ACS Publications. Most Trusted. Most Cited. Most Read
Neurotoxic Effects of Mixtures of Perfluoroalkyl Substances (PFAS) at Environmental and Human Blood Concentrations
More

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:Environ. Sci. Technol. 2024, 58, 38, 16774-16784
  • Open Access
Ecotoxicology and Public Health

Neurotoxic Effects of Mixtures of Perfluoroalkyl Substances (PFAS) at Environmental and Human Blood Concentrations
Click to copy article linkArticle link copied!

Open PDFSupporting Information (1)

Environmental Science & Technology

Cite this: Environ. Sci. Technol. 2024, 58, 38, 16774–16784
Click to copy citationCitation copied!
https://doi.org/10.1021/acs.est.4c06017
Published September 11, 2024

Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Abstract

Click to copy section linkSection link copied!
High Resolution Image
Download MS PowerPoint Slide

Per- and polyfluoroalkyl substances (PFAS) may cause various deleterious health effects. Epidemiological studies have demonstrated associations between PFAS exposure and adverse neurodevelopmental outcomes. The cytotoxicity, neurotoxicity, and mitochondrial toxicity of up to 12 PFAS including perfluoroalkyl carboxylates, perfluoroalkyl sulfonates, 6:2 fluorotelomer sulfonic acid (6:2 FTSA), and hexafluoropropylene oxide-dimer acid (HPFO-DA) were tested at concentrations typically observed in the environment (e.g., wastewater, biosolids) and in human blood using high-throughput in vitro assays. The cytotoxicity of all individual PFAS was classified as baseline toxicity, for which prediction models based on partition constants of PFAS between biomembrane lipids and water exist. No inhibition of the mitochondrial membrane potential and activation of oxidative stress response were observed below the cytotoxic concentrations of any PFAS tested. All mixture components and the designed mixtures inhibited the neurite outgrowth in differentiated neuronal cells derived from the SH-SY5Y cell line at concentrations around or below cytotoxicity. All designed mixtures acted according to concentration addition at low effect and concentration levels for cytotoxicity and neurotoxicity. The mixture effects were predictable from the experimental single compounds’ concentration–response curves. These findings have important implications for the mixture risk assessment of PFAS.

This publication is licensed under

CC-BY 4.0 .
  • cc licence
  • by licence
Copyright © 2024 The Authors. Published by American Chemical Society

Subjects

what are subjects

Keywords

what are keywords

Synopsis

Mixtures of 12 anionic PFAS at concentration ratios representative of their environmental occurrence revealed neurotoxicity and mitochondrial toxicity using in vitro assays, which follow the concentration addition model.

Introduction

Click to copy section linkSection link copied!
Per- and polyfluoroalkyl substances (PFAS) have been utilized in various products since the 1950s due to their effective water- and grease-repellent properties. (1,2) Known for their persistence in the environment, PFAS have been detected in various matrices, including water, soil, plants, sludge, human and animal serum, and tissues. (3−8) Legacy PFAS, such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), have raised concerns regarding their impact on health and the environment. As a result, there has been an increased use of alternative PFAS, such as hexafluoropropylene oxide-dimer acid (HFPO-DA) and perfluorobutane sulfonic acid (PFBS), leading to their frequent occurrence in the environment. (9)
PFAS enter ecosystems through different pathways, including consumer goods, firefighting foams, industrial emissions, and effluents from wastewater treatment plants (WWTPs). Their solubility in water, mobility, and persistence contribute to the widespread contamination of the environment by PFAS. (10,11) The incomplete removal of PFAS from wastewater and biosolids often results in the release of these substances into surface waters that receive WWTP effluents and in croplands where biosolids are applied. (12,13)
PFAS are structurally diverse and vary in chain lengths, molecular geometry, and head groups (e.g., carboxylates, sulfonates), which impacts their bioactivity and their tendency to bind with biomolecules. (14) While there are over 10,000 PFAS (15) listed in the chemical registry, very limited toxicity data are available, creating a significant gap in our understanding of their potential health effects. (2,16) PFAS can adversely affect biological systems, especially the nervous system, (17) through mechanisms such as oxidative stress, (18,19) and receptor-mediated signaling pathways. (20,21) Mixtures of PFAS have caused neurobehavioral and developmental toxicity in rats (22) and altered epigenetic and transcriptomic regulations in mice. (23) A mixture of persistent organic pollutants, including six PFAS at concentration ratios similar to those present in human blood, has been shown to affect neural connectivity in vitro. (24,25) As summarized in a recent review by McCarthy et al., (26) few studies have investigated how PFAS act together in mixtures. Anionic PFAS mixtures mainly exhibited additive mixture effects on lipid metabolism in HepaRG cells. (27)
For risk assessment it is vital to know how chemicals act together in mixtures. (28) Chemicals that act according to the same mode of action can be grouped in common assessment groups and their mixture effect typically follows the established mixture toxicity concept of concentration addition (CA). (29) The model of independent action (IA) is typically applicable for mixtures of chemicals that have strictly different modes of action. (29) While synergy and antagonism result from the interaction of mixture components, they are rare in realistic mixtures and most often caused by toxicokinetic interactions and not true toxicodynamic interferences. (30)
New approach methodologies (NAM) based on high-throughput screening (HTS) with in vitro cellular assays provide a way to screen molecular key events within adverse outcome pathways. (31,32) Various NAM assays have been used to assess the effects of PFAS in general and specifically for developmental neurotoxicity. (33) However, PFAS are challenging to test even in HTS assays. In a study focusing on 160 PFAS, only a limited number of PFAS tested showed activity in a developmental neurotoxicity HTS test battery, with the most anionic PFAS being inactive up to the highest concentrations tested. (33) Anionic PFAS exhibited specific toxic effects unique to their chemical structure and interaction with biological targets such as the peroxisome-proliferator-activated receptor in cell line-based assays. (34) Nonetheless, their activity in many in vitro assays can often be explained by nonspecific effects related to baseline toxicity associated with membrane disruption. (35) Intracellular key events leading to neurodevelopmental disorders include synaptogenesis, degeneration of dopaminergic neurons, and disturbances of neuronal networks and their functions (31,36−38) but also encompass cell death in neurons, mitochondrial dysfunction, (39) activation of oxidative stress response, and endocrine disruption related to the thyroid hormone metabolism. (40)
In the present study, we evaluated mixture toxicity of PFAS at concentration ratios relevant in the environment and in human blood, focusing on their impacts on two cell lines (Figure 1). Human neuroblastoma (SH-SY5Y) cells differentiated into neuron cells were used as a screening tool to assess cytotoxicity and neurite outgrowth, serving as proxies for neurotoxicity. (38) Oxidative stress response, mediated via the nuclear factor erythroid 2-related factor 2-Antioxidant Response Element (Nrf2-ARE) pathway, was quantified using the reporter protein luciferase, while mitochondrial toxicity was assessed using the mitochondrial membrane potential (MMP) indicator in the reporter gene cell line AREc32. (41)

Figure 1

Figure 1. Study design. Differentiated SH-SY5Y and AREc32 cells were exposed to single PFAS and to several representative PFAS mixtures and extracts from the biosolids samples. Effects recorded after 24-h exposure included cytotoxicity in both cell lines. Inhibition of neurite length in the differentiated SH-SY5Y cells was detected by phase contrast imaging (top right– gray cell bodies, pink neurites). Oxidative stress response via the reporter gene activation of the Nrf2-ARE pathway as well as mitochondrial membrane potential inhibition was measured in AREc32 cells. Figure was partially created with BioRender.

High Resolution Image
Download MS PowerPoint Slide
We tested twelve anionic PFAS individually and in four realistic mixtures to evaluate how PFAS behave together (Figure 1). These twelve PFAS, identified by the United States (U.S.) Geological Survey from 2022, (42,43) were selected for their distinct environmental relevance in WWTPs across the U.S. A four-component PFAS mixture, representing concentration ratios in human blood, was also designed based on mean blood concentrations from the U.S. National Health and Nutrition Examination Survey (NHANES). (44) Furthermore, we extracted two types of biosolids from municipal WWTPs, quantified their PFAS content by liquid chromatography-tandem mass spectrometry(LC-MS/MS), (45) and prepared representative mixtures in proportions of detected PFAS. Additionally, we compared the neurotoxic effects caused by the components of the biosolid extracts, which contained PFAS and other (unidentified) organic chemicals. This comparison aimed to estimate the contribution of PFAS to the complex mixture effects of organic chemicals in biosolids.

Materials and Methods

Click to copy section linkSection link copied!

Mixture Preparation

Mixtures were prepared from methanolic stock solutions of 12 single PFAS (Table 1) at concentrations ranging from 0.037–0.186 M. For the PFAS mixture design, all the concentrations were converted from ng/g to molar (M) concentrations (Table 1). To calculate the molar fraction pi of each PFAS in the mixtures, eq 1 was used, where Ci is the concentration of the component i and Ctot is the total concentration of all PFAS (Ctot=∑i=1nCi).
pi=CiCtot
(1)
Table 1. PFAS Included in This Study, Design of the Environmental Mixture (Envmix), the Blood Mixture (Bloodmix), the Mixtures of Wastewater Activated Sludge (WASmix) and Primary Solid (PSmix)
  environmental mixture (envmix) 
chemical nameabbreviationconcentration Ci (ng/L)concentration Ci in molar units (pM)molar fraction pi in envmixmolar fraction pi in bloodmixamolar fraction pi in WASmixbmolar fraction pi in PSmixc
perfluorobutanoic acidPFBA8.138.10.139   
perfluoropentanoic acidPFPeA6.123.10.086   
perfluorohexanoic acidPFHxA5.618.30.0660.1270.207 
perfluoroheptanoic acidPFHpA7.420.30.075   
perfluorooctanoic acidPFOA11.026.60.0980.2890.1810.249
perfluorononanoic acidPFNA8.017.20.0640.107  
perfluorobutane sulfonic acidPFBS4.916.30.061   
perfluoropentane sulfonic acidPFPeS5.113.70.051   
perfluorohexane sulfonic acidPFHxS5.914.70.055   
perfluorooctanoic sulfonic acidPFOS2042.30.1500.4770.6120.751
6:2 fluorotelomer sulfonic acid6:2 FTS1023.40.086   
2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoic acidHPFO-DA5.817.60.065   
a

Mean of detected concentrations in children’s serum: 96 μg/L (4.7 pM) PFOA, 0.81 μg/L (1.8 pM) PFNA, 0.83 μg/L (2.1 pM) PFHxS and 3.90 μg/L (7.8 pM) PFOS.

b

Mean of detected concentrations in WAS: 4.2 ng/gsolid (10.1 pmol/gsolid) PFOA, and 15.3 ng/gsolid (30.6 pmol/gsolid) PFOS. (45)

c

Mean of detected concentrations in PS: 8.5 ng/gsolid (20.7 pmol/gsolid) PFHxA, 7.5 ng/gsolid (18.1 pmol/gsolid) PFOA, and 30.6 ng/gsolid (61.2 pmol/gsolid) PFOS. (45)

Mixtures were prepared by mixing methanolic stock solutions in appropriate fraction, aliquoting the desired quantity, evaporating the methanol, and reconstituting the final dosing solution in bioassay medium at 4× the highest concentration targeted.

Mixture Design

Twelve PFAS in the environmental mixture (envmix) were selected based on high detection frequency observed in the U.S. WWTP effluents. (43) The selected PFAS were mixed in the concentration ratios of the mean detected concentrations with fractions pi given in Table 1.
PFOA, PFNA, PFHxS, and PFOS were the most frequently detected PFAS in children’s serum, as reported in NHANES biomonitoring studies from 2013 to 2014. (44) The blood mixture (bloodmix) was designed based on the geometric mean of serum concentrations for the U.S. population from the NHANES report with fractions pi in Table 1 according to the mean of the detected concentrations.

WWTP Samples

Three grab samples of two types of biosolids, wastewater activated sludge (WAS) and lime-stabilized primary solids (PS), were collected from a WWTP. These samples were lyophilized, pulverized, and extracted as described by Dickman et al. (45) The resulting extracts were concentrated, suspended in the starting mobile phase, and fortified with a 13C-labeled internal standard (MPFOA). The PFAS concentrations in the extracts were analyzed and previously reported by Dickman et al. (45) Designed mixtures (PSmix and WASmix) were based on quantified amounts of PFHxA, PFOS and PFOA (Table 1).
Independently prepared extracts of these samples were dosed to the bioassays following previous procedures. (46) The extracts had an enrichment factor (EF) of 250 gsolid/Lmethanol. For dosing, an aliquot of the methanolic extract was blown down to dryness and then dissolved in bioassay medium at relative enrichment factors (REF) of up to 100 gsolid/Lbioassay.

MitoOxTox Assay

The AREc32 cell line was used to test mitochondrial toxicity and oxidative stress response of individual PFAS, mixtures, and extracts as described by Lee et al. (41) with details of the experiments given in the Supporting Information (SI), Text S2 and quality control measures described in Text S3. (47−49) The effect concentration for 10% effect (EC10) or inhibitory concentration for 10% cytotoxicity (IC10) were derived from the concentration–response curves (CRC) as described in Text S4. (50)

Neurotoxicity Assay

Differentiated human neuroblastoma SH-SY5Y cells were applied to test neurotoxicity of individual chemicals and mixtures according to Lee et al. (38) with details of the experiments given in the SI, Text S5 and quality control measures in Text S6. The EC10 for shortening of neurite length (neurite outgrowth inhibition NOI) and IC10 for cytotoxicity were derived as above (Text S4). (50)

Specificity Analysis

The ratio of IC10 to EC10 is a measure of the degree of specificity of effect, called the specificity ratio, SR (eq 2).
SR=IC10EC10
(2)
If SR > 10, the effect is highly specific. For 10 > SR > 1, the effect is valid but only moderately specific and could be caused indirectly by nonspecific toxicity that affects many different cellular processes. If the SR < 1, the inhibition of the neurite length is likely caused by nonspecific cytotoxicity, which kills the cells including the neurite, so the overall neurite length also decreases. In other words, only if the neurite length decreases at lower concentrations than those that cause cytotoxicity, the effect is specifically neurotoxic, else it is general toxicity.
Baseline toxicity, which is the minimum toxicity of every chemical, can be easily predicted from their tendency to accumulate in biological membranes, which can be simulated by the liposome–water distribution ratio Dlip/w. Anionic PFAS have a slightly different baseline model than neutral PFAS because anionic chemicals bind stronger than neutral chemicals to proteins in bioassay medium. (51) Therefore, there are separate baseline toxicity prediction models for anionic and neutral chemicals, which also differentiate between anionic and neutral PFAS. (35) Equation 3 is valid for cytotoxicity of anionic PFAS in the AREc32 cell line and eq 4 for cytotoxicity of anionic PFAS in SH-SY5Y cells. (35) The Dlip/w of the anionic PFAS are either available in the literature (52,53) or had been previously predicted, (35) and are listed in Table 2.
log(1/IC10,baseline(M)AREc32)=1.22+3.78×(1−e−0.263log⁡Dlip/w(pH7.4))
(3)
log(1/IC10,baseline(M)SH‐SY5Y)=1.22+4.07×(1−e−0.247log⁡Dlip/w(pH7.4))
(4)
Table 2. Liposome–Water Distribution Ratio of the Anionic PFAS Species, Dlip/w, and Cytotoxicity Inhibitory Concentrations IC10 for AREc32 and SH-SY5Y Cells and Effect Concentration EC10 for 10% Reduction of Neurite Lengtha
  AREc32 cytotoxicitySH-SY5Y cytotoxicitySH-SY5Y neurite outgrowth inhibition
PFASlogDlip/w[Lw/Llip]IC10SE IC10TRIC10SE IC10TREC10SE EC10SR
PFBA1.00b3.92 × 10–35.02 × 10–42.061.95 × 10–38.86 × 10–53.972.13 × 10–31.20 × 10–30.92
PFPeA1.75d1.05 × 10–38.06 × 10–52.311.67 × 10–31.02 × 10–41.343.41 × 10–31.51 × 10–30.49
PFHxA2.32c2.82 × 10–41.76 × 10–54.021.23 × 10–31.13 × 10–40.821.23 × 10–31.72 × 10–40.99
PFHpA2.91c1.67 × 10–49.32 × 10–63.438.65 × 10–47.85 × 10–50.575.44 × 10–49.83 × 10–51.59
PFOA3.52c5.43 × 10–53.03 × 10–65.802.76 × 10–42.66 × 10–50.952.42 × 10–41.70 × 10–51.14
PFNA4.25c1.15 × 10–41.20 × 10–51.494.97 × 10–45.62 × 10–50.271.99 × 10–42.49 × 10–52.50
PFBS3.51c7.58 × 10–45.25 × 10–50.421.09 × 10–36.00 × 10–50.249.68 × 10–43.77 × 10–51.12
PFPeS3.33d2.82 × 10–42.08 × 10–51.334.92 × 10–42.36 × 10–50.645.72 × 10–48.76 × 10–50.86
PFHxS4.13c1.66 × 10–41.27 × 10–51.134.05 × 10–43.85 × 10–50.372.80 × 10–44.60 × 10–51.45
PFOS4.89c5.64 × 10–45.82 × 10–50.204.12 × 10–43.85 × 10–50.203.03 × 10–45.12 × 10–51.36
6:2 FTSA3.87d7.22 × 10–44.66 × 10–50.321.21 × 10–22.30 × 10–30.023.86 × 10–38.05 × 10–43.15
HFPO-DA2.41c4.22 × 10–42.65 × 10–52.401.18 × 10–35.58 × 10–50.762.80 × 10–35.61 × 10–40.42
a

Full names of the abbreviated PFAS are given in Table 1. The toxic ratio TR is the ratio of the predicted IC10 of baseline toxicity and the measured IC10 (eq 5). The specificity ratio (SR) is the ratio of the predicted IC10 of baseline toxicity and the measured EC10 (eq 2).

b

Experimental log Dlip/w from Droge. (52)

c

Experimental log Dlip/w from Ebert et al. (53)

d

Predicted log Dlip/w from Qin et al. (35)

The measured cytotoxicity IC10 can also be compared with baseline toxicity. The toxic ratio TR is a measure of the excess cytotoxicity (eq 5).
TR=IC10,baselineIC10
(5)

Mixture Toxicity Evaluation

The 10% inhibitory concentration for cytotoxicity of a concentration-additive mixture IC10(CA) can be predicted with eq 6, if the n components i, present in fractions pi, with ∑pi = 1 act jointly according to CA. (29)
IC10(CA)=1∑i=1npiIC10,i
(6)
For low effect levels (<10%) and linear CRC (eq S1), the CA model simplifies to eq 7, which is equally valid for chemicals acting according to independent action (IA). (50)
IC10(CA)=1∑i=1npi×slopei10%=10%∑i=1npi×slopei
(7)
The same model can be applied for the effect concentration EC10(CA).
The slope of the CRC for the CA prediction (slopeCA) is defined by eq 8 and its SE(slope mixture) by eq 9. (50)
slopeCA=∑i=1npi×slopei
(8)
SE(slopeCA)=∑i=1npi2×SE(slopei)2
(9)
The IC10(CA) and EC10(CA) of the CA mixture prediction can then be derived by implementing the slopeCA and its SE into eqs S2 and S3. A measure of the quality of the mixture prediction is the index of prediction quality (IPQ), (54) which is defined by eq 10.
IPQ=1−IC10(exp)IC10(CA)forIC10(exp)<IC10(CA)andIPQ=IC10(exp)IC10(CA)−1forIC10(exp)>IC10(CA)
(10)
The contribution of one mixture component i to the overall mixture effect, Toxi, was calculated with eq 11.
Toxi=pi×slopei∑i=1npi×slopei
(11)
The relative effect potency, REPi, is the ratio between the EC10 of PFOA and that of chemical i.
REPi=EC10,PFOAEC10,i
(12)
The CRC of the mixture is calculated by eq 13 for any effect level below 10%. Above 10% the predictions become nonlinear. (50)
effecty(mixture)=∑i=1npi×slopei×Ctot=(∑i=1npi×slopei)Ctot=slopemixture×Ctot
(13)

Results and Discussion

Click to copy section linkSection link copied!

Measured Effects of Single PFAS

The assays were robust and repeatable as demonstrated by the quality control measures detailed in Text S3 (Figures S1 and S2) for the MitoOxTox and in Text S6 (Figure S3) for the neurotoxicity assay. In the MitoOxTox assay cytotoxicity was the dominant effect of the single PFAS (concentration–response curves, CRCs, in Figure S4, IC10 in Table 2). No activation of oxidative stress response was detected. MMP inhibition was detected only at concentrations that also caused cytotoxicity (Figure S4), which means that mitochondrial toxicity was a consequence of cytotoxicity and not a specific mode of action triggered by PFAS and no EC10 values could be derived.
All investigated PFAS caused cytotoxicity on differentiated SH-SY5Y cells (CRCs in Figure S5, IC10 in Table 2). The neurite outgrowth inhibition was often affected only at concentrations that caused cytotoxicity (Figure S5). Nevertheless, we recorded this end point and derived EC10 (Table 2) and included the end point of NOI in the mixture evaluation.
As there was a little difference in the two methods for quantification of confluency using phase contrast imaging with and without nuclei staining (Figure S6a), only the data using phase contrast imaging with nuclei staining will be reported below. The cytotoxicity IC10 (Table 2) agreed well between the two cell lines (Figure S6b) with the exception of 6:2 FTSA, which was less potent in SH-SY5Y.

Comparison of Measured Cytotoxicity with Baseline Toxicity

All PFAS in AREc32 (Figure 2a) and SH-SY5Y cells (Figure 2b) showed nonspecific cytotoxicity with a toxic ratio 0.1 < TR < 10 (Table 2). Only 6:2 FTSA had a TR of 0.02 in SH-SY5Y cells, which might be related to metabolism. The cytochrome P450 2D6 enzyme is constitutively expressed in differentiated SH-SY5Y cells, (55) and other types are inducible. (56) Because 6:2 FTSA is relatively degradable compared to all tested PFAS due to its ethane functional unit, it is likely that its low TR is caused by metabolism and formation of smaller perfluorinated carboxylic acids, which are less potent. This is also substantiated by AREc32 having a higher TR of 0.3 for 6:2 FTSA. AREc32 cells do not constitutively express cytochrome P450s; however, their expression can be induced as a response to exposure to xenobiotics. (57) Therefore, it is reasonable that the TR is higher for SH-SY5Y cells, but still lower than 1.

