contemporary public health problems relevant to DNTP’s core mission is one of the program’s main objectives, he noted.
Some of those capabilities include animal model substitutes such as embryoid bodies, 3D liver models, organ-on-a-chip in vitro disease models, and high-throughput data streams involving metabolomics and transcriptomics. Metabolomics is the study of molecules and their interactions within the body, and transcriptomics is the investigation of gene expression, or how cells process and act upon genetic information.
“We're not interested in this work just for the sake of developing a new and fun tool to use; we want to design capabilities that are really aimed at answering questions that DNTP is trying to solve,” Crizer told board members.
(Florencia Pascual, Ph.D., is a contractor in the NIEHS Pediatric Neuroendocrinology Group and a science writer.)