Per- and polyfluoroalkyl substances (PFASs) are important environmental contaminants, yet relatively few analytical reference standards exist for this class. Nontarget analyses performed by means of high-resolution mass spectrometry (HRMS) are increasingly common for the discovery and identification of PFASs in environmental and biological samples. The certainty of PFAS identifications made via HRMS must be communicated through a reliable and harmonized approach. Here, we present a confidence scale along with identification criteria specific to suspect or nontarget analysis of PFASs by means of nontarget HRMS. Confidence levels range from level 1a—“Confirmed by Reference Standard,” and level 1b—“Indistinguishable from Reference Standard,” to level 5—“Exact Masses of Interest,” which are identified by suspect screening or data filtering, two common forms of feature prioritization. This confidence scale is consistent with general criteria for communicating confidence in the identification of small organic molecules by HRMS (e.g., through a match to analytical reference standards, library MS/MS, and/or retention times) but incorporates the specific conventions and tools used in PFAS classification and analysis (e.g., detection of homologous series and specific ranges of mass defects). Our scale clarifies the level of certainty in PFAS identification and, in doing so, facilitates more efficient identification.
Per- and polyfluoroalkyl substances (PFAS) are ubiquitously detected in the environment, and some pose significant human and environmental health concerns globally. While some PFAS induce adverse health effects, relatively few toxicological studies adequately address the broad structural diversity of this chemical class. In the current study, we evaluated 58 individual PFAS spanning 14 structural subclasses and 2 mixtures at single concentrations for developmental toxicity in zebrafish using highly sensitive behavior endpoints. Following developmental exposure to PFAS, zebrafish were assessed for mortality and challenged with an embryonic photomotor response (EPR) assay at 24 h postfertilization (hpf) and with larval photomotor response (LPR) and larval startle response assays at 120 hpf. We found that none of the tested PFAS exposures elicited significant mortality or aberrant EPR; however, exposure to 21 individual PFAS from multiple structural subclasses and 1 mixture induced aberrant larval behavior. We then evaluated developmental toxicity across a concentration range of 0–100 μM for 10 perfluoroalkyl carboxylic acids (PFCAs; 4-carbon perfluorobutanoic acid through the 13-carbon perfluorotridecanoic acid). Exposure to the PFCAs did not cause significant mortality or morphological effects, with the exception of perfluorooctanoic acid and perfluorononanoic acid, and did not induce aberrant EPR. All PFCAs, except for longer-chain perfluorododecanoic acid caused abnormal LPR following exposure to at least one concentration. In this study, we evaluated a broad set of PFAS not previously assessed for in vivo sublethal behavior endpoints and confirmed previous findings that exposure to some PFAS induces abnormal behavior in developing zebrafish. The data from this study will guide the selection of PFAS for which to investigate modes of toxic action.
Summary Per- and polyfluoroalkyl substances (PFAS) are ubiquitously detected in environmental and biological samples and cause adverse health effects. Studies have predominately focused on long-chain PFAS, with far fewer addressing short-chain alternatives. This study leveraged embryonic zebrafish to investigate developmental toxicity of a short-chain series: perfluorobutane sulfonate (PFBS), perfluoropentanoic acid (PFPeA), perfluorobutane sulfonamide (FBSA), and 4:2 fluorotelomer sulfonic acid (4:2 FTS). Following static exposures at 8 h postfertilization (hpf) to each chemical (1–100 μM), morphological and behavioral endpoints were assessed at 24 and 120 hpf. Only FBSA induced abnormal morphology, while exposure to all chemicals caused aberrant larval behavior. RNA sequencing at 48 hpf following 47 μM exposures revealed only FBSA significantly disrupted normal gene expression. Measured tissue concentrations were FBSA > PFBS > 4:2 FTS > PFPeA. This study demonstrates functional head groups impact bioactivity and bioconcentration.
Semiquantitation of suspect per-and polyfluoroalkyl substances (PFAS) in complex mixtures is challenging due to the increasing number of suspect PFAS. Traditional 1:1 matching strategies require selecting calibrants (target−surrogate standard pairs) based on head group, fluorinated chain length, and retention time, which is time-consuming and requires expert knowledge. Lack of uniformity in calibrant selection for estimating suspect concentrations among different laboratories makes comparing reported suspect concentrations difficult. In this study, a practical approach whereby the area counts for 50 anionic and 5 zwitterionic/cationic target PFAS were ratioed to the average area of their respective stable-isotope labeled surrogates to create "average PFAS calibration curves" for suspects detected in negative-and positive-ionization mode liquid chromatography quadrupole time-of-flight mass spectrometry. The calibration curves were fitted with log−log and weighted linear regression models. The two models were evaluated for their accuracy and prediction interval in predicting the target PFAS concentrations. The average PFAS calibration curves were then used to estimate the suspect PFAS concentration in a well-characterized aqueous film-forming foam. Weighted linear regression resulted in more target PFAS that fell within 70−130% of their known standard value and narrower prediction intervals than the log−log transformation approach. The summed suspect PFAS concentrations calculated by weighted linear regression and log−log transformation were within 8 and 16% of those estimated by a 1:1 matching strategy. The average PFAS calibration curve can be easily expanded and can be applied to any suspect PFAS even if the confidence in the suspect structure is low or unknown.
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