Figure 2

Figure 2. Comparison between predicted baseline toxicity IC10,baseline and measured cytotoxicity IC10 for (a) AREc32 cells and (b) SH-SY5Y cells. (c) Comparison of measured cytotoxicity IC10 and neurite outgrowth inhibition EC10 in differentiated SH-SY5Y cells. TR, toxic ratio; SR, specificity ratio.

High Resolution Image
Download MS PowerPoint Slide
The effects on neurite outgrowth inhibition occurred just around the experimental cytotoxicity with specificity ratio (SR) between 0.4 and 0.2 (Figure 2c, Table 2), which means that the effect was presumably a side effect of cytotoxicity and not a specific inhibition on neurite development. A more detailed analysis of the single chemicals effects and comparison with previous experiments (35) is given in Text S7 and Figure S7.

Mixtures

The mixtures, envmix and bloodmix, showed only cytotoxicity in the MitoOxTox assay (Figure S8) but the EC10 for neurite outgrowth inhibition could be derived in the neurotoxicity assay in addition to cytotoxicity IC10 (Figure S9, Table 3). Because all PFAS tested act as baseline toxicants, and mixture of baseline toxicants act according to CA, (58) we can posit that the mixture effect follows CA. As we deduced the IC10 and EC10 from the linear portion of the CRC < 30% effect, the simplified CA model (eqs 8–10) was applied for mixture toxicity prediction. The resulting IC10(CA) and EC10(CA) are listed in Table 3 together with the IPQ (eq 10). Both designed mixtures envmix and bloodmix had an IPQ < 0.5, which confirmed that their mixture effect could be well predicted by CA for cytotoxicity in both cell lines and neurite outgrowth inhibition (Figure 3). The IPQs ranged from 0.11 to 0.28 for cytotoxicity (Table 3), which is an excellent agreement, and were slightly higher (0.32 and 0.42) for NOI but still within the prediction range for CA.

Figure 3

Figure 3. Comparison between the experimental mixture IC10 (inhibitory concentration causing 10% cytotoxicity) with the predicted mixture IC10(CA) calculated with the mixture model of concentration addition (CA) (eqs 6–9) for AREc32 and SH-SY5Y cells for the envmix and bloodmix; comparison of experimental and predicted EC10 (effect concentration causing 10% reduction of neurite length) for neurite outgrowth inhibition (NOI) in SH-SY5Y. The line corresponds to perfect agreement between model and prediction (index of prediction quality (eq 10) IPQ = 0), the dashed lines mark the area of IPQ up to 0.5. No data lay in the upper left corner, where synergistic effects would be displayed or the bottom right corner, where antagonistic effects would be displayed.

High Resolution Image
Download MS PowerPoint Slide
Table 3. Cytotoxicity Inhibitory Concentrations IC10 for AREc32 and SH SY5Y Cells and Effect Concentration EC10 for 10% Reduction of Neurite Length (NOI) for the Two Designed Mixtures Envmix and Bloodmix (Table 1)a
  AREc32 cytotoxicitySH-SY5Y cytotoxicitySH-SY5Y neurite outgrowth inhibition
 mixtureIC10SE IC10IPQIC10SE IC10IPQEC10SE EC10IPQ
envmixCA prediction2.30 × 10–46.88 × 10–6 6.77 × 10–42.47 × 10–5 5.24 × 10–43.16 × 10–5 
 experimental2.98 × 10–43.36 × 10–50.287.52 × 10–45.29 × 10–50.113.01 × 10–41.45 × 10–50.42
bloodmixprediction1.27 × 10–45.33 × 10–6 3.66 × 10–42.05 × 10–5 2.66 × 10–42.10 × 10–5 
 experimental1.41 × 10–41.31 × 10–50.113.03 × 10–43.04 × 10–50.171.80 × 10–41.57 × 10–50.32
a

The mixture IC10 and EC10 were predicted with the mixture model of concentration addition (CA, eqs 6–9), and the index of prediction quality (IPQ) was calculated with eq 10.

Representative Environmental Mixture (Envmix)

The envmix contained 12 PFAS in relatively similar proportions (Table 1, Figures S8 and 4) and is representative of groundwater and surface water. The relative effect potency, REPi in relation to PFOA (eq 12) is plotted as gray bars for all active bioassays in Figure 4. For easier visual comparison we plotted the fraction of effect (Toxi). The sum of the Toxi of the CA prediction would be 1, and the experimental effect of the mixture was 0.78 for cytotoxicity in AREc32 (Figure 4a), 0.90 for cytotoxicity in SH-SY5Y (Figure 4b) and 1.74 for neurite outgrowth inhibition (Figure 4c), which means that the experiment came close to the prediction. Typically, any deviation up to a factor of 2 (0.5 < ΣToxi < 2) can be considered as adequate prediction because this range is typically within the experimental variability of in vitro bioassays.

Figure 4

Figure 4. Environmental mixture (envmix): comparison of contribution of individual PFAS i to the fraction in the mixture (pi), their relative effect potency compared to PFOA (REPi = IC10,PFOA/IC10,i or EC10,PFOA/EC10,i) and their contribution to the mixture toxicity (Toxi, eq 13). (A) cytotoxicity in AREc32, (B) cytotoxicity in SH-SY5Y, (C) neurite outgrowth inhibition in SH-SY5Y.

High Resolution Image
Download MS PowerPoint Slide
PFOA was by far the most cytotoxic of the 12 PFAS in the mixture. Despite its low concentration, it was the most important mixture effect driver for the cytotoxicity in AREc32 (Figure 4a). PFNA was the second most cytotoxic in AREc32 and despite its even lower concentration, it was the second most important contributor to the mixture effect. The mixture effect of 7 PFAS made up 90% of the mixture cytotoxicity. In order of contribution, these were PFOA (42%), PFNA (12.9%), PFHpA (10.4%), PFHxS (7.7%), PFOS (6.3%), PFHxA (5.4%), PFPeS (4.2%).
The cytotoxicity of envmix in SH-SY5Y cells was more balanced: 8 PFAS contributed to 90% of cytotoxicity because several additional PFAS had high REPi (Figure 4b). The main mixture effect contributors were PFOS (25%), PFOA (24%), PFHxS (9.2%), PFNA (8.7%), PFPeS (7.0%), PFHpA (5.9%), PFBA (4.8%) and PFBS (3.7%).
With respect to neurite outgrowth inhibition, PFNA was more potent than PFOA and PFHxS, and PFOS was only slightly less potent than PFOA. Accordingly, PFOS dominated the mixture effect with a contribution (Toxi) of 26.6% despite a molar contribution (pi) of 15%, followed by PFOA (21.2%), PFNA (16.6%), PFHxS (10.3%), PFHpA (7.2%), PFPeS (4.7%) and PFBA (3.4%) (Figure 4c).

Representative Blood Mixture (Bloodmix)

The bloodmix had only 4 components. PFOA dominated the cytotoxicity in both cell lines (Figure 5a,b). Despite its molar contribution being only 29%, it triggered 68% of the cytotoxicity in AREc32 (Figure 5a) and 38% in SH-SY5Y (Figure 5b). Neurite outgrowth inhibition was almost equally attributed to PFOA (38%) and PFOS (43%). PFNA had only a low molar fraction (10%) but the highest REPi of the four mixture components, resulting in 14% contribution to the mixture effect (Figure 5c).

Figure 5

Figure 5. Blood mixture (bloodmix): comparison of contribution of individual PFAS to the fraction in the mixture (pi), their relative effect potency compared to PFOA (REPi = IC10,PFOA/IC10,i or EC10,PFOA/EC10,i) and their contribution to the mixture toxicity (Toxi, eq 13). (A) cytotoxicity in AREc32, (B) cytotoxicity in SH-SY5Y, (C) neurite outgrowth inhibition (NOI) in SH-SY5Y.

High Resolution Image
Download MS PowerPoint Slide

How to Communicate Mixture Effects?

The calculations used for the mixture effect predictions are not too complex given that we worked in the linear range of the CRCs, where effects and concentrations scale linearly. Nevertheless, the Toxi descriptors are not intuitive. We can use the analogy of the “risk cup” that has been recently phrased for mixture risk assessment, (59) where all components of a mixture are translated into a common currency and added up. We can use bioanalytical equivalent concentrations (BEQchem) to translate the contribution of any mixture component i as the concentration that an equivalent quantity of a reference compound would have. Here, we use PFOA as reference chemical and express effects as PFOA equivalent concentration PFOA-EQchem. PFOA-EQi for each mixture component i can be computed from the REPi, and its concentration, Ci (eq 14). (60) The mixture effects PFOA-EQchem are the sum of individual PFOA-EQi.
PFOA‐EQchem=∑i=1nPFOA‐EQi=∑i=1nREPi·Ci
(14)
This calculation is only made possible once we have established that the mixture of anionic PFAS could be predicted by CA for all investigated end points, mixture compositions, and ratios. PFOA-EQ can also be expressed in units of ng/L for a more intuitive comparison with analytically determined concentrations because it is convention in the field of analytical chemistry to use mass-based concentrations. However, toxicology is based on the action of molecules, therefore molar concentrations are preferred in environmental toxicology for the mixture calculations (REPi are molar ratios) but the PFOA-EQ are at the end converted back to ng/L for easier communication of results. It must be noted that PFOA-EQ does not mean that the same amount PFOA is in the mixture, but that the mixture will have the same effect as if such a concentration of PFOA were present.
The concentration of PFOA was 11 ng/L in the envmix. (43) Taking the mixture effect of the additional 11 anionic PFAS into account, the predicted PFOA-EQchem were 26 ng/L for cytotoxicity in AREc32, 46 ng/L for cytotoxicity in SH-SY5Y and 52 ng/L for NOI (Table S2). The PFOA-EQchem differ for each end point due to variations in REPi of the mixture components (Table S2).
The bloodmix, which was based on NHANES biomonitoring data, comprised only of four components, and while it contained only 2.0 ng/L PFOA, the PFOA-EQchem were 2.9 ng/L for cytotoxicity in AREc32, 5.1 ng/L for cytotoxicity in SH-SY5Y and 6.2 ng/L for NOI (Table S2). We can also calculate the PFOA-EQbio,mix directly from the experimental effect data of the designed mixtures (eq 15). PFOA-EQbio,mix and PFOA-EQchem agreed (Table S2) as expected for CA. The ratios of PFOA-EQbio,mix to PFOA-EQchem varied from 0.78 to 1.74 ng/L for the envmix and 0.90 to 1.48 for the bloodmix (Table S2), which is equivalent to the Toxi in Figures 4 and 5.
PFOA‐EQbio,mix=slopedesignedmixtureslopePFOA
(15)

Effects of Biosolid Extracts

The CRCs of the extracts of PS and WAS indicated activity in all end points in the MitoOxTox assay (Figure S10) and the neurotoxicity assay (Figure S11). The extracts even activated the oxidative stress response and inhibited the MMP, which were not activated/inhibited by PFAS individually or by the designed mixtures PSmix and WASmix. Evidently, there are many more chemicals in the biosolid extracts beyond PFAS that can trigger these specific effects. The three independent measurements using the extract of the same biosolid sample had variable IC10 and EC10 (Table S1), which is presumably caused by heterogeneities of the biosolid. No blanks could be obtained, so further investigation was not possible.
The designed mixtures of PSmix and WASmix were active in MMP (Figure S12) and NOI (Figure S13) and showed cytotoxicity in both cell lines but did not activate oxidative stress response just like the mixture components. Although only two and three PFAS were detected in PS and WAS and were included in the designed mixtures PSmix and WASmix, we performed the same mixture diagnostic analysis as for envmix and bloodmix. The IPQ were within the validity range for CA (IPQ < 0.5) for the NOI, but cytotoxicity had a tendency toward antagonism (Figure S14). In PSmix, PFOA dominated cytotoxicity in AREc32 and PFOS dominated cytotoxicity and NOI in SH-SY5Y cells (Figure S15). Potency differences between the three components of WAS (PFOA, PFHxS, PFOS) were small in the neurotoxicity assays and accordingly all components contributed to the mixture effect, while cytotoxicity in AREc32 cells was dominated by PFOA (Figure S16). The PFOA-EQbio,mix of the designed mixtures and the predicted PFOA-EQchem agreed within a factor of 5 (Table 4).
Table 4. Effects of Mixture Components Expressed as PFOA Equivalent Concentrations (PFOA-EQ) of the Experimental Mixture Effect (PFOA-EQbio) of Primary Solid (PSmix) and Wastewater Activated Sludge (WASmix) and their Experimental (PFOA-EQbio,mix) and Predicted (PFOA-EQchem) Mixture Effect of the Two (PSmix) or Three (WASmix) PFAS Detected and Quantified in the Samples
 PSmixWASmix
abbreviationPFOA-EQchem,i (ngPFOA/gsolid) or (mgPFOA/gsolid) cytotoxicity AREc32PFOA-EQchem,i (ngPFOA/gsolid) or (mgPFOA/gsolid) cytotoxicity SH SY5YPFOA-EQchem,i (ngPFOA/gsolid) or (mgPFOA/gsolid) NOIPFOA-EQchem,i (ngPFOA/gsolid) or (mgPFOA/gsolid) cytotoxicity AREc32PFOA-EQchem,i (ng/g) or (mg/g) cytotoxicity SH SY5YPFOA-EQchem,i (ng/g) or (mg/g) NOI
 4.204.204.207.507.507.50
PFOA-EQi of PFHxS (ngPFOA/gsolid)   2.85.823.17
PFOA-EQi of PFOS (ngPFOA/gsolid)1.228.4510.12.4416.98.42
PFOA-EQchem (ngPFOA/gsolid)5.4212.614.312.7330.310.1
PFOA-EQbio, mix (ngPFOA/gsolid) designed mixture1.094.919.163.1517.720.4
PFOA-EQbio (mgPFOA/gsolid) extract5.8032.288.33.6036.650.3
fraction of effect in extract explained by PFAS9.34 × 10–73.91 × 10–71.62 × 10–73.54 × 10–68.27 × 10–72.01 × 10–7
More interestingly, we observed that PFOA-EQbio,mix of the designed mixtures were 106 times lower than the PFOA-EQbio of the entire extract (Table 4). PFOA-EQbio can be directly derived for the extracts of the PS and WAS samples from their IC10 and EC10 with eq 16.
PFOA‐BEQbio=EC10,PFOAEC10,sampleextract
(16)
It should be noted that there are many more PFAS and other chemicals in biosolids that may have contributed to the toxicity in the extracts. However, because of the high persistence of PFAS, it is likely that PFAS concentrations in environments where biosolids are applied are more important relative to the other biodegradable chemicals that also contribute to biosolids’ toxicity.

Implications for the Risk Assessment of PFAS

The comparison between PFOA concentration and PFOA-EQchem of the designed mixtures clearly demonstrates that replacing one PFAS by another will hardly mitigate risks posed by PFAS. PFOA-EQchem is a simple measure of the mixture effects and for any additional PFAS we add to the mixture that is bioactive, the PFOA-EQchem will inevitably increase. A recent study used cytotoxicity in HepG2 cells to investigate 50 complex mixtures that contained PFOA, PFNA and PFHxS among other organic chemicals and metals. (61) Only 6 of 50 components had slightly antagonistic effects, most acted according to CA. The results of our study on PFAS mixture toxicity are reasonable considering that interactive mixture effects are more common in mixtures of metals and organics. (62)
It has been proposed that the relative potency factor approach can be used for the mixture risk assessment of PFAS. (63) Bil et al. (64) demonstrated the utility of this approach on a case study of liver toxicity (weight gain) on male rats that were orally dosed with PFAS for 42 to 90 days. They derived relative potency factors for this end point that ranged from 0.001 to 10, while the REP for cytotoxicity ranged from 0.01 to 1 but relative ranges agreed well (Figure S17). It should be checked if cytotoxicity to a liver cell line gives even better associations between relative potencies in vivo and in vitro. The relative potency factor approach in risk assessment implies concentration-additive mixture effects. The validity of the assumption of concentration addition is hardly ever tested in vivo because such experiments are expensive. The present in vitro study helps to justify this mixture toxicity assumption.
Most importantly, we demonstrated that all tested anionic PFAS were toxic to neurons at concentrations close to where nonspecific baseline toxicity occurs. As baseline toxicity is predictable from the physicochemical descriptor Dlip/w, (35) and concentration-additive mixture effects at low effect levels follow a simple prediction model, (60) it is possible to predict the mixture effects of PFAS with high confidence. Colnot et al. (65) have proposed to separate perfluorocarboxylic and perfluoro-sulfonic acids in independent assessment groups for risk assessment but the present study does not support this separation because all mixture effects were consistent with CA and hence should be grouped into a common assessment group for risk assessment.
However, one limitation of the present study is that only anionic PFAS were combined in mixtures. Future work should go beyond these homogeneous groups of perfluorocarboxylic and perfluorosulfonic acids and should include neutral PFAS, and other polyfluorinated chemicals. Extension to other, especially specific, end points and inclusion of other organic chemicals are the natural next step, but the present work lays the foundation for a new approach on how to tackle the risks of PFAS mixtures in various environmental matrices.

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.est.4c06017.

  • Additional information on chemicals, experimental details, concentration–response curves, additional analyses (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!
  • Corresponding Author
  • Authors
    • Karla M. Ríos-Bonilla - Department of Chemistry, University at Buffalo - The State University of New York, Buffalo, New York 14260, United States;  Orcidhttps://orcid.org/0009-0000-7051-1744
    • Diana S. Aga - Department of Chemistry, University at Buffalo - The State University of New York, Buffalo, New York 14260, United States;  Orcidhttps://orcid.org/0000-0001-6512-7713
    • Jungeun Lee - Department of Cell Toxicology, Helmholtz-Centre for Environmental Research − UFZ, Leipzig 04318, Germany;  Orcidhttps://orcid.org/0000-0001-8336-2952
    • Maria König - Department of Cell Toxicology, Helmholtz-Centre for Environmental Research − UFZ, Leipzig 04318, Germany
    • Weiping Qin - Department of Cell Toxicology, Helmholtz-Centre for Environmental Research − UFZ, Leipzig 04318, Germany
    • Judith R. Cristobal - Department of Chemistry, University at Buffalo - The State University of New York, Buffalo, New York 14260, United States
    • Gunes Ekin Atilla-Gokcumen - Department of Chemistry, University at Buffalo - The State University of New York, Buffalo, New York 14260, United States;  Orcidhttps://orcid.org/0000-0002-7132-3873
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

Click to copy section linkSection link copied!

Authors would like to acknowledge funding support from the U.S. Environmental Protection Agency STAR grant (Award No. R840451). Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the USEPA. K. Ríos-Bonilla also acknowledges Fellowship support from the National Institute of Health, through NIEHS supplement to Award R01ES032717. This study was additionally supported by the Helmholtz Association under the recruiting initiative scheme, which is funded by the German Ministry of Education and Research and was conducted within the Helmholtz POF IV Topic 9 and the Integrated Project “Healthy Planet- towards a non-toxic environment”. We gratefully acknowledge access to the platform CITEPro (Chemicals in the Environment Profiler) funded by the Helmholtz Association for bioassay measurements. We also thank Niklas Wojtysiak, Jenny Braasch and Christin Kühnert for experimental assistance with the bioassays, and John Michael Aguilar and Preeyaporn Phosiri for experimental support with the biosolids extraction.

Abbreviations

Click to copy section linkSection link copied!
CA

concentration addition

CRC

concentration–response curves

EC10

effect concentration for 10% effect

PFAS

per- and polyfluoroalkyl substances

HTS

high-throughput screening

IA

independent action

MMP

mitochondrial membrane potential

NAM

new approach methodologies

NOI

neurite outgrowth inhibition

PS

primary solid

(R)EF

(relative) enrichment factor

SR

specificity ratio

TR

toxic ratio

WAS

wastewater activated sludge

WWTP

wastewater treatment plants

References

Click to copy section linkSection link copied!

This article references 65 other publications.

