Next Generation Risk Assessment of Emerging PFOA Alternatives Using Integrated New Approach Methodologies

The global restriction of legacy per- and polyfluoroalkyl
substances
(PFASs), such as perfluorooctanoic acid (PFOA), has led to increased
production and environmental occurrence of emerging alternatives.
This study applied a next generation risk assessment (NGRA) framework
to evaluate and compare the local environmental risks of eight PFOA
alternatives using multiple lines of evidence from new approach methodologies
(NAMs). Targeted chemical analysis was conducted to quantify environmental
concentrations in wastewater and surface waters near an industrial
source. Hazard characterization integrated in silico modeling, in
vitro assays using zebrafish liver cells, in vivo zebrafish embryo
toxicity tests, and transcriptomic profiling. Multiple points of departure
(PODs), including conventional effect concentrations, benchmark concentrations
(BMC), transcriptomic POD (tPOD), and species sensitivity distributions
(SSD), were derived. The results showed that HFPO-TA and HFPO-TeA
were cytotoxic, while HFPO-DA, HFPO-TA, and HFPO-TeA caused significant
embryo toxicity. HFPO-TeA emerged as the most potent alternative,
with transcriptomic signatures implicating disruption of metabolic
and cardiovascular functions. Risk quotients (RQ) for HFPO-DA exceeded
concern thresholds across end points, while those for HFPO-TA and
HFPO-TeA declined with appropriate assessment factor adjustments.
These findings highlight potential local environmental risks from
PFOA alternatives and demonstrate the utility of NAM-based NGRA frameworks.