Assembly and Curation of Lists of Per- and Polyfluoroalkyl Substances (PFAS) to Support Environmental Science Research

Abstract

Per- and polyfluoroalkyl substances (PFAS) are a class of man-made chemicals of global concern for many health and regulatory agencies due to their widespread use and persistence in the environment (in soil, air, and water), bioaccumulation, and toxicity. This concern has catalyzed a need to aggregate data to support research efforts that can, in turn, inform regulatory and statutory actions. An ongoing challenge regarding PFAS has been the shifting definition of what qualifies a substance to be a member of the PFAS class. There is no single definition for a PFAS, but various attempts have been made to utilize substructural definitions that either encompass broad working scopes or satisfy narrower regulatory guidelines. Depending on the size and specificity of PFAS substructural filters applied to the U.S. Environmental Protection Agency (EPA) DSSTox database, currently exceeding 900,000 unique substances, PFAS substructure-defined space can span hundreds to tens of thousands of compounds. This manuscript reports on the curation of PFAS chemicals and assembly of lists that have been made publicly available to the community via the EPA’s CompTox Chemicals Dashboard. Creation of these PFAS lists required the harvesting of data from EPA and online databases, peer-reviewed publications, and regulatory documents. These data have been extracted and manually curated, annotated with structures, and made available to the community in the form of lists defined by structure filters, as well as lists comprising non-structurable PFAS, such as polymers and complex mixtures. These lists, along with their associated linkages to predicted and measured data, are fueling PFAS research efforts within the EPA and are serving as a valuable resource to the international scientific community.

A New CSRML Structure-Based Fingerprint Method for Profiling and Categorizing Per- and Polyfluoroalkyl Substances (PFAS)

“…An example is DTXSID40880388 whose IUPAC systematic name is 3,3,4,4,5,5,6,6,6-Nonafluorohexane-1-thiol, which can be condensed to the name 2-(Perfluorobutyl)­ethanethiol or 4:2 Fluorotelomer thiol. DSSTox expert manual curation has added fluorotelomer-type names either as DSSTox preferred names or synonyms to many PFAS substances, , but there remain hundreds of structures lacking such a synonym. Hence, a simple text search for the term “fluorotelomer” in the DSSTox list of preferred names in PFASSTRUCT (SI Table S5) will retrieve only 242 hits, which is a small fraction of the 1845 hits provided by the structure-based query using the TxP_PFAS FT chemotypes.…”

“…A recent publication by Williams et al detailed the evolution of EPA's DSSTox PFAS curation efforts and list expansion through to PFASSTRUCTV4 (https://comptox.epa.gov/ dashboard/chemical-lists/PFASSTRUCTV4), comparing this list definition to several other proposed working definitions, including those serving varied needs of EPA regulatory programs. 11,12 The most expansive PFAS definition to date has been put forth by the OECD PFAS workgroup as "containing an aliphatic and saturated −CF2−". 13 Although many would consider this an overly simplistic definition, yielding more than 40,000 PFAS in the current DSSTox database, it provides a practical and unambiguous filter to identify potential PFAS, with the understanding that the list is likely to be further filtered to serve research and regulatory needs across OECD Member Countries.…”

Evaluation of Per- and Polyfluoroalkyl Substances (PFAS) In Vitro Toxicity Testing for Developmental Neurotoxicity

“…The chemical concentration−response data were normalized on a plate-by-plate basis to the median of the control wells and curve-fit using the ToxCast Pipeline (tcpl). 44 PFAS bioactivity in the DNT NAMs was evaluated using several different approaches: (1) hierarchical clustering of potency and efficacy to determine patterns of activity in distinct neurodevelopmental processes; (2) enrichment analysis of PFAS structure feature descriptors present in active PFAS;…”

“…A set of 160 PFAS, constituting the Tier 1 testing portion of EPA's research PFAS library, was screened in DNT in vitro assays, which included the microelectrode array neuronal network formation assay (NFA) 39−41 and high-content imaging (HCI) assays, to evaluate proliferation, apoptosis, 42 and neurite outgrowth. 43 The DNT NAMs PFAS screening data were evaluated for: (1) possible bioactivity in DNT NAMs suggestive of effects on specific neurodevelopmental processes; (2) associations between PFAS physicochemical properties and structural feature descriptors with observed bioactivity; and (3) PFAS potency in the DNT NAMs compared to other chemicals and non-neural in vitro model systems.…”

“…PFAS have widespread commercial and industrial applications, such as water- and oil-repellents, surfactants, surface protectors, and fire-fighting foams. As of 2021, the OECD adopted a broad definition of PFAS that requires a minimum of one perfluorinated carbon, which results in a list of PFAS that may approach 40,000 substances, with more stringent definitions of PFAS structures resulting in shorter lists in the thousands. , Only a small number of legacy PFAS have been extensively evaluated for adverse human health potential, such as perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), which are currently under regulation internationally. − Given widespread human exposure to PFAS, and the limited empirical information available for many PFAS, further predicting and characterizing the hazard(s) associated with PFAS is a global interest.…”