  1. 1
    Buck, R. C.; Franklin, J.; Berger, U.; Conder, J. M.; Cousins, I. T.; de Voogt, P.; Jensen, A. A.; Kannan, K.; Mabury, S. A.; van Leeuwen, S. P. Perfluoroalkyl and polyfluoroalkyl substances in the environment: Terminology, classification, and origins. Integr. Environ. Assess. Manage. 2011, 7, 513– 541,  DOI: 10.1002/ieam.258
    Google Scholar
    1
    Perfluoroalkyl and polyfluoroalkyl substances in the environment: Terminology, classification, and origins
    Buck, Robert C.; Franklin, James; Berger, Urs; Conder, Jason M.; Cousins, Ian T.; de Voogt, Pim; Jensen, Allan Astrup; Kannan, Kurunthachalam; Mabury, Scott A.; van Leeuwen, Stefan P. J.
    Integrated Environmental Assessment and Management (2011), 7 (4), 513-541CODEN: IEAMCK; ISSN:1551-3777. (John Wiley & Sons Inc.)
    A review. The primary aim of this article is to provide an overview of perfluoroalkyl and polyfluoroalkyl substances (PFASs) detected in the environment, wildlife, and humans, and recommend clear, specific, and descriptive terminol., names, and acronyms for PFASs. The overarching objective is to unify and harmonize communication on PFASs by offering terminol. for use by the global scientific, regulatory, and industrial communities. A particular emphasis is placed on long-chain perfluoroalkyl acids, substances related to the long-chain perfluoroalkyl acids, and substances intended as alternatives to the use of the long-chain perfluoroalkyl acids or their precursors. First, we define PFASs, classify them into various families, and recommend a pragmatic set of common names and acronyms for both the families and their individual members. Terminol. related to fluorinated polymers is an important aspect of our classification. Second, we provide a brief description of the 2 main prodn. processes, electrochem. fluorination and telomerization, used for introducing perfluoroalkyl moieties into org. compds., and we specify the types of byproducts (isomers and homologues) likely to arise in these processes. Third, we show how the principal families of PFASs are interrelated as industrial, environmental, or metabolic precursors or transformation products of one another. We pay particular attention to those PFASs that have the potential to be converted, by abiotic or biotic environmental processes or by human metab., into long-chain perfluoroalkyl carboxylic or sulfonic acids, which are currently the focus of regulatory action. The Supplemental Data lists 42 families and subfamilies of PFASs and 268 selected individual compds., providing recommended names and acronyms, and structural formulas, as well as Chem. Abstrs. Service registry nos. Integr Environ Assess Manag 2011;7:513-541. © 2011 SETAC.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtF2jtrnM&md5=b3bbf89fd9b71a0a30c5e8c390ccfdda
  2. 2
    Glüge, J.; Scheringer, M.; Cousins, I. T.; DeWitt, J. C.; Goldenman, G.; Herzke, D.; Lohmann, R.; Ng, C. A.; Trier, X.; Wang, Z. Y. An overview of the uses of per- and polyfluoroalkyl substances (PFAS). Environ. Sci.: Processes Impacts 2020, 22, 2345– 2373,  DOI: 10.1039/D0EM00291G
    Google Scholar
    There is no corresponding record for this reference.
  3. 3
    Ghisi, R.; Vamerali, T.; Manzetti, S. Accumulation of perfluorinated alkyl substances (PFAS) in agricultural plants: A review. Environ. Res. 2019, 169, 326– 341,  DOI: 10.1016/j.envres.2018.10.023
    Google Scholar
    3
    Accumulation of perfluorinated alkyl substances (PFAS) in agricultural plants: A review
    Ghisi, Rossella; Vamerali, Teofilo; Manzetti, Sergio
    Environmental Research (2019), 169 (), 326-341CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)
    PFASs are a class of compds. that include perfluoroalkyl and polyfluoroalkyl substances, some of the most persistent pollutants still allowed - or only partially restricted - in several product fabrications and industrial applications worldwide. PFASs have been shown to interact with blood proteins and are suspected of causing a no. of pathol. responses, including cancer. Given this threat to living organisms, we carried out a broad review of possible sources of PFASs and their potential accumulation in agricultural plants, from where they can transfer to humans through the food chain. Anal. of the literature indicates a direct correlation between PFAS concns. in soil and bioaccumulation in plants. Furthermore, plant uptake largely changes with chain length, functional group, plant species and organ. Low accumulations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) have been found in peeled potatoes and cereal seeds, while short-chain compds. can accumulate at high levels in leafy vegetables and fruits. Significant variations in PFAS buildup in plants according to soil amendment are also found, suggesting a particular interaction with soil org. matter. Here, we identify a series of challenges that PFASs pose to the development of a safe agriculture for future generations.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlKls7jK&md5=57570aba68a72ae145822ff36d81fc7c
  4. 4
    Johnson, G. R. PFAS in soil and groundwater following historical land application of biosolids. Water Res. 2022, 211, 118035  DOI: 10.1016/j.watres.2021.118035
    Google Scholar
    4
    PFAS in soil and groundwater following historical land application of biosolids
    Johnson, Gwynn R.
    Water Research (2022), 211 (), 118035CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
    The land application of digested sewage sludge (biosolids) is widely employed across the globe. Studies show that biosolids contain significant amts. of inorg. and org. materials, as well as emerging pollutants, including per- and polyfluorinated alkyl substances (PFAS). With the wide range of pollutants commonly reported in biosolids, the potential risks assocd. with long-term land application operations are concerning. In this study, PFAS in surface soils, deeper soils into the vadose zone, and immediately-underlying groundwater was measured at an agricultural station with a long record of biosolids applications plus irrigation using treated wastewater. Twelve PFAS homologues were detected in every near surface soil sampled 0-30 cm depth below ground surface with multiple PFAS (esp. short-chain) distributed through the soil profile. Av. measured concns. of PFAS in these soils suggest the soil burden PFOS>PFDA>PFOA for all substations sampled, independent of the historical loading rates and patterns of agricultural operations on those substations. Measured concns. of PFOA and PFOS in the soil profile (0-90 cm) suggest these compds. have migrated to deeper soil depths (up to 9 m below the surface) with quantifiable concns. in the soil and the immediate underlying groundwater located approx. 17 m below. Ests. of the total mass of PFAS in surface soils were effectively made using PFAS levels reported in sludges from the USEPA NSSS combined with long-term loading rates on record at the substations. With the land application of biosolids in the USA regulated by the USEPA, addnl. and updated risk assessments and surveys to include emerging pollutants such as PFAS are needed to protect public health and the environment.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XpvF2qtA%253D%253D&md5=2446b812dd40a7fd8ca11361debb2761
  5. 5
    Lu, Y.; Meng, L.; Ma, D.; Cao, H.; Liang, Y.; Liu, H.; Wang, Y.; Jiang, G. The occurrence of PFAS in human placenta and their binding abilities to human serum albumin and organic anion transporter 4. Environ. Pollut. 2021, 273, 116460  DOI: 10.1016/j.envpol.2021.116460
    Google Scholar
    5
    The occurrence of PFAS in human placenta and their binding abilities to human serum albumin and organic anion transporter 4
    Lu, Yao; Meng, Lingyi; Ma, Donghui; Cao, Huiming; Liang, Yong; Liu, Hongwei; Wang, Yawei; Jiang, Guibin
    Environmental Pollution (Oxford, United Kingdom) (2021), 273 (), 116460CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)
    Both legacy and emerging per- and polyfluoroalkyl substances (PFAS) have been found to be threats to human health. In particular, fetuses are sensitive to xenobiotics and the placenta functions as a significant barrier for environmental pollutants. The placental transfer of PFAS is closely related to their interactions with proteins. In this study, 54 human placental samples were collected to investigate the occurrence of legacy and emerging PFAS in human placenta, including perfluorinated carboxylates (PFCAs), perfluorinated sulfonates (PFSAs), chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs), and fluorotelomer sulfonates (FTSAs). Among the legacy PFAS, perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were detected in all samples, with PFOS and PFOA being the two predominant (mean: 0.457 and 0.242 ng/g wet wt., resp.). Among the emerging PFAS, 6:2 Cl-PFESA was detected in all samples with the mean value of 0.104 ng/g wet wt., while the detect frequency (DF) of 8:2 Cl-PFESAs was only 24%. The concn. and DF of the four FTSA congeners were low in the placentas. Mol. docking calcn. results showed that the binding affinities of PFAS to the human serum albumin (HSA) were increased with chain length in each category except for the PFCAs, of which the perfluoroundecanoic acid (PFUnDA) was the turning point of binding affinity to HSA. For PFSAs, their binding affinities to org. anion transporter 4 (OAT4) were increased with the chain length except for the sodium perfluoro-1-heptanesulfonate (PFHpS) and sodium perfluoro-1-nonanesulfonate (PFNS). The calcn. results demonstrated that the placental transfer of PFAS is closely related to chain length. The findings in the study can help better understand the occurrence of the PFAS in the human placenta and the placental transfer mechanisms of PFAS in human beings.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhslWmt78%253D&md5=cf5c9644622dfada8edd8fd1d41a49fa
  6. 6
    Poothong, S.; Thomsen, C.; Padilla-Sanchez, J. A.; Papadopoulou, E.; Haug, L. S. Distribution of novel and well-known poly-and perfluoroalkyl substances (PFASs) in human serum, plasma, and whole blood. Environ. Sci. Technol. 2017, 51, 13388– 13396,  DOI: 10.1021/acs.est.7b03299
    Google Scholar
    There is no corresponding record for this reference.
  7. 7
    Wang, W.; Rhodes, G.; Ge, J.; Yu, X.; Li, H. Uptake and accumulation of per-and polyfluoroalkyl substances in plants. Chemosphere 2020, 261, 127584  DOI: 10.1016/j.chemosphere.2020.127584
    Google Scholar
    There is no corresponding record for this reference.
  8. 8
    Hu, X. C.; Andrews, D. Q.; Lindstrom, A. B.; Bruton, T. A.; Schaider, L. A.; Grandjean, P.; Lohmann, R.; Carignan, C. C.; Blum, A.; Balan, S. A.; Higgins, C. P.; Sunderland, E. M. Detection of Poly- and Perfluoroalkyl Substances (PFASs) in U.S. Drinking Water Linked to Industrial Sites, Military Fire Training Areas, and Wastewater Treatment Plants. Environ Sci. Technol. Lett. 2016, 3, 344– 350,  DOI: 10.1021/acs.estlett.6b00260
    Google Scholar
    8
    Detection of Poly- and Perfluoroalkyl Substances (PFASs) in U.S. Drinking Water Linked to Industrial Sites, Military Fire Training Areas, and Wastewater Treatment Plants
    Hu, Xindi C.; Andrews, David Q.; Lindstrom, Andrew B.; Bruton, Thomas A.; Schaider, Laurel A.; Grandjean, Philippe; Lohmann, Rainer; Carignan, Courtney C.; Blum, Arlene; Balan, Simona A.; Higgins, Christopher P.; Sunderland, Elsie M.
    Environmental Science & Technology Letters (2016), 3 (10), 344-350CODEN: ESTLCU; ISSN:2328-8930. (American Chemical Society)
    Drinking water contamination with poly- and perfluoroalkyl substances (PFASs) poses risks to the developmental, immune, metabolic, and endocrine health of consumers. We present a spatial anal. of 2013-2015 national drinking water PFAS concns. from the US EPA 3rd Unregulated Contaminant Monitoring Rule (UCMR3) program. The no. of industrial sites that manuf. or use these compds., the no. of military fire training areas, and the no. of wastewater treatment plants are all significant predictors of PFAS detection frequencies and concns. in public water supplies. Among samples with detectable PFAS levels, each addnl. military site within a watershed's 8-digit hydrol. unit is assocd. with a 20% increase in PFHxS, a 10% increase in both PFHpA and PFOA, and a 35% increase in PFOS. The no. of civilian airports with personnel trained in the use of aq. film-forming foams is significantly assocd. with the detection of PFASs above the minimal reporting level. We find drinking water supplies for 6 million US residents exceed US EPA's lifetime health advisory (70 ng/L) for PFOS and PFOA. Lower anal. reporting limits and addnl. sampling of smaller utilities serving <10000 individuals and private wells would greatly assist in further identifying PFAS contamination sources.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12msb7J&md5=b51d66969dbcd86fe394437b0c7795b3
  9. 9
    Brase, R. A.; Mullin, E. J.; Spink, D. C. Legacy and emerging per-and polyfluoroalkyl substances: analytical techniques, environmental fate, and health effects. Int J Mol Sci 2021, 22, 995,  DOI: 10.3390/ijms22030995
    Google Scholar
    9
    Legacy and emerging per- and polyfluoroalkyl substances: analytical techniques, environmental fate, and health effects
    Brase, Richard A.; Mullin, Elizabeth J.; Spink, David C.
    International Journal of Molecular Sciences (2021), 22 (3), 995CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
    A review. Due to their unique chem. properties, per- and polyfluoroalkyl substances (PFAS) have been used extensively as industrial surfactants and processing aids. While several types of PFAS have been voluntarily phased out by their manufacturers, these chems. continue to be of ecol. and public health concern due to their persistence in the environment and their presence in living organisms. Moreover, while the compds. referred to as "legacy" PFAS remain in the environment, alternative compds. have emerged as replacements for their legacy predecessors and are now detected in numerous matrixes. In this review, we discuss the historical uses of PFAS, recent advances in anal. techniques for anal. of these compds., and the fate of PFAS in the environment. In addn., we evaluate current biomonitoring studies of human exposure to legacy and emerging PFAS and examine the assocns. of PFAS exposure with human health impacts, including cancer- and non-cancer-related outcomes. Special focus is given to short-chain perfluoroalkyl acids (PFAAs) and ether-substituted, polyfluoroalkyl alternatives including hexafluoropropylene oxide dimer acid (HFPO-DA; tradename GenX), 4,8-dioxa-3H-perfluorononanoic acid (DONA), and 6:2 chlorinated polyfluoroethersulfonic acid (6:2 Cl-PFESA; tradename F-53B).
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXlsVaisLk%253D&md5=2682cd563b22b88f07655ddb3d519aca
  10. 10
    Saawarn, B.; Mahanty, B.; Hait, S.; Hussain, S. Sources, occurrence, and treatment techniques of per-and polyfluoroalkyl substances in aqueous matrices: A comprehensive review. Environ. Res. 2022, 214, 114004  DOI: 10.1016/j.envres.2022.114004
    Google Scholar
    There is no corresponding record for this reference.
  11. 11
    Wanninayake, D. M. Comparison of currently available PFAS remediation technologies in water: A review. J. Environ. Manage. 2021, 283, 111977 10.1016/j.jenvman.2021.111977  DOI: 10.1016/j.jenvman.2021.111977
    Google Scholar
    11
    Comparison of currently available PFAS remediation technologies in water: A review
    Wanninayake, Dushanthi M.
    Journal of Environmental Management (2021), 283 (), 111977CODEN: JEVMAW; ISSN:0301-4797. (Elsevier Ltd.)
    A review. Remediation of Poly- and perfluoroalkyl substances (PFASs) in the environment has rapidly increased due to growing concerns of environmental contamination and assocd. adverse toxicol. effects on wildlife and humans due to bioaccumulation and extreme persistence. Although, PFASs are highly recalcitrant to conventional water treatment processes, there are some effective techniques available. Those techniques involve exceedingly high costs due to high energy use, and high capital or operational costs. Thus, most remediation techniques have limitations in field applications even though the lab. scale expts. are promising. As a result of stringent new health and environmental regulatory stds. are being established, development of suitable water treatment methodol. is more challenging. Most of the sepn. and destruction techniques have their own limitations in field applications while the biol. approaches to treat PFASs are extremely limited and are not currently considered as viable. In this review, extra consideration is given to novel advanced techniques for wide array of PFAS classes including short chain PFAS removal, and compare their efficiencies, effectiveness, energy use, sustainability, cost, and simplicity in lab. scale to field applications. Electrochem., sonochem., advanced oxidn. processers (AOPs) and plasma together with novel hybrid techniques are considered as effective approaches for PFASs removal and have shown promising results for long chain and some short chain PFASs, as well as extremely persistent per-fluoro alkyl acids (PFAAs). Therefore, it is essential to better understand the removal mechanisms to optimize the advanced treatment processes like hybrid techniques because, the unique physicochem. characteristics of various PFASs impose difficult challenges. Careful selection of a combined effective treatment methodol. in an integrated processing unit, would be a revolutionary approach for complete elimination of PFASs from the environment. Considering the site-specific water quality parameters together with community perspectives will also make it more viable in real world field applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXis1Klur0%253D&md5=9c926e89a2c09b87133e7c23f8d3df2f
  12. 12
    Lenka, S. P.; Kah, M.; Padhye, L. P. A review of the occurrence, transformation, and removal of poly-and perfluoroalkyl substances (PFAS) in wastewater treatment plants. Water Res. 2021, 199, 117187  DOI: 10.1016/j.watres.2021.117187
    Google Scholar
    12
    A review of the occurrence, transformation, and removal of poly- and perfluoroalkyl substances (PFAS) in wastewater treatment plants
    Lenka, Swadhina Priyadarshini; Kah, Melanie; Padhye, Lokesh P.
    Water Research (2021), 199 (), 117187CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
    A review. Poly- and perfluoroalkyl substances (PFAS) comprise more than 4,000 anthropogenically manufd. compds. with widescale consumer and industrial applications. This crit. review compiles the latest information on the worldwide distribution of PFAS and evaluates their fate in wastewater treatment plants (WWTPs). A large proportion (>30%) of monitoring studies in WWTPs were conducted in China, followed by Europe (30%) and North America (16%), whereas information is generally lacking for other parts of the world, including most of the developing countries. Short and long-chain perfluoroalkyl acids (PFAAs) were widely detected in both the influents (up to 1,000 ng/L) and effluents (15 to >1,500 ng/L) of WWTPs. To date, limited data is available regarding levels of PFAS precursors and ultra-short chain PFAS in WWTPs. Most WWTPs exhibited low removal efficiencies for PFAS, and many studies reported an increase in the levels of PFAAs after wastewater treatment. The anal. of the fate of various classes of PFAS at different wastewater treatment stages (aerobic and/aerobic biodegrdn., photodegrdn., and chem. degrdn.) revealed biodegrdn. as the primary mechanism responsible for the transformation of PFAS precursors to PFAAs in WWTPs. Remediation studies at full scale and lab. scale suggest advanced processes such as adsorption using ion exchange resins, electrochem. degrdn., and nanofiltration are more effective in removing PFAS (∼95-100%) than conventional processes. However, the applicability of such treatments for real-world WWTPs faces significant challenges due to the scaling-up requirements, mass-transfer limitations, and management of treatment byproducts and wastes. Combining more than one technique for effective removal of PFAS, while addressing limitations of the individual treatments, could be beneficial. Considering environmental concns. of PFAS, cost-effectiveness, and ease of operation, nanofiltration followed by adsorption using wood-derived biochar and/or activated carbons could be a viable option if introduced to conventional treatment systems. However, the large-scale applicability of the same needs to be further verified.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtV2gtbzF&md5=b1a69359d89811bb4c1dadd99e23009a
  13. 13
    Sepulvado, J. G.; Blaine, A. C.; Hundal, L. S.; Higgins, C. P. Occurrence and fate of perfluorochemicals in soil following the land application of municipal biosolids. Environ. Sci. Technol. 2011, 45, 8106– 8112,  DOI: 10.1021/es103903d
    Google Scholar
    13
    Occurrence and fate of perfluorochemicals in soil following the land application of municipal biosolids
    Sepulvado, Jennifer G.; Blaine, Andrea C.; Hundal, Lakhwinder S.; Higgins, Christopher P.
    Environmental Science & Technology (2011), 45 (19), 8106-8112CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    The recent implementation of soil and drinking water screening guidance values for 2 perfluorochems. (PFCs), perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) by the US EPA, reflects the growing concerns regarding the presence of these persistent and bioaccumulative chems. in the natural environment. Previous work has established the potential risk to the environment from the land application of industrially contaminated biosolids, but studies focusing on environmental risk from land application of typical municipal biosolids are lacking. This study examd. the occurrence and fate of PFCs from land-applied municipal biosolids by evaluating the levels, mass balance, desorption, and transport of PFCs in soils receiving application of municipal biosolids at various loading rates. This study is the 1st to report levels of PFCs in agricultural soils amended with typical municipal biosolids. PFOS was the dominant PFC in both biosolids (80-219 ng/g) and biosolids-amended soil (2-483 ng/g). Concns. of all PFCs in soil increased linearly with increasing biosolids loading rate. These data were used to develop a model for predicting PFC soil concns. in soils amended with typical municipal biosolids using cumulative biosolids loading rates. Mass balance calcns. comparing PFCs applied vs. those recovered in the surface soil interval indicated the potential transformation of PFC precursors. Lab. desorption expts. indicated that the leaching potential of PFCs decreases with increasing chain length and that previously derived org.-C normalized partition coeffs. may not be accurate predictors of the desorption of long-chain PFCs from biosolids-amended soils. Trace levels of PFCs were also detected in soil cores from biosolids-amended soils to depths of 120 cm, suggesting potential movement of these compds. within the soil profile over time and confirming the higher transport potential for short-chain PFCs in soils amended with municipal biosolids.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjvVOls7Y%253D&md5=f28dd098381463ee4eeb1ef16d7c8931
  14. 14
    Houck, K. A.; Patlewicz, G.; Richard, A. M.; Williams, A. J.; Shobair, M. A.; Smeltz, M.; Clifton, M. S.; Wetmore, B.; Medvedev, A.; Makarov, S. Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identifies potential toxicity pathways related to molecular structure. Toxicology 2021, 457, 152789  DOI: 10.1016/j.tox.2021.152789
    Google Scholar
    14
    Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identifies potential toxicity pathways related to molecular structure
    Houck, Keith A.; Patlewicz, Grace; Richard, Ann M.; Williams, Antony J.; Shobair, Mahmoud A.; Smeltz, Marci; Clifton, M. Scott; Wetmore, Barbara; Medvedev, Alex; Makarov, Sergei
    Toxicology (2021), 457 (), 152789CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Ltd.)
    Per- and polyfluoroalkyl substances (PFAS) are a broad class of hundreds of fluorinated chems. with environmental health concerns due to their widespread presence and persistence in the environment. Several of these chems. have been comprehensively studied for exptl. toxicity, environmental fate and exposure, and human epidemiol.; however, most chems. have limited or no data available. To inform methods for prioritizing these data-poor chems. for detailed toxicity studies, we evaluated 142 PFAS using an in vitro screening platform consisting of two multiplexed transactivation assays encompassing 81 diverse transcription factor activities and tested in concn.-response format ranging from 137 nM to 300μM. Results showed activity for various nuclear receptors, including three known PFAS targets--specifically estrogen receptor alpha and peroxisome proliferator receptors alpha and gamma. We also report activity against the retinoid X receptor beta, the key heterodimeric partner of type II, non-steroidal nuclear receptors. Addnl. activities were found against the pregnane X receptor, nuclear receptor related-1 protein, and nuclear factor erythroid 2-related factor 2, a sensor of oxidative stress. Using orthogonal assay approaches, we confirmed activity of representative PFAS against several of these targets. Finally, we identified key PFAS structural features assocd. with nuclear receptor activity that can inform future predictive models for use in prioritizing chems. for risk assessment and in the design of new structures devoid of biol. activity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVejsL7M&md5=422a0baefb73b2fe2d59755e65821c3e
  15. 15
    United States Environmental Protection Agency, PFAS|EPA: PFAS Structures in DSSTox (update August 2022). https://comptox.epa.gov/dashboard/chemical-lists/PFASSTRUCTV5 (accessed March 14, 2024).
    Google Scholar
    There is no corresponding record for this reference.
  16. 16
    Cao, Y. X.; Ng, C. Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review. Environ. Sci.: Processes Impacts 2021, 23, 1623– 1640,  DOI: 10.1039/D1EM00228G
    Google Scholar
    16
    Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review
    Cao, Yuexin; Ng, Carla
    Environmental Science: Processes & Impacts (2021), 23 (11), 1623-1640CODEN: ESPICZ; ISSN:2050-7895. (Royal Society of Chemistry)
    A review. Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chems. colloquially known as "forever chems." because of their high persistence. PFAS have been detected in the blood, liver, kidney, heart, muscle and brain of various species. Although brain is not a dominant tissue for PFAS accumulation compared to blood and liver, adverse effects of PFAS on brain functions have been identified. Here, we review studies related to the absorption, accumulation, distribution and toxicity of PFAS in the brain. We summarize evidence on two potential mechanisms of PFAS entering the brain: initiating blood-brain barrier (BBB) disassembly through disrupting tight junctions and relying on transporters located at the BBB. PFAS with diverse structures and properties enter and accumulate in the brain with varying efficiencies. Compared to long-chain PFAS, short-chain PFAS may not cross cerebral barriers effectively. According to biomonitoring studies and PFAS exposure expts., PFAS can accumulate in the brain of humans and wildlife species. With respect to the distribution of PFAS in specific brain regions, the brain stem, hippocampus, hypothalamus, pons/medulla and thalamus are dominant for PFAS accumulation. The accumulation and distribution of PFAS in the brain may lead to toxic effects in the central nervous system (CNS), including PFAS-induced behavioral and cognitive disorders. The specific mechanisms underlying such PFAS-induced neurotoxicity remain to be explored, but two major potential mechanisms based on current understanding are PFAS effects on calcium homeostasis and neurotransmitter alterations in neurons. Based on the information available about PFAS uptake, accumulation, distribution and impacts on the brain, PFAS have the potential to enter and accumulate in the brain at varying levels. The balance of existing studies shows there is some indication of risk in animals, while the human evidence is mixed and warrants further scrutiny.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvF2isrvF&md5=10fe32a2c1557e7b0a93d92c02183219
  17. 17
    Delcourt, N.; Pouget, A.-M.; Grivaud, A.; Nogueira, L.; Larvor, F.; Marchand, P.; Schmidt, E.; Le Bizec, B. First Observations of a Potential Association Between Accumulation of Per- and Polyfluoroalkyl Substances in the Central Nervous System and Markers of Alzheimer’s Disease. J. Gerontol., Ser. A 2024, 79, glad208  DOI: 10.1093/gerona/glad208
    Google Scholar
    There is no corresponding record for this reference.
  18. 18
    Wielsøe, M.; Long, M.; Ghisari, M.; Bonefeld-Jørgensen, E. C. Perfluoroalkylated substances (PFAS) affect oxidative stress biomarkers in vitro. Chemosphere 2015, 129, 239– 245,  DOI: 10.1016/j.chemosphere.2014.10.014
    Google Scholar
    18
    Perfluoroalkylated substances (PFAS) affect oxidative stress biomarkers in vitro
    Wielsoe Maria; Long Manhai; Ghisari Mandana; Bonefeld-Jorgensen Eva C
    Chemosphere (2015), 129 (), 239-45 ISSN:.
    Perfluoroalkylated substances (PFAS) have been widely used since 1950s and humans are exposed through food, drinking water, consumer products, dust, etc. The long-chained PFAS are persistent in the environment and accumulate in wildlife and humans. They are suspected carcinogens and a potential mode of action is through generation of oxidative stress. Seven long-chained PFAS found in human serum were investigated for the potential to generate reactive oxygen species (ROS), induce DNA damage and disturb the total antioxidant capacity (TAC). The tested PFAS were perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluoroctanoic acid (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA). Using the human hepatoma cell line (HepG2) and an exposure time of 24h we found that all three endpoints were affected by one or more of the compounds. PFHxS, PFOA, PFOS and PFNA showed a dose dependent increase in DNA damage in the concentration range from 2×10(-7) to 2×10(-5)M determined by the comet assay. Except for PFDoA, all the other PFAS increased ROS generation significantly. For PFHxS and PFUnA the observed ROS increases were dose-dependent. Cells exposed to PFOA were found to have a significant lower TAC compared with the solvent control, whereas a non-significant trend in TAC decrease was observed for PFOS and PFDoA and an increase tendency for PFHxS, PFNA and PFUnA. Our results indicate a possible genotoxic and cytotoxic potential of the PFAS in human liver cells.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MzjtVejuw%253D%253D&md5=1eb430b05c182c1f77c29f9beda4afa8
  19. 19
    Fang, X.; Wu, C.; Li, H.; Yuan, W.; Wang, X. Elevation of intracellular calcium and oxidative stress is involved in perfluorononanoic acid–induced neurotoxicity. Toxicol. Ind. Health 2018, 34, 139– 145,  DOI: 10.1177/0748233717742262
    Google Scholar
    There is no corresponding record for this reference.

