Safe and Sustainable Alternatives Research Program

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

In FY24-25, the SSA program of the DTT continued work to understand the landscape of PFAS toxicology research and advance projects within our portfolio to achieve the aspirations of stated objectives. Active efforts included multiple invited presentations to researchers with the US Department of Defense and US-EPA (TSCA) on our groundbreaking work to understand the effects of PFAS mixtures in the form of military-qualified aqueous film-forming foams (AFFF) on human liver using NAM-based in vitro hepatocyte screening with cellular imaging and high throughput transcriptomics. A high impact toxicology manuscript (i.e., ~11) was successfully published in February 2025 in Environmental Science & Technology revealing a scalable solution to address the hazard potential of thousands of PFAS within our environment. The research portfolio also continued to make progress in understand the ways and degree to which PFAS accumulate in humans and rats. Human-based NAMs that model PFAS bioaccumulation were established using single and pooled 3D microtissue models and organ-on-a-chip platforms, which revealed clear evidence of renal reuptake of long half-life PFAS vs. shorter half-life chemicals and filled important data gaps with modern PFAS fluorotelomers present in military-qualified AFFFs. Multiple manuscripts are in preparation for this work along with a new concept proposal to expand the use of in silico computational models alongside in vitro screening and microphysiological systems to address more than 15,000 PFAS identified by US-EPA within our environment. This includes the work led by the PFAS/AFFF team to develop a first-in-class decision framework that integrates in silico, in vitro, and in vivo data streams to guide safer product development using data-driven approaches in collaboration with the US Department of Defense. Central to this framework, and tuned to the unique challenges of PFAS toxicity, is the inclusion of innovative study designs to address PFAS bioaccumulation from complex AFFF mixtures exposures. One such partnership includes our support of collaborators at Texas A&M and members of the TEX-VAL Consortium of research teams from industry (pharmaceutical, environmental chemical) working on a range of microphysiological systems that include an upcoming PFAS accumulation manuscript for renal re-uptake of PFAS. A recent publication listed in this report (PMID: 38917890) in collaboration with TEX-VAL researchers revealed novel combinatorial NAMs that were effective to predict renal clearance of PFAS as a key driver of their accumulation in humans. In addition to the focused work of the SSA program, leaders in this program have also led and contributed to a number of publications for FY24-25 that are listed in this annual report. These include NAM-based workshop reports, botanical food safety collaborations to understand botanical exposures in humans, NAM-based approaches for liver and kidney toxicity and PFAS accumulation, mechanistic Tox21 assays for a range of pathways (e.g., p53, AChe, nuclear receptors, CYP450s), cardiotoxicity, and the validation of NAMs and microphysiological systems for toxicology research. Overall, FY24-25 efforts led to numerous publications for the DTT and collectively contribute to the innovative evolution of NAMs and toxicology research tools for applied science that contribute to our understanding of environmental health effects and enable progress towards a safer environment.