    DOI 0.1177/0748233717742262.

  20. 20
    Behr, A. C.; Plinsch, C.; Braeuning, A.; Buhrke, T. Activation of human nuclear receptors by perfluoroalkylated substances (PFAS). Toxicol. in Vitro 2020, 62, 104700  DOI: 10.1016/j.tiv.2019.104700
    Google Scholar
    20
    Activation of human nuclear receptors by perfluoroalkylated substances (PFAS)
    Behr Anne-Cathrin; Plinsch Christin; Braeuning Albert; Buhrke Thorsten
    Toxicology in vitro : an international journal published in association with BIBRA (2020), 62 (), 104700 ISSN:.
    Perfluoralkylated substances (PFAS) such as perfluorooctanoic acid (PFOA) or perfluorooctanesulfonic acid (PFOS) are used to produce, e.g., surface coatings with water- and dirt-repellent properties. These substances have been shown to be hepatotoxic in rodents, and the mechanism of action is mostly attributed to the PFAS-mediated activation of the peroxisome proliferator-activated receptor alpha (PPARα). In the present study, we investigated by using luciferase-based reporter gene assays whether PFOA, PFOS and six alternative PFAS can activate, in addition to PPARα, eight other human nuclear receptors. All tested PFAS except for perfluorobutanesulfonic acid (PFBS) were able to activate human PPARα. Perfluoro-2-methyl-3-oxahexanoic acid (PMOH) and 3H-perfluoro-3-[(3-methoxypropoxy) propanoic acid] (PMPP) were weak agonists of human PPARγ. The other human nuclear receptors (PPARδ, CAR, PXR, FXR, LXRα, RXRα and RARα) were not affected by any PFAS tested in this study. Although PMOH was more effective than PFOA in stimulating PPARα in the transactivation assay, it was less effective in stimulating PPARα-dependent target gene expression in human HepG2 hepatocarcinoma cells. Notably, any effect observed in this in vitro study only occurred at concentrations higher than 10 μM of the respective PFAS which is in all cases several magnitudes above the average blood concentration in the Western population. Thus, the results suggest that nuclear receptor activation may only play a minor role in potential PFAS-mediated adverse effects in humans.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MjktFahtg%253D%253D&md5=6199bb0d4cce237ca78569c9aec11fb1
  21. 21
    Brown-Leung, J. M.; Cannon, J. R. Neurotransmission targets of per-and polyfluoroalkyl substance neurotoxicity: mechanisms and potential implications for adverse neurological outcomes. Chem. Res. Toxicol. 2022, 35, 1312– 1333,  DOI: 10.1021/acs.chemrestox.2c00072
    Google Scholar
    There is no corresponding record for this reference.
  22. 22
    Marchese, M. J.; Zhu, T.; Hawkey, A. B.; Wang, K.; Yuan, E.; Wen, J.; Be, S. E.; Levin, E. D.; Feng, L. Prenatal and perinatal exposure to Per- and polyfluoroalkyl substances (PFAS)-contaminated drinking water impacts offspring neurobehavior and development. Sci. Total Environ. 2024, 917, 170459  DOI: 10.1016/j.scitotenv.2024.170459
    Google Scholar
    There is no corresponding record for this reference.
  23. 23
    Maxwell, D. L.; Oluwayiose, O. A.; Houle, E.; Roth, K.; Nowak, K.; Sawant, S.; Paskavitz, A. L.; Liu, W.; Gurdziel, K.; Petriello, M. C.; Richard Pilsner, J. Mixtures of per- and polyfluoroalkyl substances (PFAS) alter sperm methylation and long-term reprogramming of offspring liver and fat transcriptome. Environ. Int. 2024, 186, 108577  DOI: 10.1016/j.envint.2024.108577
    Google Scholar
    There is no corresponding record for this reference.
  24. 24
    Berntsen, H. F.; Berg, V.; Thomsen, C.; Ropstad, E.; Zimmer, K. E. The design of an environmentally relevant mixture of persistent organic pollutants for use in in vivo and in vitro studies. J. Toxicol. Environ. Health 2017, 80, 1002– 1016,  DOI: 10.1080/15287394.2017.1354439
    Google Scholar
    There is no corresponding record for this reference.
  25. 25
    Berntsen, H. F.; Duale, N.; Bjorlund, C. G.; Rangel-Huerta, O. D.; Dyrberg, K.; Hofer, T.; Rakkestad, K. E.; Ostby, G.; Halsne, R.; Boge, G.; Paulsen, R. E.; Myhre, O.; Ropstad, E. Effects of a human-based mixture of persistent organic pollutants on the in vivo exposed cerebellum and cerebellar neuronal cultures exposed in vitro. Environ. Int.. 2021, 146, 106240  DOI: 10.1016/j.envint.2020.106240
    Google Scholar
    There is no corresponding record for this reference.
  26. 26
    McCarthy, C. J.; Roark, S. A.; Middleton, E. T. Considerations for toxicity experiments and risk assessments with PFAS mixtures. Integr. Environ. Assess. Manage. 2021, 17, 697– 704,  DOI: 10.1002/ieam.4415
    Google Scholar
    There is no corresponding record for this reference.
  27. 27
    Sadrabadi, F.; Alarcan, J.; Sprenger, H.; Braeuning, A.; Buhrke, T. Impact of perfluoroalkyl substances (PFAS) and PFAS mixtures on lipid metabolism in differentiated HepaRG cells as a model for human hepatocytes. Arch. Toxicol. 2024, 98, 507– 524,  DOI: 10.1007/s00204-023-03649-3
    Google Scholar
    There is no corresponding record for this reference.
  28. 28
    Bopp, S. K.; Kienzler, A.; Richarz, A. N.; van der Linden, S. C.; Paini, A.; Parissis, N.; Worth, A. P. Regulatory assessment and risk management of chemical mixtures: challenges and ways forward. Crit. Rev. Toxicol. 2019, 49, 174– 189,  DOI: 10.1080/10408444.2019.1579169
    Google Scholar
    There is no corresponding record for this reference.
  29. 29
    Backhaus, T.; Faust, M. Predictive Environmental Risk Assessment of Chemical Mixtures: A Conceptual Framework. Environ. Sci. Technol. 2012, 46, 2564– 2573,  DOI: 10.1021/es2034125
    Google Scholar
    29
    Predictive environmental risk assessment of chemical mixtures: A conceptual framework
    Backhaus, Thomas; Faust, Michael
    Environmental Science & Technology (2012), 46 (5), 2564-2573CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    Environmental risks of chems. are still often assessed substance-by-substance, neglecting mixt. effects. This may result in risk underestimations, as the typical exposure is toward multicomponent chem. "cocktails". The two well established mixt. toxicity concepts (Concn. Addn. (CA) and Independent Action (IA)) are used for providing a tiered outline for environmental hazard and risk assessments of mixts., focusing on general industrial chems. and assuming that the "base set" of data (EC50s for algae, crustaceans, fish) is available. As mixt. toxicities higher than predicted by CA are rare findings, applying CA is suggested as a precautious first tier, irresp. of the modes/mechanisms of action of the mixt. components. This study proves that summing up PEC/PNEC ratios might serve as a justifiable CA-approxn., in order to est. in a first tier assessment whether there is a potential risk for an exposed ecosystem if only base-set data are available. This makes optimum use of existing single substance assessments as more demanding mixt. investigations are requested only if there are first indications of an environmental risk. This study suggests to call for mode-of-action driven analyses only if error estns. indicate the possibility for substantial differences between CA- and IA-based assessments.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XntFKjtg%253D%253D&md5=50df097faa36f7d58918e9817d32caf9
  30. 30
    Martin, O.; Scholze, M.; Ermler, S.; McPhie, J.; Bopp, S. K.; Kienzler, A.; Parissis, N.; Kortenkamp, A. Ten years of research on synergisms and antagonisms in chemical mixtures: A systematic review and quantitative reappraisal of mixture studies. Environ. Int. 2021, 146, 106206  DOI: 10.1016/j.envint.2020.106206
    Google Scholar
    30
    Ten years of research on synergisms and antagonisms in chemical mixtures: A systematic review and quantitative reappraisal of mixture studies
    Martin, Olwenn; Scholze, Martin; Ermler, Sibylle; McPhie, Joanne; Bopp, Stephanie K.; Kienzler, Aude; Parissis, Nikolaos; Kortenkamp, Andreas
    Environment International (2021), 146 (), 106206CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
    A review. Several reviews of synergisms and antagonisms in chem. mixts. have concluded that synergisms are relatively rare. However, these reviews focused on mixts. composed of specific groups of chems., such as pesticides or metals and on toxicity endpoints mostly relevant to ecotoxicol. Doubts remain whether these findings can be generalised. A systematic review not restricted to specific chem. mixts. and including mammalian and human toxicity endpoints is missing. We conducted a systematic review and quant. reappraisal of 10 years' of exptl. mixt. studies to investigate the frequency and reliability of evaluations of mixt. effects as synergistic or antagonistic. Unlike previous reviews, we did not limit our efforts to certain groups of chems. or specific toxicity outcomes and covered mixt. studies relevant to ecotoxicol. and human/mammalian toxicol. published between 2007 and 2017. We undertook searches for peer-reviewed articles in PubMed, Web of Science, Scopus, GreenFile, ScienceDirect and Toxline and included studies of controlled exposures of environmental chem. pollutants, defined as unintentional exposures leading to unintended effects. Studies with viruses, prions or therapeutic agents were excluded, as were records with missing details on chems.' identities, toxicities, doses, or concns. To examine the internal validity of studies we developed a risk-of-bias tool tailored to mixt. toxicol. For a subset of 388 entries that claimed synergisms or antagonisms, we conducted a quant. reappraisal of authors' evaluations by deriving ratios of predicted and obsd. effective mixt. doses (concns.). Our searches produced an inventory of 1220 mixt. expts. which we subjected to subgroup analyses. Approx. two thirds of studies did not incorporate more than 2 components. Most expts. relied on low-cost assays with readily quantifiable endpoints. Important toxicity outcomes of relevance for human risk assessment (e.g. carcinogenicity, genotoxicity, reproductive toxicity, immunotoxicity, neurotoxicity) were rarely addressed. The proportion of studies that declared additivity, synergism or antagonisms was approx. equal (one quarter each); the remaining quarter arrived at different evaluations. About half of the 1220 entries were rated as "definitely" or "probably" low risk of bias. Strikingly, relatively few claims of synergistic or antagonistic effects stood up to scrutiny in terms of deviations from expected additivity that exceed the boundaries of acceptable between-study variability. In most cases, the obsd. mixt. doses were not more than two-fold higher or lower than the predicted additive doses. Twenty percent of the entries (N = 78) reported synergisms in excess of that degree of deviation. Our efforts of pinpointing specific factors that predispose to synergistic interactions confirmed previous concerns about the synergistic potential of combinations of triazine, azole and pyrethroid pesticides at environmentally relevant doses. New evidence of synergisms with endocrine disrupting chems. and metal compds. such as chromium (VI) and nickel in combination with cadmium has emerged. These specific cases of synergisms apart, our results confirm the utility of default application of the dose (concn.) addn. concept for predictive assessments of simultaneous exposures to multiple chems. However, this strategy must be complemented by an awareness of the synergistic potential of specific classes of chems. Our conclusions only apply to the chem. space captured in published mixt. studies which is biased towards relatively well-researched chems.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitlemsr3J&md5=a7bfd5918f30642c4fb721846bcc3ca6
  31. 31
    Spinu, N.; Bal-Price, A.; Cronin, M. T. D.; Enoch, S. J.; Madden, J. C.; Worth, A. P. Development and analysis of an adverse outcome pathway network for human neurotoxicity. Arch. Toxicol. 2019, 93, 2759– 2772,  DOI: 10.1007/s00204-019-02551-1
    Google Scholar
    31
    Development and analysis of an adverse outcome pathway network for human neurotoxicity
    Spinu, Nicoleta; Bal-Price, Anna; Cronin, Mark T. D.; Enoch, Steven J.; Madden, Judith C.; Worth, Andrew P.
    Archives of Toxicology (2019), 93 (10), 2759-2772CODEN: ARTODN; ISSN:0340-5761. (Springer)
    An adverse outcome pathway (AOP) network is an attempt to represent the complexity of systems toxicol. This study illustrates how an AOP network can be derived and analyzed in terms of its topol. features to guide research and support chem. risk assessment. A four-step workflow describing general design principles and applied design principles was established and implemented. An AOP network linking nine linear AOPs was mapped and made available in AOPXplorer. The resultant AOP network was modelled and analyzed in terms of its topol. features, including level of degree, eccentricity and betweenness centrality. Several well-connected KEs were identified, and cell injury/death was established as the most hyperlinked KE across the network. The derived network expands the utility of linear AOPs to better understand signalling pathways involved in developmental and adult/ageing neurotoxicity. The results provide a solid basis to guide the development of in vitro test method batteries, as well as further quant. modeling of key events (KEs) and key event relationships (KERs) in the AOP network, with an eventual aim to support hazard characterization and chem. risk assessment.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1eksb%252FM&md5=10fea911e316d1f08d448c53b855fc37
  32. 32
    Masjosthusmann, S.; Blum, J.; Bartmann, K.; Dolde, X.; Holzer, A.-K.; Stürzl, L.-C.; Keßel, E. H.; Förster, N.; Dönmez, A.; Klose, J.; Pahl, M.; Waldmann, T.; Bendt, F.; Kisitu, J.; Suciu, I.; Hübenthal, U.; Mosig, A.; Leist, M.; Fritsche, E. Establishment of an a priori protocol for the implementation and interpretation of an in-vitro testing battery for the assessment of developmental neurotoxicity. EFSA Supporting Publ. 2020, 17, 1938E  DOI: 10.2903/sp.efsa.2020.EN-1938
    Google Scholar
    There is no corresponding record for this reference.
  33. 33
    Carstens, K. E.; Freudenrich, T.; Wallace, K.; Choo, S.; Carpenter, A.; Smeltz, M.; Clifton, M. S.; Henderson, W. M.; Richard, A. M.; Patlewicz, G.; Wetmore, B. A.; Friedman, K. P.; Shafer, T. Evaluation of Per- and Polyfluoroalkyl Substances (PFAS) In Vitro Toxicity Testing for Developmental Neurotoxicity. Chem. Res. Toxicol. 2023, 36, 402– 419,  DOI: 10.1021/acs.chemrestox.2c00344
    Google Scholar
    There is no corresponding record for this reference.
  34. 34
    Evans, N.; Conley, J. M.; Cardon, M.; Hartig, P.; Medlock-Kakaley, E.; Gray, L. E. In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays. Toxicol. Appl. Pharmacol. 2022, 449, 116136  DOI: 10.1016/j.taap.2022.116136
    Google Scholar
    34
    In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays
    Evans, Nicola; Conley, Justin M.; Cardon, Mary; Hartig, Phillip; Medlock-Kakaley, Elizabeth; Gray, L. Earl Jr
    Toxicology and Applied Pharmacology (2022), 449 (), 116136CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)
    Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPARα), however, addnl. work is needed to characterize PFAS activity on PPAR gamma (PPARγ) and other nuclear receptors. We utilized in vitro assays with either human or rat PPARα or PPARγ ligand binding domains to evaluate 16 PFAS (HFPO-DA, HFPO-DA-AS, NBP2, PFMOAA, PFHxA, PFOA, PFNA, PFDA, PFOS, PFBS, PFHxS, PFOSA, EtPFOSA, and 4:2, 6:2 and 8:2 FTOH), 3 endogenous fatty acids (oleic, linoleic, and octanoic), and 3 pharmaceuticals (WY14643, clofibrate, and the metabolite clofibric acid). We also tested chems. for human estrogen receptor (hER) transcriptional activation. Nearly all compds. activated both PPARα and PPARγ in both human and rat ligand binding domain assays, except for the FTOH compds. and PFOSA. Receptor activation and relative potencies were evaluated based on effect concn. 20% (EC20), top percent of max fold induction (pmaxtop), and area under the curve (AUC). HFPO-DA and HFPO-DA-AS were the most potent (lowest EC20, highest pmaxtop and AUC) of all PFAS in rat and human PPARα assays, being slightly less potent than oleic and linoleic acid, while NBP2 was the most potent in rat and human PPARγ assays. Only PFHxS, 8:2 and 6:2 FTOH exhibited hER agonism >20% pmax. In vitro measures of human and rat PPARαand PPARγ activity did not correlate with oral doses or serum concns. of PFAS that induced increases in male rat liver wt. from the National Toxicol. Program 28-d toxicity studies. Data indicate that both PPARα and PPARγ activation may be mol. initiating events that contribute to the in vivo effects obsd. for many PFAS.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsF2qsLfI&md5=2597e1699966d9cff7285ba43d030103
  35. 35
    Qin, W.; Henneberger, L.; Glüge, J.; König, M.; Escher, B. I. Baseline Toxicity Model to Identify the Specific and Nonspecific Effects of Per- and Polyfluoroalkyl Substances in Cell-Based Bioassays. Environ. Sci. Technol. 2024, 58, 5727– 5738,  DOI: 10.1021/acs.est.3c09950
    Google Scholar
    There is no corresponding record for this reference.
  36. 36
    Deepika, D.; Sharma, R. P.; Schuhmacher, M.; Kumar, V. An integrative translational framework for chemical induced neurotoxicity - a systematic review. Crit. Rev. Toxicol. 2020, 50, 424– 438,  DOI: 10.1080/10408444.2020.1763253
    Google Scholar
    There is no corresponding record for this reference.
  37. 37
    Delp, J.; Gutbier, S.; Klima, S.; Hoelting, L.; Pinto-Gil, K.; Hsieh, J. H.; Aichem, M.; Klein, K.; Schreiber, F.; Tice, R. R.; Pastor, M.; Behl, M.; Leist, M. A High-Throughput Approach to Identify Specific Neurotoxicants/Developmental Toxicants in Human Neuronal Cell Function Assays. ALTEX 2018, 35, 235– 253,  DOI: 10.14573/altex.1712182
    Google Scholar
    There is no corresponding record for this reference.
  38. 38
    Lee, J.; Escher, B. I.; Scholz, S.; Schlichting, R. Inhibition of neurite outgrowth and enhanced effects compared to baseline toxicity in SH-SY5Y cells. Arch. Toxicol. 2022, 96, 1039– 1053,  DOI: 10.1007/s00204-022-03237-x
    Google Scholar
    38
    Inhibition of neurite outgrowth and enhanced effects compared to baseline toxicity in SH-SY5Y cells
    Lee, Jungeun; Escher, Beate I.; Scholz, Stefan; Schlichting, Rita
    Archives of Toxicology (2022), 96 (4), 1039-1053CODEN: ARTODN; ISSN:0340-5761. (Springer)
    Abstr.: Early life exposure to environmental chems. can cause developmental neurotoxicity (DNT). The impairment of key neurodevelopmental processes such as neurite outgrowth inhibition can be used as endpoints for screening of DNT effects. We quantified neurite-specific effects using the ratio of effect concns. for cytotoxicity and neurite outgrowth inhibition (SRcytotoxicity). Baseline cytotoxicity, the minimal toxicity of any chem., was used to quantify enhanced cytotoxicity (toxic ratio, TR) and neuronal-specific toxicity (SRbaseline) by comparing baseline cytotoxicity with the effects on cell viability and neurite outgrowth, resp. The effects on cell viability and neurite length were measured based on image anal. in human neuroblastoma SH-SY5Y cells. Baseline cytotoxicity was predicted from hydrophobicity descriptors using a previously published model for SH-SY5Y cells. Enhanced cytotoxicity and neuronal-specific toxicity were more often obsd. for hydrophilic chems., which indicates that they are more likely to act through specific modes of action (MOA) on cell viability and neurite outgrowth. Hydrophobic chems. showed a tendency to act through baseline toxicity without showing specific or enhanced toxicity, but were highly potent considering their low effect concns. for both cytotoxicity and neurite outgrowth inhibition. The endpoint-specific controls (narciclasine, colchicine, cycloheximide, and rotenone), two carbamates (3-hydroxycarbofuran and carbaryl), and two redox cyclers (diquat and paraquat) showed distinct neurite-specific effects (SRcytotoxicity > 4). By comparing neurite-specific effects with enhanced cytotoxicity, one can explain whether the obsd. effects involve specific inhibition of neurite outgrowth, other specific MOAs, or merely baseline toxicity arising from hydrophobicity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xktlyrtr8%253D&md5=18dee4f05ec437cccdffe0150244c6f0
  39. 39
    Delp, J.; Cediel-Ulloa, A.; Suciu, I.; Kranaster, P.; van Vugt-Lussenburg, B. M. A.; Kos, V. M.; van der Stel, W.; Carta, G.; Bennekou, S. H.; Jennings, P.; van de Water, B.; Forsby, A.; Leist, M. Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch. Toxicol. 2021, 95, 591– 615,  DOI: 10.1007/s00204-020-02970-5
    Google Scholar
    There is no corresponding record for this reference.
  40. 40
    Cediel-Ulloa, A.; Lupu, D. L.; Johansson, Y.; Hinojosa, M.; Ozel, F.; Ruegg, J. Impact of endocrine disrupting chemicals on neurodevelopment: the need for better testing strategies for endocrine disruption-induced developmental neurotoxicity. Expert Rev. Endocrinol. Metab. 2022, 17, 131– 141,  DOI: 10.1080/17446651.2022.2044788
    Google Scholar
    There is no corresponding record for this reference.
  41. 41
    Lee, J.; König, M.; Braun, G.; Escher, B. I. Water Quality Monitoring with the Multiplexed Assay MitoOxTox for Mitochondrial Toxicity, Oxidative Stress Response, and Cytotoxicity in AREc32 Cells. Environ. Sci. Technol. 2024, 58, 5716– 5726,  DOI: 10.1021/acs.est.3c09844
    Google Scholar
    There is no corresponding record for this reference.
  42. 42
    Hawbaker, T.; Vanderhoof, M.; Schmidt, G.; Beal, Y.; Picotte, J.; Takacs, J.; Falgout, J.; Dwyer, J., The Landsat Burned Area products for the conterminous United States (ver. 3.0, March 2022): US Geological Survey data release. https://www.usgs.gov/data/landsat-burned-area-products-conterminous-united-states-ver-30-march-2022 (accessed Aug 25, 2024).
    Google Scholar
    There is no corresponding record for this reference.
  43. 43
    McAdoo, M. A.; Connock, G. T.; Messinger, T. Occurrence of per- and polyfluoroalkyl substances and inorganic analytes in groundwater and surface water used as sources for public water supply in West Virginia, Scientific Investigations Report 2022–5067 2022–5067; https://pubs.usgs.gov/publication/sir20225067 (accessed July 12, 2023).
    Google Scholar
    There is no corresponding record for this reference.
  44. 44
    Center for Disease Control (CDC), Biomonitoring Data Tables for Environmental Chemicals. Analysis of Whole Blood, Serum, and Urine Samples, NHANES 1999–2018, www.cdc.gov/exposurereport/data_tables.html. (accessed July 12, 2023).
    Google Scholar
    There is no corresponding record for this reference.
  45. 45
    Dickman, R. A.; Aga, D. S. Efficient workflow for suspect screening analysis to characterize novel and legacy per-and polyfluoroalkyl substances (PFAS) in biosolids. Anal. Bioanal. Chem. 2022, 414, 4497– 4507,  DOI: 10.1007/s00216-022-04088-2
    Google Scholar
    There is no corresponding record for this reference.
  46. 46
    Escher, B.; Neale, P.; Leusch, F. Bioanalytical tools in water quality assessment, 2nd ed.; IWA Publishing: London, UK, 2021. www.iwapublishing.com/books/9781789061970/bioanalytical-tools-water-quality-assessment-2nd-edition.
    Google Scholar
    There is no corresponding record for this reference.
  47. 47
    Stringer, C.; Wang, T.; Michaelos, M.; Pachitariu, M. Cellpose: a generalist algorithm for cellular segmentation. Nat. Methods 2021, 18, 100,  DOI: 10.1038/s41592-020-01018-x
    Google Scholar
    47
    Cellpose: a generalist algorithm for cellular segmentation
    Stringer, Carsen; Wang, Tim; Michaelos, Michalis; Pachitariu, Marius
    Nature Methods (2021), 18 (1), 100-106CODEN: NMAEA3; ISSN:1548-7091. (Nature Research)
    Abstr.: Many biol. applications require the segmentation of cell bodies, membranes and nuclei from microscopy images. Deep learning has enabled great progress on this problem, but current methods are specialized for images that have large training datasets. Here we introduce a generalist, deep learning-based segmentation method called Cellpose, which can precisely segment cells from a wide range of image types and does not require model retraining or parameter adjustments. Cellpose was trained on a new dataset of highly varied images of cells, contg. over 70,000 segmented objects. We also demonstrate a three-dimensional (3D) extension of Cellpose that reuses the two-dimensional (2D) model and does not require 3D-labeled data. To support community contributions to the training data, we developed software for manual labeling and for curation of the automated results. Periodically retraining the model on the community-contributed data will ensure that Cellpose improves constantly.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1Sgs77K&md5=6282c22e874931f6f7b2239926aee7c8
  48. 48
    Stirling, D. R.; Swain-Bowden, M. J.; Lucas, A. M.; Carpenter, A. E.; Cimini, B. A.; Goodman, A. CellProfiler 4: improvements in speed, utility and usability. BMC Bioinformatics 2021, 22, 433  DOI: 10.1186/s12859-021-04344-9
    Google Scholar
    There is no corresponding record for this reference.
  49. 49
    Sakamuru, S.; Li, X.; Attene-Ramos, M. S.; Huang, R. L.; Lu, J. M.; Shou, L.; Shen, M.; Tice, R. R.; Austin, C. P.; Xia, M. H. Application of a homogenous membrane potential assay to assess mitochondrial function. Physiol. Genomics 2012, 44, 495– 503,  DOI: 10.1152/physiolgenomics.00161.2011
    Google Scholar
    49
    Application of a homogenous membrane potential assay to assess mitochondrial function
    Sakamuru, Srilatha; Li, Xiao; Attene-Ramos, Matias S.; Huang, Ruili; Lu, Jianming; Shou, Louie; Shen, Min; Tice, Raymond R.; Austin, Christopher P.; Xia, Menghang
    Physiological Genomics (2012), 44 (9), 495-503CODEN: PHGEFP; ISSN:1094-8341. (American Physiological Society)
    Decreases in mitochondrial membrane potential (MMP) have been assocd. with mitochondrial dysfunction that could lead to cell death. The MMP is generated by an electrochem. gradient via the mitochondrial electron transport chain coupled to a series of redox reactions. Measuring the MMP in living cells is commonly used to assess the effect of chems. on mitochondrial function; decreases in MMP can be detected using lipophilic cationic fluorescent dyes. To identify an optimal dye for use in a high-throughput screening (HTS) format, we compared the ability of mitochondrial membrane potential sensor (Mito-MPS), 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolylcarbocyanine iodide, rhodamine 123, and tetramethylrhodamine to quantify a decrease in MMP in chem. exposed HepG2 cells cultured in 1,536-well plates. Under the conditions used, the optimal dye for this purpose is Mito-MPS. Next, we developed and optimized a homogenous cell-based Mito-MPS assay for use in 1,536-well plate format and demonstrated the utility of this assay by screening 1,280 compds. in the library of pharmacol. active compds. in HepG2 cells using a quant. high-throughput screening platform. From the screening, we identified 14 compds. that disrupted the MMP, with half-maximal potencies ranging from 0.15 to 18 μM; among these, compd. clusters that contained tyrphostin and 3'-substituted indolone analogs exhibited a structure-activity relationship. Our results demonstrate that this homogenous cell-based Mito-MPS assay can be used to evaluate the ability of large nos. of chems. to decrease mitochondrial function.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVKjurbN&md5=0334b08ad3d3b87cc0a47f6e768b8289
  50. 50
    Escher, B. I.; Neale, P. A.; Villeneuve, D. The advantages of linear concentration-response curves for in vitro bioassays with environmental samples. Environ. Toxicol. Chem. 2018, 37, 2273– 2280,  DOI: 10.1002/etc.4178
    Google Scholar
    50
    The advantages of linear concentration-response curves for in vitro bioassays with environmental samples
    Escher, Beate I.; Neale, Peta A.; Villeneuve, Daniel L.
    Environmental Toxicology and Chemistry (2018), 37 (9), 2273-2280CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
    In vitro assays and high-throughput screening (HTS) tools are increasingly being employed as replacements for animal testing, but most concn.-response curves are still evaluated with models developed for animal testing. The authors argue that application of in vitro assays, particularly reporter gene assays, to environmental samples can benefit from a different approach to concn.-response modeling. First, cytotoxicity often occurs at higher concns., esp. for weakly acting compds. and in complex environmental mixts. with many components. In these cases, specific effects can be masked by cytotoxicity. Second, for many HTS assays, low effect levels can be precisely quantified because of the low variability of controls in cell-based assays and the opportunity to run many concns. and replicates when using high-d. well-plate formats (e.g., 384 or more wells per plate). Hence, the authors recommend focusing concn.-response modeling on the lower portion of the concn.-response curve, which is approx. linear. Effect concns. derived from low-effect level linear concn.-response models facilitate simple derivation of relative effect potencies and the correct application of mixt. toxicity models in the calcn. of bioanal. equiv. concns.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht12ltrvP&md5=4049489a714d0c5d9fcc59fa806dc778
  51. 51
    Qin, W.; Henneberger, L.; Huchthausen, J.; König, M.; Escher, B. I. Role of bioavailability and protein binding of four anionic perfluoroalkyl substances in cell-based bioassays for quantitative in vitro to in vivo extrapolations. Environ. Int. 2023, 173, 107857  DOI: 10.1016/j.envint.2023.107857
    Google Scholar
    51
    Role of bioavailability and protein binding of four anionic perfluoroalkyl substances in cell-based bioassays for quantitative in vitro to in vivo extrapolations
    Qin, Weiping; Henneberger, Luise; Huchthausen, Julia; Koenig, Maria; Escher, Beate I.
    Environment International (2023), 173 (), 107857CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
    Perfluoroalkyl substances (PFAS) are persistent and pose a risk to human health. High throughput screening (HTS) cell-based bioassays may inform risk assessment of PFAS provided that quant. in vitro to in vivo extrapolation (QIVIVE) can be developed. The QIVIVE ratio is the ratio of nominal (Cnom) or freely dissolved concn. (Cfree) in human blood to Cnom or Cfree in the bioassays. Considering that the concns. of PFAS in human plasma and in vitro bioassays may vary by orders of magnitude, we tested the hypothesis that anionic PFAS bind to proteins concn.-dependently and therefore the binding differs substantially between human plasma and bioassays, which has an impact on QIVIVE. Solid phase microextn. (SPME) with C18-coated fibers served to quantify the Cfree of four anionic PFAS (perfluorobutanoate (PFBA), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS)) in the presence of proteins and lipid, medium components, cells and human plasma over five orders of magnitude in concns. The C18-SPME method was used to quantify the non-linear binding to proteins, human plasma and medium, and the partition consts. to cells. These binding parameters were used to predict Cfree of PFAS in cell bioassays and human plasma by a concn.-dependent mass balance model (MBM). The approach was illustrated with a reporter gene assay indicating activation of the peroxisome proliferator-activated receptor gamma (PPARγ-GeneBLAzer). Blood plasma levels were collected from literature for occupational exposure and the general population. The QIVIVEnom ratios were higher than the QIVIVEfree ratios due to the strong affinity to proteins and large differences in protein contents between human blood and bioassays. For human health risk assessment, the QIVIVEfree ratios of many in vitro assays need to be combined to cover all health relevant endpoints. If Cfree cannot be measured, they can be estd. with the MBM and concn.-dependent distribution ratios.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXkvVOnurw%253D&md5=f798d07da6dc0365eb1fbdadf21eb82c
  52. 52
    Droge, S. T. J. Membrane-Water Partition Coefficients to Aid Risk Assessment of Perfluoroalkyl Anions and Alkyl Sulfates. Environ. Sci. Technol. 2019, 53, 760– 770,  DOI: 10.1021/acs.est.8b05052
    Google Scholar
    52
    Membrane-Water Partition Coefficients to Aid Risk Assessment of Perfluoroalkyl Anions and Alkyl Sulfates
    Droge, Steven T. J.
    Environmental Science & Technology (2019), 53 (2), 760-770CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    This study detd. the sorption affinity to artificial phospholipid membranes (KmW) for series of perfluorinated carboxylates (PFCAs), perfluorinated sulfonates (PFSAs), alkyl sulfates (CxSO4), and 1-alkanesulfonates (CxSO3). A sorbent diln. assay with solid supported lipid membranes (SSLM) showed consistent CF2 unit increments of 0.59, and CH2 unit increments of 0.53, for the log KmW of perfluorinated and hydrogenated anions, resp. PFSAs sorbed 0.90 log units stronger than analog PFCAs; CxSO4 sorbed 0.75 log units stronger than analog CxSO3 anions. The log KmW values for the octyl analogs increase in the order H(CH2)8SO3- (1.74) < H(CH2)8SO4- (2.58) < F(CF2)8CO2- (PFNA, 4.04) < F(CF2)8SO3- (PFOS, 4.88). Intrinsic partition ratios detd. on a phospholipid coated HPLC column (IAM-HPLC) closely aligned with SSLM KmW values. COSMO-RS based mol. calcns. of KmW aligned with SSLM KmW values for hydrogenated anions with C8-C14 alkyl chains but strongly underestimated CF2 and CH2 unit increments for C4-C8 based anions. Dividing the crit. narcotic membrane burden of 100 mmol/kg by the exptl. KmW predicts lethal baseline toxicity concns. (LC50,narc). The LC50,narc coincides with the lowest reported acute LC50 values for several anionic surfactants but were on av. about an order of magnitude lower.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFOks7zN&md5=4bf9f4f1a42c91e66dd4865d8f94af73
  53. 53
    Ebert, A.; Allendorf, F.; Berger, U.; Goss, K. U.; Ulrich, N. Membrane/Water Partitioning and Permeabilities of Perfluoroalkyl Acids and Four of their Alternatives and the Effects on Toxicokinetic Behavior. Environ. Sci. Technol. 2020, 54, 5051– 5061,  DOI: 10.1021/acs.est.0c00175
    Google Scholar
    53
    Membrane/Water Partitioning and Permeabilities of Perfluoroalkyl Acids and Four of their Alternatives and the Effects on Toxicokinetic Behavior
    Ebert, Andrea; Allendorf, Flora; Berger, Urs; Goss, Kai-Uwe; Ulrich, Nadin
    Environmental Science & Technology (2020), 54 (8), 5051-5061CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    The search for alternatives to bioaccumulative perfluoroalkyl acids (PFAAs) is ongoing. New, still highly fluorinated alternatives are produced in hopes of reducing bioaccumulation. To better est. this bioaccumulative behavior, we performed dialysis expts. and detd. membrane/water partition coeffs., Kmem/w, of six perfluoroalkyl carboxylic acids (PFCAs), three perfluoroalkanesulfonic acids, and four alternatives. We also investigated how passive permeation might influence the uptake kinetics into cells, measuring the passive anionic membrane permeability Pion through planar lipid bilayers for six PFAAs and three alternatives. Exptl. Kmem/w and Pion were both predicted well by the COSMO-RS theory (log RMSE 0.61 and 0.46, resp.). Kmem/w values were consistent with the literature data, and alternatives showed similar sorption behavior as PFAAs. Exptl. Pion values were high enough to explain obsd. cellular uptake by passive diffusion with no need to postulate the existence of active uptake processes. However, predicted pKa and neutral permeabilities suggest that also the permeation of the neutral species should be significant in case of PFCAs. This can have direct consequences on the steady-state distribution of PFAAs across cell membranes and thus toxicity. Consequently, we propose a model to predict pH-dependent baseline toxicity based on Kmem/w, which considers the permeation of both neutral and anionic species.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvVGms7c%253D&md5=5888488c435b3f603b14beb2a96a6af6
  54. 54
    Altenburger, R.; Boedeker, W.; Faust, M.; Grimme, L. H. Regulations for combined effects of pollutants: consequences from risk assessment in aquatic toxicology. Food. Chem. Toxicol. 1996, 34, 1155– 1157,  DOI: 10.1016/S0278-6915(97)00088-4
    Google Scholar
    54
    Regulations for combined effects of pollutants: consequences from risk assessment in aquatic toxicology
    Altenburger R; Boedeker W; Faust M; Grimme L H
    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (1996), 34 (11-12), 1155-7 ISSN:0278-6915.
    In the analysis of combined effects two reference concepts are currently considered as equally valid for the assessment of mixture toxicities: these are LOEWE additivity (concentration addition) and BLISS independence (response addition) (Greco et al., 1995). The aim of this study of 137 binary mixtures of pesticides and surfactants using an algal biotest was to find rational procedures for the assessment of mixture toxicities in the aquatic environment. By introducing an index on prediction quality the quantitative relationships between predicted and observed effects are evaluated for each concept. It is shown that LOEWE additivity leads to good predictions of mixture toxicities for most combinations, whereas BLISS independence tends to underestimate mixture toxicities. By this it is reaffirmed that there is a solid basis for forthcoming regulatory activities on mixtures of chemicals.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3ktVansg%253D%253D&md5=13a713e23c3986e0621968a128c169d3
  55. 55
    Mann, A.; Tyndale, R. F. Cytochrome P450 2D6 enzyme neuroprotects against 1-methyl-4-phenylpyridinium toxicity in SH-SY5Y neuronal cells. Eur. J. Neurosci. 2010, 31, 1185– 1193,  DOI: 10.1111/j.1460-9568.2010.07142.x
    Google Scholar
    There is no corresponding record for this reference.
  56. 56
    Fernandez-Abascal, J.; Ripullone, M.; Valeri, A.; Leone, C.; Valoti, M. β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP+ Toxicity in Human Neuroblastoma SH-SY5Y Cells. Int. J. Mol. Sci. 2018, 19, 3369,  DOI: 10.3390/ijms19113369
    Google Scholar
    There is no corresponding record for this reference.
  57. 57
    Fischer, F. C.; Abele, C.; Henneberger, L.; Klüver, N.; König, M.; Mühlenbrink, M.; Schlichting, R.; Escher, B. I. Characterizing cellular metabolism in high-throughput in vitro reporter gene assays. Chem. Res. Toxicol. 2020, 33, 1770– 17797,  DOI: 10.1021/acs.chemrestox.0c00037
    Google Scholar
    There is no corresponding record for this reference.
  58. 58
    Warne, M. S. J.; Hawker, D. W. The number of components in a mixture determines whether synergistic and antagonistic or additive toxicity predominate - the funnel hypothesis. Ecotoxicol. Environ. Saf. 1995, 31, 23– 28,  DOI: 10.1006/eesa.1995.1039
    Google Scholar
    There is no corresponding record for this reference.
  59. 59
    CHEM Trust, Chemical cocktails - The neglected threat from toxic mixtures and how to fix it. https://chemtrust.org/chemicalcocktails/ (accessed June 1, 2024).
    Google Scholar
    There is no corresponding record for this reference.
  60. 60
    Escher, B. I.; Braun, G.; Zarfl, C. Exploring the concepts of concentration addition and independent action using a linear low-effect mixture model. Environ. Toxicol. Chem. 2020, 39, 2552– 2559,  DOI: 10.1002/etc.4868
    Google Scholar
    60
    Exploring the Concepts of Concentration Addition and Independent Action Using a Linear Low-Effect Mixture Model
    Escher, Beate; Braun, Georg; Zarfl, Christiane
    Environmental Toxicology and Chemistry (2020), 39 (12), 2552-2559CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
    Chems. emitted into the environment are typically present at low concns. but may act together in mixts. Concn.-response curves of in vitro bioassays were often linear for effect levels <30%, and the predictions for concn. addn. (CA) of similarly acting chems. and for independent action (IA) of dissimilarly acting chems. overlapped. We derived a joint CA/IA mixt. model for the low-effect level portion of concn.-response curves. In a first case study, we evaluated the cytotoxicity of over 200 mixts. of up to 17 components that were mixed in concn. ratios as they occurred in river water. The predictions of the full IA model were indistinguishable from the predictions of the full CA model up to 10% effect, confirming the applicability of the joint CA/IA mixt. model at low effect levels. In a second case study, we evaluated if environmental concns. trigger effects at levels low enough for the joint CA/IA mixt. model to apply. The detected concns. were scaled by their toxic potencies to est. the mixt. effect of the detected chems. in a complex mixt. In 86% of 156 samples the effects fell in the validity range of the joint CA/IA mixt. model (<10% effect level), confirming the CA assumption for toxic unit summation. The joint CA/IA mixt. model is not suitable for testing specific mixt. hypotheses and interactions of chems. in mixts., where more refined models are required; but it is helpful for the interpretation of effects of complex (multicomponent) environmental mixts., esp. for water samples with relatively low effect level. Environ Toxicol Chem 2020;00:1-8. 2020 The Authors. Environmental Toxicol. and Chem. published by Wiley Periodicals LLC on behalf of SETAC.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFWis7fJ&md5=4c2ddddc298f9d28c965d46d8444c4c0
  61. 61
    Kim, S.; Kang, K.; Kim, H.; Seo, M. In Vitro Toxicity Screening of Fifty Complex Mixtures in HepG2 Cells. Toxics 2024, 12, 126,  DOI: 10.3390/toxics12020126
    Google Scholar
    There is no corresponding record for this reference.
  62. 62
    Cedergreen, N. Quantifying synergy: A systematic review of mixture toxicity studies within environmental toxicology. PLoS One 2014, 9, e96580  DOI: 10.1371/journal.pone.0096580
    Google Scholar
    62
    Quantifying synergy: a systematic review of mixture toxicity studies within environmental toxicology
    Cedergreen, Nina
    PLoS One (2014), 9 (5), e96580/1-e96580/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    A review. Cocktail effects and synergistic interactions of chems. in mixts. are an area of great concern to both the public and regulatory authorities. The main concern is whether some chems. can enhance the effect of other chems., so that they jointly exert a larger effect than predicted. This phenomenon is called synergy. Here we present a review of the scientific literature on three main groups of environmentally relevant chem. toxicants: pesticides, metal ions and antifouling compds. The aim of the review is to det. 1) the frequency of synergy, 2) the extent of synergy, 3) whether any particular groups or classes of chems. tend to induce synergy, and 4) which physiol. mechanisms might be responsible for this synergy. Synergy is here defined as mixts. with min. two-fold difference between obsd. and predicted effect concns. using Concn. Addn. (CA) as a ref. model and including both lethal and sub-lethal endpoints. The results showed that synergy occurred in 7%, 3% and 26% of the 194, 21 and 136 binary pesticide, metal and antifoulants mixts. included in the data compilation on frequency. The difference between obsd. and predicted effect concns. was rarely more than 10-fold. For pesticides, synergistic mixts. included cholinesterase inhibitors or azole fungicides in 95% of 69 described cases. Both groups of pesticides are known to interfere with metabolic degrdn. of other xenobiotics. For the four synergistic metal and 47 synergistic antifoulant mixts. the pattern in terms of chem. groups inducing synergy was less clear. Hypotheses in terms of mechanisms governing these interactions are discussed. It was concluded that true synergistic interactions between chems. are rare and often occur at high concns. Addressing the cumulative rather than synergistic effect of co-occurring chems., using std. models as CA, is therefore regarded as the most important step in the risk assessment of chem. cocktails.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVKgsL%252FJ&md5=6a8cbc65fb2485c16d95e5d4d4aee7fe
  63. 63
    Bil, W.; Govarts, E.; Zeilmaker, M. J.; Woutersen, M.; Bessems, J.; Ma, Y.; Thomsen, C.; Haug, L. S.; Lignell, S.; Gyllenhammar, I.; Murinova, L. P.; Fabelova, L.; Tratnik, J. S.; Kosjek, T.; Gabriel, C.; Sarigiannis, D.; Pedraza-Diaz, S.; Esteban-Lopez, M.; Castano, A.; Rambaud, L.; Riou, M.; Franken, C.; Colles, A.; Vogel, N.; Kolossa-Gehring, M.; Halldorsson, T. I.; Uhl, M.; Schoeters, G.; Santonen, T.; Vinggaard, A. M. Approaches to mixture risk assessment of PFASs in the European population based on human hazard and biomonitoring data. Int. J. Hyg. Environ. Health 2023, 247, 114071  DOI: 10.1016/j.ijheh.2022.114071
    Google Scholar
    There is no corresponding record for this reference.
  64. 64
    Bil, W.; Zeilmaker, M.; Fragki, S.; Lijzen, J.; Verbruggen, E.; Bokkers, B. Risk Assessment of Per- and Polyfluoroalkyl Substance Mixtures: A Relative Potency Factor Approach. Environ. Toxicol. Chem. 2021, 40, 859,  DOI: 10.1002/etc.4835
    Google Scholar
    64
    Risk Assessment of Per- and Polyfluoroalkyl Substance Mixtures: A Relative Potency Factor Approach
    Bil, Wieneke; Zeilmaker, Marco; Fragki, Styliani; Lijzen, Johannes; Verbruggen, Eric; Bokkers, Bas
    Environmental Toxicology and Chemistry (2021), 40 (3), 859-870CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
    Per- and polyfluoroalkyl substances (PFAS) often occur together as contamination in exposure media such as drinking water or food. The relative potency factor (RPF) methodol. facilitates the risk assessment of mixt. exposure. A database of liver endpoints was established for 16 PFAS, using data with the same species (rat), sex (male), and exposure route (oral) and comparable exposure duration (42-90 d). Dose-response anal. was applied to derive the relative potencies of 3 perfluoroalkyl sulfonic acids (perfluorobutane sulfonic acid, perfluorohexane sulfonic acid, perfluorooctane sulfonic acid), 8 perfluoroalkyl carboxylic acids (perfluorobutanoic acid, perfluorohexanoic acid, perfluorononanoic acid, perfluoroundecanoic acid, perfluorododecanoic acid, perfluorotetradecanoic acid, perfluorohexadecanoic acid, perfluorooctadecanoic acid), 2 perfluoroalkyl ether carboxylic acids (tetrafluoro-2-[heptafluoropropoxy]propanoic acid, 3H-perfluoro-3-[(3-methoxy-propoxy)propanoic acid]), and 2 fluorotelomer alcs. (6:2 FTOH, 8:2 FTOH) compared to perfluorooctanoic acid (PFOA), based on liver effects. In addn., the RPFs of 7 other perfluoroalkyl acids were estd. based on read-across. This resulted in the relative potencies of 22 PFAS compared to the potency of index compd. PFOA. The obtained RPFs can be applied to measured PFAS quantities, resulting in the sum of PFOA equiv. in a mixt. This sum can be compared with an established PFOA concn. limit (e.g., in drinking water or food) or an external health-based guidance value (e.g., tolerable daily intake, acceptable daily intake, or ref. dose) to est. the risk resulting from direct oral exposure to mixts. Assessing mixt. exposure is particularly relevant for PFAS, with omnipresent exposure in our daily lives.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslKhurbF&md5=9bedd6f8f0ab0461bc151f98aeed87b5
  65. 65
    Colnot, T.; Dekant, W. Commentary: cumulative risk assessment of perfluoroalkyl carboxylic acids and perfluoralkyl sulfonic acids: what is the scientific support for deriving tolerable exposures by assembling 27 PFAS into 1 common assessment group?. Arch. Toxicol. 2022, 96, 3127– 3139,  DOI: 10.1007/s00204-022-03336-9
    Google Scholar
    There is no corresponding record for this reference.

Cited By

Click to copy section linkSection link copied!

This article is cited by 1 publications.

  1. Logan Running, Judith R. Cristobal, Charikleia Karageorgiou, Michelle Camdzic, John Michael N. Aguilar, Omer Gokcumen, Diana S. Aga, G. Ekin Atilla-Gokcumen. Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells through Transcriptomics and Lipidomics Analysis. ACS Chemical Neuroscience 2024, Article ASAP.
Download PDF
Go to Environmental Science & Technology
Get e-Alerts
Get e-Alerts

Environmental Science & Technology

Cite this: Environ. Sci. Technol. 2024, 58, 38, 16774–16784
Click to copy citationCitation copied!
https://doi.org/10.1021/acs.est.4c06017
Published September 11, 2024

Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Article Views

5660

Altmetric

-

Citations

1
Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Study design. Differentiated SH-SY5Y and AREc32 cells were exposed to single PFAS and to several representative PFAS mixtures and extracts from the biosolids samples. Effects recorded after 24-h exposure included cytotoxicity in both cell lines. Inhibition of neurite length in the differentiated SH-SY5Y cells was detected by phase contrast imaging (top right– gray cell bodies, pink neurites). Oxidative stress response via the reporter gene activation of the Nrf2-ARE pathway as well as mitochondrial membrane potential inhibition was measured in AREc32 cells. Figure was partially created with BioRender.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. Comparison between predicted baseline toxicity IC10,baseline and measured cytotoxicity IC10 for (a) AREc32 cells and (b) SH-SY5Y cells. (c) Comparison of measured cytotoxicity IC10 and neurite outgrowth inhibition EC10 in differentiated SH-SY5Y cells. TR, toxic ratio; SR, specificity ratio.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. Comparison between the experimental mixture IC10 (inhibitory concentration causing 10% cytotoxicity) with the predicted mixture IC10(CA) calculated with the mixture model of concentration addition (CA) (eqs 6–9) for AREc32 and SH-SY5Y cells for the envmix and bloodmix; comparison of experimental and predicted EC10 (effect concentration causing 10% reduction of neurite length) for neurite outgrowth inhibition (NOI) in SH-SY5Y. The line corresponds to perfect agreement between model and prediction (index of prediction quality (eq 10) IPQ = 0), the dashed lines mark the area of IPQ up to 0.5. No data lay in the upper left corner, where synergistic effects would be displayed or the bottom right corner, where antagonistic effects would be displayed.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. Environmental mixture (envmix): comparison of contribution of individual PFAS i to the fraction in the mixture (pi), their relative effect potency compared to PFOA (REPi = IC10,PFOA/IC10,i or EC10,PFOA/EC10,i) and their contribution to the mixture toxicity (Toxi, eq 13). (A) cytotoxicity in AREc32, (B) cytotoxicity in SH-SY5Y, (C) neurite outgrowth inhibition in SH-SY5Y.

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 5

    Figure 5. Blood mixture (bloodmix): comparison of contribution of individual PFAS to the fraction in the mixture (pi), their relative effect potency compared to PFOA (REPi = IC10,PFOA/IC10,i or EC10,PFOA/EC10,i) and their contribution to the mixture toxicity (Toxi, eq 13). (A) cytotoxicity in AREc32, (B) cytotoxicity in SH-SY5Y, (C) neurite outgrowth inhibition (NOI) in SH-SY5Y.

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    This article references 65 other publications.

    1. 1
      Buck, R. C.; Franklin, J.; Berger, U.; Conder, J. M.; Cousins, I. T.; de Voogt, P.; Jensen, A. A.; Kannan, K.; Mabury, S. A.; van Leeuwen, S. P. Perfluoroalkyl and polyfluoroalkyl substances in the environment: Terminology, classification, and origins. Integr. Environ. Assess. Manage. 2011, 7, 513– 541,  DOI: 10.1002/ieam.258
      1
      Perfluoroalkyl and polyfluoroalkyl substances in the environment: Terminology, classification, and origins
      Buck, Robert C.; Franklin, James; Berger, Urs; Conder, Jason M.; Cousins, Ian T.; de Voogt, Pim; Jensen, Allan Astrup; Kannan, Kurunthachalam; Mabury, Scott A.; van Leeuwen, Stefan P. J.
      Integrated Environmental Assessment and Management (2011), 7 (4), 513-541CODEN: IEAMCK; ISSN:1551-3777. (John Wiley & Sons Inc.)
      A review. The primary aim of this article is to provide an overview of perfluoroalkyl and polyfluoroalkyl substances (PFASs) detected in the environment, wildlife, and humans, and recommend clear, specific, and descriptive terminol., names, and acronyms for PFASs. The overarching objective is to unify and harmonize communication on PFASs by offering terminol. for use by the global scientific, regulatory, and industrial communities. A particular emphasis is placed on long-chain perfluoroalkyl acids, substances related to the long-chain perfluoroalkyl acids, and substances intended as alternatives to the use of the long-chain perfluoroalkyl acids or their precursors. First, we define PFASs, classify them into various families, and recommend a pragmatic set of common names and acronyms for both the families and their individual members. Terminol. related to fluorinated polymers is an important aspect of our classification. Second, we provide a brief description of the 2 main prodn. processes, electrochem. fluorination and telomerization, used for introducing perfluoroalkyl moieties into org. compds., and we specify the types of byproducts (isomers and homologues) likely to arise in these processes. Third, we show how the principal families of PFASs are interrelated as industrial, environmental, or metabolic precursors or transformation products of one another. We pay particular attention to those PFASs that have the potential to be converted, by abiotic or biotic environmental processes or by human metab., into long-chain perfluoroalkyl carboxylic or sulfonic acids, which are currently the focus of regulatory action. The Supplemental Data lists 42 families and subfamilies of PFASs and 268 selected individual compds., providing recommended names and acronyms, and structural formulas, as well as Chem. Abstrs. Service registry nos. Integr Environ Assess Manag 2011;7:513-541. © 2011 SETAC.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtF2jtrnM&md5=b3bbf89fd9b71a0a30c5e8c390ccfdda
    2. 2
      Glüge, J.; Scheringer, M.; Cousins, I. T.; DeWitt, J. C.; Goldenman, G.; Herzke, D.; Lohmann, R.; Ng, C. A.; Trier, X.; Wang, Z. Y. An overview of the uses of per- and polyfluoroalkyl substances (PFAS). Environ. Sci.: Processes Impacts 2020, 22, 2345– 2373,  DOI: 10.1039/D0EM00291G
      There is no corresponding record for this reference.
    3. 3
      Ghisi, R.; Vamerali, T.; Manzetti, S. Accumulation of perfluorinated alkyl substances (PFAS) in agricultural plants: A review. Environ. Res. 2019, 169, 326– 341,  DOI: 10.1016/j.envres.2018.10.023
      3
      Accumulation of perfluorinated alkyl substances (PFAS) in agricultural plants: A review
      Ghisi, Rossella; Vamerali, Teofilo; Manzetti, Sergio
      Environmental Research (2019), 169 (), 326-341CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)
      PFASs are a class of compds. that include perfluoroalkyl and polyfluoroalkyl substances, some of the most persistent pollutants still allowed - or only partially restricted - in several product fabrications and industrial applications worldwide. PFASs have been shown to interact with blood proteins and are suspected of causing a no. of pathol. responses, including cancer. Given this threat to living organisms, we carried out a broad review of possible sources of PFASs and their potential accumulation in agricultural plants, from where they can transfer to humans through the food chain. Anal. of the literature indicates a direct correlation between PFAS concns. in soil and bioaccumulation in plants. Furthermore, plant uptake largely changes with chain length, functional group, plant species and organ. Low accumulations of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) have been found in peeled potatoes and cereal seeds, while short-chain compds. can accumulate at high levels in leafy vegetables and fruits. Significant variations in PFAS buildup in plants according to soil amendment are also found, suggesting a particular interaction with soil org. matter. Here, we identify a series of challenges that PFASs pose to the development of a safe agriculture for future generations.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlKls7jK&md5=57570aba68a72ae145822ff36d81fc7c
    4. 4
      Johnson, G. R. PFAS in soil and groundwater following historical land application of biosolids. Water Res. 2022, 211, 118035  DOI: 10.1016/j.watres.2021.118035
      4
      PFAS in soil and groundwater following historical land application of biosolids
      Johnson, Gwynn R.
      Water Research (2022), 211 (), 118035CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
      The land application of digested sewage sludge (biosolids) is widely employed across the globe. Studies show that biosolids contain significant amts. of inorg. and org. materials, as well as emerging pollutants, including per- and polyfluorinated alkyl substances (PFAS). With the wide range of pollutants commonly reported in biosolids, the potential risks assocd. with long-term land application operations are concerning. In this study, PFAS in surface soils, deeper soils into the vadose zone, and immediately-underlying groundwater was measured at an agricultural station with a long record of biosolids applications plus irrigation using treated wastewater. Twelve PFAS homologues were detected in every near surface soil sampled 0-30 cm depth below ground surface with multiple PFAS (esp. short-chain) distributed through the soil profile. Av. measured concns. of PFAS in these soils suggest the soil burden PFOS>PFDA>PFOA for all substations sampled, independent of the historical loading rates and patterns of agricultural operations on those substations. Measured concns. of PFOA and PFOS in the soil profile (0-90 cm) suggest these compds. have migrated to deeper soil depths (up to 9 m below the surface) with quantifiable concns. in the soil and the immediate underlying groundwater located approx. 17 m below. Ests. of the total mass of PFAS in surface soils were effectively made using PFAS levels reported in sludges from the USEPA NSSS combined with long-term loading rates on record at the substations. With the land application of biosolids in the USA regulated by the USEPA, addnl. and updated risk assessments and surveys to include emerging pollutants such as PFAS are needed to protect public health and the environment.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XpvF2qtA%253D%253D&md5=2446b812dd40a7fd8ca11361debb2761
    5. 5
      Lu, Y.; Meng, L.; Ma, D.; Cao, H.; Liang, Y.; Liu, H.; Wang, Y.; Jiang, G. The occurrence of PFAS in human placenta and their binding abilities to human serum albumin and organic anion transporter 4. Environ. Pollut. 2021, 273, 116460  DOI: 10.1016/j.envpol.2021.116460
      5
      The occurrence of PFAS in human placenta and their binding abilities to human serum albumin and organic anion transporter 4
      Lu, Yao; Meng, Lingyi; Ma, Donghui; Cao, Huiming; Liang, Yong; Liu, Hongwei; Wang, Yawei; Jiang, Guibin
      Environmental Pollution (Oxford, United Kingdom) (2021), 273 (), 116460CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)
      Both legacy and emerging per- and polyfluoroalkyl substances (PFAS) have been found to be threats to human health. In particular, fetuses are sensitive to xenobiotics and the placenta functions as a significant barrier for environmental pollutants. The placental transfer of PFAS is closely related to their interactions with proteins. In this study, 54 human placental samples were collected to investigate the occurrence of legacy and emerging PFAS in human placenta, including perfluorinated carboxylates (PFCAs), perfluorinated sulfonates (PFSAs), chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs), and fluorotelomer sulfonates (FTSAs). Among the legacy PFAS, perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were detected in all samples, with PFOS and PFOA being the two predominant (mean: 0.457 and 0.242 ng/g wet wt., resp.). Among the emerging PFAS, 6:2 Cl-PFESA was detected in all samples with the mean value of 0.104 ng/g wet wt., while the detect frequency (DF) of 8:2 Cl-PFESAs was only 24%. The concn. and DF of the four FTSA congeners were low in the placentas. Mol. docking calcn. results showed that the binding affinities of PFAS to the human serum albumin (HSA) were increased with chain length in each category except for the PFCAs, of which the perfluoroundecanoic acid (PFUnDA) was the turning point of binding affinity to HSA. For PFSAs, their binding affinities to org. anion transporter 4 (OAT4) were increased with the chain length except for the sodium perfluoro-1-heptanesulfonate (PFHpS) and sodium perfluoro-1-nonanesulfonate (PFNS). The calcn. results demonstrated that the placental transfer of PFAS is closely related to chain length. The findings in the study can help better understand the occurrence of the PFAS in the human placenta and the placental transfer mechanisms of PFAS in human beings.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhslWmt78%253D&md5=cf5c9644622dfada8edd8fd1d41a49fa
    6. 6
      Poothong, S.; Thomsen, C.; Padilla-Sanchez, J. A.; Papadopoulou, E.; Haug, L. S. Distribution of novel and well-known poly-and perfluoroalkyl substances (PFASs) in human serum, plasma, and whole blood. Environ. Sci. Technol. 2017, 51, 13388– 13396,  DOI: 10.1021/acs.est.7b03299
      There is no corresponding record for this reference.
    7. 7
      Wang, W.; Rhodes, G.; Ge, J.; Yu, X.; Li, H. Uptake and accumulation of per-and polyfluoroalkyl substances in plants. Chemosphere 2020, 261, 127584  DOI: 10.1016/j.chemosphere.2020.127584
      There is no corresponding record for this reference.
    8. 8
      Hu, X. C.; Andrews, D. Q.; Lindstrom, A. B.; Bruton, T. A.; Schaider, L. A.; Grandjean, P.; Lohmann, R.; Carignan, C. C.; Blum, A.; Balan, S. A.; Higgins, C. P.; Sunderland, E. M. Detection of Poly- and Perfluoroalkyl Substances (PFASs) in U.S. Drinking Water Linked to Industrial Sites, Military Fire Training Areas, and Wastewater Treatment Plants. Environ Sci. Technol. Lett. 2016, 3, 344– 350,  DOI: 10.1021/acs.estlett.6b00260
      8
      Detection of Poly- and Perfluoroalkyl Substances (PFASs) in U.S. Drinking Water Linked to Industrial Sites, Military Fire Training Areas, and Wastewater Treatment Plants
      Hu, Xindi C.; Andrews, David Q.; Lindstrom, Andrew B.; Bruton, Thomas A.; Schaider, Laurel A.; Grandjean, Philippe; Lohmann, Rainer; Carignan, Courtney C.; Blum, Arlene; Balan, Simona A.; Higgins, Christopher P.; Sunderland, Elsie M.
      Environmental Science & Technology Letters (2016), 3 (10), 344-350CODEN: ESTLCU; ISSN:2328-8930. (American Chemical Society)
      Drinking water contamination with poly- and perfluoroalkyl substances (PFASs) poses risks to the developmental, immune, metabolic, and endocrine health of consumers. We present a spatial anal. of 2013-2015 national drinking water PFAS concns. from the US EPA 3rd Unregulated Contaminant Monitoring Rule (UCMR3) program. The no. of industrial sites that manuf. or use these compds., the no. of military fire training areas, and the no. of wastewater treatment plants are all significant predictors of PFAS detection frequencies and concns. in public water supplies. Among samples with detectable PFAS levels, each addnl. military site within a watershed's 8-digit hydrol. unit is assocd. with a 20% increase in PFHxS, a 10% increase in both PFHpA and PFOA, and a 35% increase in PFOS. The no. of civilian airports with personnel trained in the use of aq. film-forming foams is significantly assocd. with the detection of PFASs above the minimal reporting level. We find drinking water supplies for 6 million US residents exceed US EPA's lifetime health advisory (70 ng/L) for PFOS and PFOA. Lower anal. reporting limits and addnl. sampling of smaller utilities serving <10000 individuals and private wells would greatly assist in further identifying PFAS contamination sources.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht12msb7J&md5=b51d66969dbcd86fe394437b0c7795b3
    9. 9
      Brase, R. A.; Mullin, E. J.; Spink, D. C. Legacy and emerging per-and polyfluoroalkyl substances: analytical techniques, environmental fate, and health effects. Int J Mol Sci 2021, 22, 995,  DOI: 10.3390/ijms22030995
      9
      Legacy and emerging per- and polyfluoroalkyl substances: analytical techniques, environmental fate, and health effects
      Brase, Richard A.; Mullin, Elizabeth J.; Spink, David C.
      International Journal of Molecular Sciences (2021), 22 (3), 995CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)
      A review. Due to their unique chem. properties, per- and polyfluoroalkyl substances (PFAS) have been used extensively as industrial surfactants and processing aids. While several types of PFAS have been voluntarily phased out by their manufacturers, these chems. continue to be of ecol. and public health concern due to their persistence in the environment and their presence in living organisms. Moreover, while the compds. referred to as "legacy" PFAS remain in the environment, alternative compds. have emerged as replacements for their legacy predecessors and are now detected in numerous matrixes. In this review, we discuss the historical uses of PFAS, recent advances in anal. techniques for anal. of these compds., and the fate of PFAS in the environment. In addn., we evaluate current biomonitoring studies of human exposure to legacy and emerging PFAS and examine the assocns. of PFAS exposure with human health impacts, including cancer- and non-cancer-related outcomes. Special focus is given to short-chain perfluoroalkyl acids (PFAAs) and ether-substituted, polyfluoroalkyl alternatives including hexafluoropropylene oxide dimer acid (HFPO-DA; tradename GenX), 4,8-dioxa-3H-perfluorononanoic acid (DONA), and 6:2 chlorinated polyfluoroethersulfonic acid (6:2 Cl-PFESA; tradename F-53B).
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXlsVaisLk%253D&md5=2682cd563b22b88f07655ddb3d519aca
    10. 10
      Saawarn, B.; Mahanty, B.; Hait, S.; Hussain, S. Sources, occurrence, and treatment techniques of per-and polyfluoroalkyl substances in aqueous matrices: A comprehensive review. Environ. Res. 2022, 214, 114004  DOI: 10.1016/j.envres.2022.114004
      There is no corresponding record for this reference.
    11. 11
      Wanninayake, D. M. Comparison of currently available PFAS remediation technologies in water: A review. J. Environ. Manage. 2021, 283, 111977 10.1016/j.jenvman.2021.111977  DOI: 10.1016/j.jenvman.2021.111977
      11
      Comparison of currently available PFAS remediation technologies in water: A review
      Wanninayake, Dushanthi M.
      Journal of Environmental Management (2021), 283 (), 111977CODEN: JEVMAW; ISSN:0301-4797. (Elsevier Ltd.)
      A review. Remediation of Poly- and perfluoroalkyl substances (PFASs) in the environment has rapidly increased due to growing concerns of environmental contamination and assocd. adverse toxicol. effects on wildlife and humans due to bioaccumulation and extreme persistence. Although, PFASs are highly recalcitrant to conventional water treatment processes, there are some effective techniques available. Those techniques involve exceedingly high costs due to high energy use, and high capital or operational costs. Thus, most remediation techniques have limitations in field applications even though the lab. scale expts. are promising. As a result of stringent new health and environmental regulatory stds. are being established, development of suitable water treatment methodol. is more challenging. Most of the sepn. and destruction techniques have their own limitations in field applications while the biol. approaches to treat PFASs are extremely limited and are not currently considered as viable. In this review, extra consideration is given to novel advanced techniques for wide array of PFAS classes including short chain PFAS removal, and compare their efficiencies, effectiveness, energy use, sustainability, cost, and simplicity in lab. scale to field applications. Electrochem., sonochem., advanced oxidn. processers (AOPs) and plasma together with novel hybrid techniques are considered as effective approaches for PFASs removal and have shown promising results for long chain and some short chain PFASs, as well as extremely persistent per-fluoro alkyl acids (PFAAs). Therefore, it is essential to better understand the removal mechanisms to optimize the advanced treatment processes like hybrid techniques because, the unique physicochem. characteristics of various PFASs impose difficult challenges. Careful selection of a combined effective treatment methodol. in an integrated processing unit, would be a revolutionary approach for complete elimination of PFASs from the environment. Considering the site-specific water quality parameters together with community perspectives will also make it more viable in real world field applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXis1Klur0%253D&md5=9c926e89a2c09b87133e7c23f8d3df2f
    12. 12
      Lenka, S. P.; Kah, M.; Padhye, L. P. A review of the occurrence, transformation, and removal of poly-and perfluoroalkyl substances (PFAS) in wastewater treatment plants. Water Res. 2021, 199, 117187  DOI: 10.1016/j.watres.2021.117187
      12
      A review of the occurrence, transformation, and removal of poly- and perfluoroalkyl substances (PFAS) in wastewater treatment plants
      Lenka, Swadhina Priyadarshini; Kah, Melanie; Padhye, Lokesh P.
      Water Research (2021), 199 (), 117187CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
      A review. Poly- and perfluoroalkyl substances (PFAS) comprise more than 4,000 anthropogenically manufd. compds. with widescale consumer and industrial applications. This crit. review compiles the latest information on the worldwide distribution of PFAS and evaluates their fate in wastewater treatment plants (WWTPs). A large proportion (>30%) of monitoring studies in WWTPs were conducted in China, followed by Europe (30%) and North America (16%), whereas information is generally lacking for other parts of the world, including most of the developing countries. Short and long-chain perfluoroalkyl acids (PFAAs) were widely detected in both the influents (up to 1,000 ng/L) and effluents (15 to >1,500 ng/L) of WWTPs. To date, limited data is available regarding levels of PFAS precursors and ultra-short chain PFAS in WWTPs. Most WWTPs exhibited low removal efficiencies for PFAS, and many studies reported an increase in the levels of PFAAs after wastewater treatment. The anal. of the fate of various classes of PFAS at different wastewater treatment stages (aerobic and/aerobic biodegrdn., photodegrdn., and chem. degrdn.) revealed biodegrdn. as the primary mechanism responsible for the transformation of PFAS precursors to PFAAs in WWTPs. Remediation studies at full scale and lab. scale suggest advanced processes such as adsorption using ion exchange resins, electrochem. degrdn., and nanofiltration are more effective in removing PFAS (∼95-100%) than conventional processes. However, the applicability of such treatments for real-world WWTPs faces significant challenges due to the scaling-up requirements, mass-transfer limitations, and management of treatment byproducts and wastes. Combining more than one technique for effective removal of PFAS, while addressing limitations of the individual treatments, could be beneficial. Considering environmental concns. of PFAS, cost-effectiveness, and ease of operation, nanofiltration followed by adsorption using wood-derived biochar and/or activated carbons could be a viable option if introduced to conventional treatment systems. However, the large-scale applicability of the same needs to be further verified.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtV2gtbzF&md5=b1a69359d89811bb4c1dadd99e23009a
    13. 13
      Sepulvado, J. G.; Blaine, A. C.; Hundal, L. S.; Higgins, C. P. Occurrence and fate of perfluorochemicals in soil following the land application of municipal biosolids. Environ. Sci. Technol. 2011, 45, 8106– 8112,  DOI: 10.1021/es103903d
      13
      Occurrence and fate of perfluorochemicals in soil following the land application of municipal biosolids
      Sepulvado, Jennifer G.; Blaine, Andrea C.; Hundal, Lakhwinder S.; Higgins, Christopher P.
      Environmental Science & Technology (2011), 45 (19), 8106-8112CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
      The recent implementation of soil and drinking water screening guidance values for 2 perfluorochems. (PFCs), perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) by the US EPA, reflects the growing concerns regarding the presence of these persistent and bioaccumulative chems. in the natural environment. Previous work has established the potential risk to the environment from the land application of industrially contaminated biosolids, but studies focusing on environmental risk from land application of typical municipal biosolids are lacking. This study examd. the occurrence and fate of PFCs from land-applied municipal biosolids by evaluating the levels, mass balance, desorption, and transport of PFCs in soils receiving application of municipal biosolids at various loading rates. This study is the 1st to report levels of PFCs in agricultural soils amended with typical municipal biosolids. PFOS was the dominant PFC in both biosolids (80-219 ng/g) and biosolids-amended soil (2-483 ng/g). Concns. of all PFCs in soil increased linearly with increasing biosolids loading rate. These data were used to develop a model for predicting PFC soil concns. in soils amended with typical municipal biosolids using cumulative biosolids loading rates. Mass balance calcns. comparing PFCs applied vs. those recovered in the surface soil interval indicated the potential transformation of PFC precursors. Lab. desorption expts. indicated that the leaching potential of PFCs decreases with increasing chain length and that previously derived org.-C normalized partition coeffs. may not be accurate predictors of the desorption of long-chain PFCs from biosolids-amended soils. Trace levels of PFCs were also detected in soil cores from biosolids-amended soils to depths of 120 cm, suggesting potential movement of these compds. within the soil profile over time and confirming the higher transport potential for short-chain PFCs in soils amended with municipal biosolids.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjvVOls7Y%253D&md5=f28dd098381463ee4eeb1ef16d7c8931
    14. 14
      Houck, K. A.; Patlewicz, G.; Richard, A. M.; Williams, A. J.; Shobair, M. A.; Smeltz, M.; Clifton, M. S.; Wetmore, B.; Medvedev, A.; Makarov, S. Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identifies potential toxicity pathways related to molecular structure. Toxicology 2021, 457, 152789  DOI: 10.1016/j.tox.2021.152789
      14
      Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identifies potential toxicity pathways related to molecular structure
      Houck, Keith A.; Patlewicz, Grace; Richard, Ann M.; Williams, Antony J.; Shobair, Mahmoud A.; Smeltz, Marci; Clifton, M. Scott; Wetmore, Barbara; Medvedev, Alex; Makarov, Sergei
      Toxicology (2021), 457 (), 152789CODEN: TXCYAC; ISSN:0300-483X. (Elsevier Ltd.)
      Per- and polyfluoroalkyl substances (PFAS) are a broad class of hundreds of fluorinated chems. with environmental health concerns due to their widespread presence and persistence in the environment. Several of these chems. have been comprehensively studied for exptl. toxicity, environmental fate and exposure, and human epidemiol.; however, most chems. have limited or no data available. To inform methods for prioritizing these data-poor chems. for detailed toxicity studies, we evaluated 142 PFAS using an in vitro screening platform consisting of two multiplexed transactivation assays encompassing 81 diverse transcription factor activities and tested in concn.-response format ranging from 137 nM to 300μM. Results showed activity for various nuclear receptors, including three known PFAS targets--specifically estrogen receptor alpha and peroxisome proliferator receptors alpha and gamma. We also report activity against the retinoid X receptor beta, the key heterodimeric partner of type II, non-steroidal nuclear receptors. Addnl. activities were found against the pregnane X receptor, nuclear receptor related-1 protein, and nuclear factor erythroid 2-related factor 2, a sensor of oxidative stress. Using orthogonal assay approaches, we confirmed activity of representative PFAS against several of these targets. Finally, we identified key PFAS structural features assocd. with nuclear receptor activity that can inform future predictive models for use in prioritizing chems. for risk assessment and in the design of new structures devoid of biol. activity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVejsL7M&md5=422a0baefb73b2fe2d59755e65821c3e
    15. 15
      United States Environmental Protection Agency, PFAS|EPA: PFAS Structures in DSSTox (update August 2022). https://comptox.epa.gov/dashboard/chemical-lists/PFASSTRUCTV5 (accessed March 14, 2024).
      There is no corresponding record for this reference.
    16. 16
      Cao, Y. X.; Ng, C. Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review. Environ. Sci.: Processes Impacts 2021, 23, 1623– 1640,  DOI: 10.1039/D1EM00228G
      16
      Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review
      Cao, Yuexin; Ng, Carla
      Environmental Science: Processes & Impacts (2021), 23 (11), 1623-1640CODEN: ESPICZ; ISSN:2050-7895. (Royal Society of Chemistry)
      A review. Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chems. colloquially known as "forever chems." because of their high persistence. PFAS have been detected in the blood, liver, kidney, heart, muscle and brain of various species. Although brain is not a dominant tissue for PFAS accumulation compared to blood and liver, adverse effects of PFAS on brain functions have been identified. Here, we review studies related to the absorption, accumulation, distribution and toxicity of PFAS in the brain. We summarize evidence on two potential mechanisms of PFAS entering the brain: initiating blood-brain barrier (BBB) disassembly through disrupting tight junctions and relying on transporters located at the BBB. PFAS with diverse structures and properties enter and accumulate in the brain with varying efficiencies. Compared to long-chain PFAS, short-chain PFAS may not cross cerebral barriers effectively. According to biomonitoring studies and PFAS exposure expts., PFAS can accumulate in the brain of humans and wildlife species. With respect to the distribution of PFAS in specific brain regions, the brain stem, hippocampus, hypothalamus, pons/medulla and thalamus are dominant for PFAS accumulation. The accumulation and distribution of PFAS in the brain may lead to toxic effects in the central nervous system (CNS), including PFAS-induced behavioral and cognitive disorders. The specific mechanisms underlying such PFAS-induced neurotoxicity remain to be explored, but two major potential mechanisms based on current understanding are PFAS effects on calcium homeostasis and neurotransmitter alterations in neurons. Based on the information available about PFAS uptake, accumulation, distribution and impacts on the brain, PFAS have the potential to enter and accumulate in the brain at varying levels. The balance of existing studies shows there is some indication of risk in animals, while the human evidence is mixed and warrants further scrutiny.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvF2isrvF&md5=10fe32a2c1557e7b0a93d92c02183219
    17. 17
      Delcourt, N.; Pouget, A.-M.; Grivaud, A.; Nogueira, L.; Larvor, F.; Marchand, P.; Schmidt, E.; Le Bizec, B. First Observations of a Potential Association Between Accumulation of Per- and Polyfluoroalkyl Substances in the Central Nervous System and Markers of Alzheimer’s Disease. J. Gerontol., Ser. A 2024, 79, glad208  DOI: 10.1093/gerona/glad208
      There is no corresponding record for this reference.
    18. 18
      Wielsøe, M.; Long, M.; Ghisari, M.; Bonefeld-Jørgensen, E. C. Perfluoroalkylated substances (PFAS) affect oxidative stress biomarkers in vitro. Chemosphere 2015, 129, 239– 245,  DOI: 10.1016/j.chemosphere.2014.10.014
      18
      Perfluoroalkylated substances (PFAS) affect oxidative stress biomarkers in vitro
      Wielsoe Maria; Long Manhai; Ghisari Mandana; Bonefeld-Jorgensen Eva C
      Chemosphere (2015), 129 (), 239-45 ISSN:.
      Perfluoroalkylated substances (PFAS) have been widely used since 1950s and humans are exposed through food, drinking water, consumer products, dust, etc. The long-chained PFAS are persistent in the environment and accumulate in wildlife and humans. They are suspected carcinogens and a potential mode of action is through generation of oxidative stress. Seven long-chained PFAS found in human serum were investigated for the potential to generate reactive oxygen species (ROS), induce DNA damage and disturb the total antioxidant capacity (TAC). The tested PFAS were perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluoroctanoic acid (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA). Using the human hepatoma cell line (HepG2) and an exposure time of 24h we found that all three endpoints were affected by one or more of the compounds. PFHxS, PFOA, PFOS and PFNA showed a dose dependent increase in DNA damage in the concentration range from 2×10(-7) to 2×10(-5)M determined by the comet assay. Except for PFDoA, all the other PFAS increased ROS generation significantly. For PFHxS and PFUnA the observed ROS increases were dose-dependent. Cells exposed to PFOA were found to have a significant lower TAC compared with the solvent control, whereas a non-significant trend in TAC decrease was observed for PFOS and PFDoA and an increase tendency for PFHxS, PFNA and PFUnA. Our results indicate a possible genotoxic and cytotoxic potential of the PFAS in human liver cells.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MzjtVejuw%253D%253D&md5=1eb430b05c182c1f77c29f9beda4afa8
    19. 19
      Fang, X.; Wu, C.; Li, H.; Yuan, W.; Wang, X. Elevation of intracellular calcium and oxidative stress is involved in perfluorononanoic acid–induced neurotoxicity. Toxicol. Ind. Health 2018, 34, 139– 145,  DOI: 10.1177/0748233717742262
      There is no corresponding record for this reference.

      DOI 0.1177/0748233717742262.

    20. 20
      Behr, A. C.; Plinsch, C.; Braeuning, A.; Buhrke, T. Activation of human nuclear receptors by perfluoroalkylated substances (PFAS). Toxicol. in Vitro 2020, 62, 104700  DOI: 10.1016/j.tiv.2019.104700
      20
      Activation of human nuclear receptors by perfluoroalkylated substances (PFAS)
      Behr Anne-Cathrin; Plinsch Christin; Braeuning Albert; Buhrke Thorsten
      Toxicology in vitro : an international journal published in association with BIBRA (2020), 62 (), 104700 ISSN:.
      Perfluoralkylated substances (PFAS) such as perfluorooctanoic acid (PFOA) or perfluorooctanesulfonic acid (PFOS) are used to produce, e.g., surface coatings with water- and dirt-repellent properties. These substances have been shown to be hepatotoxic in rodents, and the mechanism of action is mostly attributed to the PFAS-mediated activation of the peroxisome proliferator-activated receptor alpha (PPARα). In the present study, we investigated by using luciferase-based reporter gene assays whether PFOA, PFOS and six alternative PFAS can activate, in addition to PPARα, eight other human nuclear receptors. All tested PFAS except for perfluorobutanesulfonic acid (PFBS) were able to activate human PPARα. Perfluoro-2-methyl-3-oxahexanoic acid (PMOH) and 3H-perfluoro-3-[(3-methoxypropoxy) propanoic acid] (PMPP) were weak agonists of human PPARγ. The other human nuclear receptors (PPARδ, CAR, PXR, FXR, LXRα, RXRα and RARα) were not affected by any PFAS tested in this study. Although PMOH was more effective than PFOA in stimulating PPARα in the transactivation assay, it was less effective in stimulating PPARα-dependent target gene expression in human HepG2 hepatocarcinoma cells. Notably, any effect observed in this in vitro study only occurred at concentrations higher than 10 μM of the respective PFAS which is in all cases several magnitudes above the average blood concentration in the Western population. Thus, the results suggest that nuclear receptor activation may only play a minor role in potential PFAS-mediated adverse effects in humans.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MjktFahtg%253D%253D&md5=6199bb0d4cce237ca78569c9aec11fb1
    21. 21
      Brown-Leung, J. M.; Cannon, J. R. Neurotransmission targets of per-and polyfluoroalkyl substance neurotoxicity: mechanisms and potential implications for adverse neurological outcomes. Chem. Res. Toxicol. 2022, 35, 1312– 1333,  DOI: 10.1021/acs.chemrestox.2c00072
      There is no corresponding record for this reference.
    22. 22
      Marchese, M. J.; Zhu, T.; Hawkey, A. B.; Wang, K.; Yuan, E.; Wen, J.; Be, S. E.; Levin, E. D.; Feng, L. Prenatal and perinatal exposure to Per- and polyfluoroalkyl substances (PFAS)-contaminated drinking water impacts offspring neurobehavior and development. Sci. Total Environ. 2024, 917, 170459  DOI: 10.1016/j.scitotenv.2024.170459
      There is no corresponding record for this reference.
    23. 23
      Maxwell, D. L.; Oluwayiose, O. A.; Houle, E.; Roth, K.; Nowak, K.; Sawant, S.; Paskavitz, A. L.; Liu, W.; Gurdziel, K.; Petriello, M. C.; Richard Pilsner, J. Mixtures of per- and polyfluoroalkyl substances (PFAS) alter sperm methylation and long-term reprogramming of offspring liver and fat transcriptome. Environ. Int. 2024, 186, 108577  DOI: 10.1016/j.envint.2024.108577
      There is no corresponding record for this reference.
    24. 24
      Berntsen, H. F.; Berg, V.; Thomsen, C.; Ropstad, E.; Zimmer, K. E. The design of an environmentally relevant mixture of persistent organic pollutants for use in in vivo and in vitro studies. J. Toxicol. Environ. Health 2017, 80, 1002– 1016,  DOI: 10.1080/15287394.2017.1354439
      There is no corresponding record for this reference.
    25. 25
      Berntsen, H. F.; Duale, N.; Bjorlund, C. G.; Rangel-Huerta, O. D.; Dyrberg, K.; Hofer, T.; Rakkestad, K. E.; Ostby, G.; Halsne, R.; Boge, G.; Paulsen, R. E.; Myhre, O.; Ropstad, E. Effects of a human-based mixture of persistent organic pollutants on the in vivo exposed cerebellum and cerebellar neuronal cultures exposed in vitro. Environ. Int.. 2021, 146, 106240  DOI: 10.1016/j.envint.2020.106240
      There is no corresponding record for this reference.
    26. 26
      McCarthy, C. J.; Roark, S. A.; Middleton, E. T. Considerations for toxicity experiments and risk assessments with PFAS mixtures. Integr. Environ. Assess. Manage. 2021, 17, 697– 704,  DOI: 10.1002/ieam.4415
      There is no corresponding record for this reference.
    27. 27
      Sadrabadi, F.; Alarcan, J.; Sprenger, H.; Braeuning, A.; Buhrke, T. Impact of perfluoroalkyl substances (PFAS) and PFAS mixtures on lipid metabolism in differentiated HepaRG cells as a model for human hepatocytes. Arch. Toxicol. 2024, 98, 507– 524,  DOI: 10.1007/s00204-023-03649-3
      There is no corresponding record for this reference.
    28. 28
      Bopp, S. K.; Kienzler, A.; Richarz, A. N.; van der Linden, S. C.; Paini, A.; Parissis, N.; Worth, A. P. Regulatory assessment and risk management of chemical mixtures: challenges and ways forward. Crit. Rev. Toxicol. 2019, 49, 174– 189,  DOI: 10.1080/10408444.2019.1579169
      There is no corresponding record for this reference.
    29. 29
      Backhaus, T.; Faust, M. Predictive Environmental Risk Assessment of Chemical Mixtures: A Conceptual Framework. Environ. Sci. Technol. 2012, 46, 2564– 2573,  DOI: 10.1021/es2034125
      29
      Predictive environmental risk assessment of chemical mixtures: A conceptual framework
      Backhaus, Thomas; Faust, Michael
      Environmental Science & Technology (2012), 46 (5), 2564-2573CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
      Environmental risks of chems. are still often assessed substance-by-substance, neglecting mixt. effects. This may result in risk underestimations, as the typical exposure is toward multicomponent chem. "cocktails". The two well established mixt. toxicity concepts (Concn. Addn. (CA) and Independent Action (IA)) are used for providing a tiered outline for environmental hazard and risk assessments of mixts., focusing on general industrial chems. and assuming that the "base set" of data (EC50s for algae, crustaceans, fish) is available. As mixt. toxicities higher than predicted by CA are rare findings, applying CA is suggested as a precautious first tier, irresp. of the modes/mechanisms of action of the mixt. components. This study proves that summing up PEC/PNEC ratios might serve as a justifiable CA-approxn., in order to est. in a first tier assessment whether there is a potential risk for an exposed ecosystem if only base-set data are available. This makes optimum use of existing single substance assessments as more demanding mixt. investigations are requested only if there are first indications of an environmental risk. This study suggests to call for mode-of-action driven analyses only if error estns. indicate the possibility for substantial differences between CA- and IA-based assessments.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XntFKjtg%253D%253D&md5=50df097faa36f7d58918e9817d32caf9
    30. 30
      Martin, O.; Scholze, M.; Ermler, S.; McPhie, J.; Bopp, S. K.; Kienzler, A.; Parissis, N.; Kortenkamp, A. Ten years of research on synergisms and antagonisms in chemical mixtures: A systematic review and quantitative reappraisal of mixture studies. Environ. Int. 2021, 146, 106206  DOI: 10.1016/j.envint.2020.106206
      30
      Ten years of research on synergisms and antagonisms in chemical mixtures: A systematic review and quantitative reappraisal of mixture studies
      Martin, Olwenn; Scholze, Martin; Ermler, Sibylle; McPhie, Joanne; Bopp, Stephanie K.; Kienzler, Aude; Parissis, Nikolaos; Kortenkamp, Andreas
      Environment International (2021), 146 (), 106206CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
      A review. Several reviews of synergisms and antagonisms in chem. mixts. have concluded that synergisms are relatively rare. However, these reviews focused on mixts. composed of specific groups of chems., such as pesticides or metals and on toxicity endpoints mostly relevant to ecotoxicol. Doubts remain whether these findings can be generalised. A systematic review not restricted to specific chem. mixts. and including mammalian and human toxicity endpoints is missing. We conducted a systematic review and quant. reappraisal of 10 years' of exptl. mixt. studies to investigate the frequency and reliability of evaluations of mixt. effects as synergistic or antagonistic. Unlike previous reviews, we did not limit our efforts to certain groups of chems. or specific toxicity outcomes and covered mixt. studies relevant to ecotoxicol. and human/mammalian toxicol. published between 2007 and 2017. We undertook searches for peer-reviewed articles in PubMed, Web of Science, Scopus, GreenFile, ScienceDirect and Toxline and included studies of controlled exposures of environmental chem. pollutants, defined as unintentional exposures leading to unintended effects. Studies with viruses, prions or therapeutic agents were excluded, as were records with missing details on chems.' identities, toxicities, doses, or concns. To examine the internal validity of studies we developed a risk-of-bias tool tailored to mixt. toxicol. For a subset of 388 entries that claimed synergisms or antagonisms, we conducted a quant. reappraisal of authors' evaluations by deriving ratios of predicted and obsd. effective mixt. doses (concns.). Our searches produced an inventory of 1220 mixt. expts. which we subjected to subgroup analyses. Approx. two thirds of studies did not incorporate more than 2 components. Most expts. relied on low-cost assays with readily quantifiable endpoints. Important toxicity outcomes of relevance for human risk assessment (e.g. carcinogenicity, genotoxicity, reproductive toxicity, immunotoxicity, neurotoxicity) were rarely addressed. The proportion of studies that declared additivity, synergism or antagonisms was approx. equal (one quarter each); the remaining quarter arrived at different evaluations. About half of the 1220 entries were rated as "definitely" or "probably" low risk of bias. Strikingly, relatively few claims of synergistic or antagonistic effects stood up to scrutiny in terms of deviations from expected additivity that exceed the boundaries of acceptable between-study variability. In most cases, the obsd. mixt. doses were not more than two-fold higher or lower than the predicted additive doses. Twenty percent of the entries (N = 78) reported synergisms in excess of that degree of deviation. Our efforts of pinpointing specific factors that predispose to synergistic interactions confirmed previous concerns about the synergistic potential of combinations of triazine, azole and pyrethroid pesticides at environmentally relevant doses. New evidence of synergisms with endocrine disrupting chems. and metal compds. such as chromium (VI) and nickel in combination with cadmium has emerged. These specific cases of synergisms apart, our results confirm the utility of default application of the dose (concn.) addn. concept for predictive assessments of simultaneous exposures to multiple chems. However, this strategy must be complemented by an awareness of the synergistic potential of specific classes of chems. Our conclusions only apply to the chem. space captured in published mixt. studies which is biased towards relatively well-researched chems.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitlemsr3J&md5=a7bfd5918f30642c4fb721846bcc3ca6
    31. 31
      Spinu, N.; Bal-Price, A.; Cronin, M. T. D.; Enoch, S. J.; Madden, J. C.; Worth, A. P. Development and analysis of an adverse outcome pathway network for human neurotoxicity. Arch. Toxicol. 2019, 93, 2759– 2772,  DOI: 10.1007/s00204-019-02551-1
      31
      Development and analysis of an adverse outcome pathway network for human neurotoxicity
      Spinu, Nicoleta; Bal-Price, Anna; Cronin, Mark T. D.; Enoch, Steven J.; Madden, Judith C.; Worth, Andrew P.
      Archives of Toxicology (2019), 93 (10), 2759-2772CODEN: ARTODN; ISSN:0340-5761. (Springer)
      An adverse outcome pathway (AOP) network is an attempt to represent the complexity of systems toxicol. This study illustrates how an AOP network can be derived and analyzed in terms of its topol. features to guide research and support chem. risk assessment. A four-step workflow describing general design principles and applied design principles was established and implemented. An AOP network linking nine linear AOPs was mapped and made available in AOPXplorer. The resultant AOP network was modelled and analyzed in terms of its topol. features, including level of degree, eccentricity and betweenness centrality. Several well-connected KEs were identified, and cell injury/death was established as the most hyperlinked KE across the network. The derived network expands the utility of linear AOPs to better understand signalling pathways involved in developmental and adult/ageing neurotoxicity. The results provide a solid basis to guide the development of in vitro test method batteries, as well as further quant. modeling of key events (KEs) and key event relationships (KERs) in the AOP network, with an eventual aim to support hazard characterization and chem. risk assessment.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1eksb%252FM&md5=10fea911e316d1f08d448c53b855fc37
    32. 32
      Masjosthusmann, S.; Blum, J.; Bartmann, K.; Dolde, X.; Holzer, A.-K.; Stürzl, L.-C.; Keßel, E. H.; Förster, N.; Dönmez, A.; Klose, J.; Pahl, M.; Waldmann, T.; Bendt, F.; Kisitu, J.; Suciu, I.; Hübenthal, U.; Mosig, A.; Leist, M.; Fritsche, E. Establishment of an a priori protocol for the implementation and interpretation of an in-vitro testing battery for the assessment of developmental neurotoxicity. EFSA Supporting Publ. 2020, 17, 1938E  DOI: 10.2903/sp.efsa.2020.EN-1938
      There is no corresponding record for this reference.
    33. 33
      Carstens, K. E.; Freudenrich, T.; Wallace, K.; Choo, S.; Carpenter, A.; Smeltz, M.; Clifton, M. S.; Henderson, W. M.; Richard, A. M.; Patlewicz, G.; Wetmore, B. A.; Friedman, K. P.; Shafer, T. Evaluation of Per- and Polyfluoroalkyl Substances (PFAS) In Vitro Toxicity Testing for Developmental Neurotoxicity. Chem. Res. Toxicol. 2023, 36, 402– 419,  DOI: 10.1021/acs.chemrestox.2c00344
      There is no corresponding record for this reference.
    34. 34
      Evans, N.; Conley, J. M.; Cardon, M.; Hartig, P.; Medlock-Kakaley, E.; Gray, L. E. In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays. Toxicol. Appl. Pharmacol. 2022, 449, 116136  DOI: 10.1016/j.taap.2022.116136
      34
      In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays
      Evans, Nicola; Conley, Justin M.; Cardon, Mary; Hartig, Phillip; Medlock-Kakaley, Elizabeth; Gray, L. Earl Jr
      Toxicology and Applied Pharmacology (2022), 449 (), 116136CODEN: TXAPA9; ISSN:0041-008X. (Elsevier Inc.)
      Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPARα), however, addnl. work is needed to characterize PFAS activity on PPAR gamma (PPARγ) and other nuclear receptors. We utilized in vitro assays with either human or rat PPARα or PPARγ ligand binding domains to evaluate 16 PFAS (HFPO-DA, HFPO-DA-AS, NBP2, PFMOAA, PFHxA, PFOA, PFNA, PFDA, PFOS, PFBS, PFHxS, PFOSA, EtPFOSA, and 4:2, 6:2 and 8:2 FTOH), 3 endogenous fatty acids (oleic, linoleic, and octanoic), and 3 pharmaceuticals (WY14643, clofibrate, and the metabolite clofibric acid). We also tested chems. for human estrogen receptor (hER) transcriptional activation. Nearly all compds. activated both PPARα and PPARγ in both human and rat ligand binding domain assays, except for the FTOH compds. and PFOSA. Receptor activation and relative potencies were evaluated based on effect concn. 20% (EC20), top percent of max fold induction (pmaxtop), and area under the curve (AUC). HFPO-DA and HFPO-DA-AS were the most potent (lowest EC20, highest pmaxtop and AUC) of all PFAS in rat and human PPARα assays, being slightly less potent than oleic and linoleic acid, while NBP2 was the most potent in rat and human PPARγ assays. Only PFHxS, 8:2 and 6:2 FTOH exhibited hER agonism >20% pmax. In vitro measures of human and rat PPARαand PPARγ activity did not correlate with oral doses or serum concns. of PFAS that induced increases in male rat liver wt. from the National Toxicol. Program 28-d toxicity studies. Data indicate that both PPARα and PPARγ activation may be mol. initiating events that contribute to the in vivo effects obsd. for many PFAS.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsF2qsLfI&md5=2597e1699966d9cff7285ba43d030103
    35. 35
      Qin, W.; Henneberger, L.; Glüge, J.; König, M.; Escher, B. I. Baseline Toxicity Model to Identify the Specific and Nonspecific Effects of Per- and Polyfluoroalkyl Substances in Cell-Based Bioassays. Environ. Sci. Technol. 2024, 58, 5727– 5738,  DOI: 10.1021/acs.est.3c09950
      There is no corresponding record for this reference.
    36. 36
      Deepika, D.; Sharma, R. P.; Schuhmacher, M.; Kumar, V. An integrative translational framework for chemical induced neurotoxicity - a systematic review. Crit. Rev. Toxicol. 2020, 50, 424– 438,  DOI: 10.1080/10408444.2020.1763253
      There is no corresponding record for this reference.
    37. 37
      Delp, J.; Gutbier, S.; Klima, S.; Hoelting, L.; Pinto-Gil, K.; Hsieh, J. H.; Aichem, M.; Klein, K.; Schreiber, F.; Tice, R. R.; Pastor, M.; Behl, M.; Leist, M. A High-Throughput Approach to Identify Specific Neurotoxicants/Developmental Toxicants in Human Neuronal Cell Function Assays. ALTEX 2018, 35, 235– 253,  DOI: 10.14573/altex.1712182
      There is no corresponding record for this reference.
    38. 38
      Lee, J.; Escher, B. I.; Scholz, S.; Schlichting, R. Inhibition of neurite outgrowth and enhanced effects compared to baseline toxicity in SH-SY5Y cells. Arch. Toxicol. 2022, 96, 1039– 1053,  DOI: 10.1007/s00204-022-03237-x
      38
      Inhibition of neurite outgrowth and enhanced effects compared to baseline toxicity in SH-SY5Y cells
      Lee, Jungeun; Escher, Beate I.; Scholz, Stefan; Schlichting, Rita
      Archives of Toxicology (2022), 96 (4), 1039-1053CODEN: ARTODN; ISSN:0340-5761. (Springer)
      Abstr.: Early life exposure to environmental chems. can cause developmental neurotoxicity (DNT). The impairment of key neurodevelopmental processes such as neurite outgrowth inhibition can be used as endpoints for screening of DNT effects. We quantified neurite-specific effects using the ratio of effect concns. for cytotoxicity and neurite outgrowth inhibition (SRcytotoxicity). Baseline cytotoxicity, the minimal toxicity of any chem., was used to quantify enhanced cytotoxicity (toxic ratio, TR) and neuronal-specific toxicity (SRbaseline) by comparing baseline cytotoxicity with the effects on cell viability and neurite outgrowth, resp. The effects on cell viability and neurite length were measured based on image anal. in human neuroblastoma SH-SY5Y cells. Baseline cytotoxicity was predicted from hydrophobicity descriptors using a previously published model for SH-SY5Y cells. Enhanced cytotoxicity and neuronal-specific toxicity were more often obsd. for hydrophilic chems., which indicates that they are more likely to act through specific modes of action (MOA) on cell viability and neurite outgrowth. Hydrophobic chems. showed a tendency to act through baseline toxicity without showing specific or enhanced toxicity, but were highly potent considering their low effect concns. for both cytotoxicity and neurite outgrowth inhibition. The endpoint-specific controls (narciclasine, colchicine, cycloheximide, and rotenone), two carbamates (3-hydroxycarbofuran and carbaryl), and two redox cyclers (diquat and paraquat) showed distinct neurite-specific effects (SRcytotoxicity > 4). By comparing neurite-specific effects with enhanced cytotoxicity, one can explain whether the obsd. effects involve specific inhibition of neurite outgrowth, other specific MOAs, or merely baseline toxicity arising from hydrophobicity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xktlyrtr8%253D&md5=18dee4f05ec437cccdffe0150244c6f0
    39. 39
      Delp, J.; Cediel-Ulloa, A.; Suciu, I.; Kranaster, P.; van Vugt-Lussenburg, B. M. A.; Kos, V. M.; van der Stel, W.; Carta, G.; Bennekou, S. H.; Jennings, P.; van de Water, B.; Forsby, A.; Leist, M. Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch. Toxicol. 2021, 95, 591– 615,  DOI: 10.1007/s00204-020-02970-5
      There is no corresponding record for this reference.
    40. 40
      Cediel-Ulloa, A.; Lupu, D. L.; Johansson, Y.; Hinojosa, M.; Ozel, F.; Ruegg, J. Impact of endocrine disrupting chemicals on neurodevelopment: the need for better testing strategies for endocrine disruption-induced developmental neurotoxicity. Expert Rev. Endocrinol. Metab. 2022, 17, 131– 141,  DOI: 10.1080/17446651.2022.2044788
      There is no corresponding record for this reference.
    41. 41
      Lee, J.; König, M.; Braun, G.; Escher, B. I. Water Quality Monitoring with the Multiplexed Assay MitoOxTox for Mitochondrial Toxicity, Oxidative Stress Response, and Cytotoxicity in AREc32 Cells. Environ. Sci. Technol. 2024, 58, 5716– 5726,  DOI: 10.1021/acs.est.3c09844
      There is no corresponding record for this reference.
    42. 42
      Hawbaker, T.; Vanderhoof, M.; Schmidt, G.; Beal, Y.; Picotte, J.; Takacs, J.; Falgout, J.; Dwyer, J., The Landsat Burned Area products for the conterminous United States (ver. 3.0, March 2022): US Geological Survey data release. https://www.usgs.gov/data/landsat-burned-area-products-conterminous-united-states-ver-30-march-2022 (accessed Aug 25, 2024).
      There is no corresponding record for this reference.
    43. 43
      McAdoo, M. A.; Connock, G. T.; Messinger, T. Occurrence of per- and polyfluoroalkyl substances and inorganic analytes in groundwater and surface water used as sources for public water supply in West Virginia, Scientific Investigations Report 2022–5067 2022–5067; https://pubs.usgs.gov/publication/sir20225067 (accessed July 12, 2023).
      There is no corresponding record for this reference.
    44. 44
      Center for Disease Control (CDC), Biomonitoring Data Tables for Environmental Chemicals. Analysis of Whole Blood, Serum, and Urine Samples, NHANES 1999–2018, www.cdc.gov/exposurereport/data_tables.html. (accessed July 12, 2023).
      There is no corresponding record for this reference.
    45. 45
      Dickman, R. A.; Aga, D. S. Efficient workflow for suspect screening analysis to characterize novel and legacy per-and polyfluoroalkyl substances (PFAS) in biosolids. Anal. Bioanal. Chem. 2022, 414, 4497– 4507,  DOI: 10.1007/s00216-022-04088-2
      There is no corresponding record for this reference.
    46. 46
      Escher, B.; Neale, P.; Leusch, F. Bioanalytical tools in water quality assessment, 2nd ed.; IWA Publishing: London, UK, 2021. www.iwapublishing.com/books/9781789061970/bioanalytical-tools-water-quality-assessment-2nd-edition.
      There is no corresponding record for this reference.
    47. 47
      Stringer, C.; Wang, T.; Michaelos, M.; Pachitariu, M. Cellpose: a generalist algorithm for cellular segmentation. Nat. Methods 2021, 18, 100,  DOI: 10.1038/s41592-020-01018-x
      47
      Cellpose: a generalist algorithm for cellular segmentation
      Stringer, Carsen; Wang, Tim; Michaelos, Michalis; Pachitariu, Marius
      Nature Methods (2021), 18 (1), 100-106CODEN: NMAEA3; ISSN:1548-7091. (Nature Research)
      Abstr.: Many biol. applications require the segmentation of cell bodies, membranes and nuclei from microscopy images. Deep learning has enabled great progress on this problem, but current methods are specialized for images that have large training datasets. Here we introduce a generalist, deep learning-based segmentation method called Cellpose, which can precisely segment cells from a wide range of image types and does not require model retraining or parameter adjustments. Cellpose was trained on a new dataset of highly varied images of cells, contg. over 70,000 segmented objects. We also demonstrate a three-dimensional (3D) extension of Cellpose that reuses the two-dimensional (2D) model and does not require 3D-labeled data. To support community contributions to the training data, we developed software for manual labeling and for curation of the automated results. Periodically retraining the model on the community-contributed data will ensure that Cellpose improves constantly.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXis1Sgs77K&md5=6282c22e874931f6f7b2239926aee7c8
    48. 48
      Stirling, D. R.; Swain-Bowden, M. J.; Lucas, A. M.; Carpenter, A. E.; Cimini, B. A.; Goodman, A. CellProfiler 4: improvements in speed, utility and usability. BMC Bioinformatics 2021, 22, 433  DOI: 10.1186/s12859-021-04344-9
      There is no corresponding record for this reference.
    49. 49
      Sakamuru, S.; Li, X.; Attene-Ramos, M. S.; Huang, R. L.; Lu, J. M.; Shou, L.; Shen, M.; Tice, R. R.; Austin, C. P.; Xia, M. H. Application of a homogenous membrane potential assay to assess mitochondrial function. Physiol. Genomics 2012, 44, 495– 503,  DOI: 10.1152/physiolgenomics.00161.2011
      49
      Application of a homogenous membrane potential assay to assess mitochondrial function
      Sakamuru, Srilatha; Li, Xiao; Attene-Ramos, Matias S.; Huang, Ruili; Lu, Jianming; Shou, Louie; Shen, Min; Tice, Raymond R.; Austin, Christopher P.; Xia, Menghang
      Physiological Genomics (2012), 44 (9), 495-503CODEN: PHGEFP; ISSN:1094-8341. (American Physiological Society)
      Decreases in mitochondrial membrane potential (MMP) have been assocd. with mitochondrial dysfunction that could lead to cell death. The MMP is generated by an electrochem. gradient via the mitochondrial electron transport chain coupled to a series of redox reactions. Measuring the MMP in living cells is commonly used to assess the effect of chems. on mitochondrial function; decreases in MMP can be detected using lipophilic cationic fluorescent dyes. To identify an optimal dye for use in a high-throughput screening (HTS) format, we compared the ability of mitochondrial membrane potential sensor (Mito-MPS), 5,5',6,6'-tetrachloro-1,1',3,3' tetraethylbenzimidazolylcarbocyanine iodide, rhodamine 123, and tetramethylrhodamine to quantify a decrease in MMP in chem. exposed HepG2 cells cultured in 1,536-well plates. Under the conditions used, the optimal dye for this purpose is Mito-MPS. Next, we developed and optimized a homogenous cell-based Mito-MPS assay for use in 1,536-well plate format and demonstrated the utility of this assay by screening 1,280 compds. in the library of pharmacol. active compds. in HepG2 cells using a quant. high-throughput screening platform. From the screening, we identified 14 compds. that disrupted the MMP, with half-maximal potencies ranging from 0.15 to 18 μM; among these, compd. clusters that contained tyrphostin and 3'-substituted indolone analogs exhibited a structure-activity relationship. Our results demonstrate that this homogenous cell-based Mito-MPS assay can be used to evaluate the ability of large nos. of chems. to decrease mitochondrial function.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVKjurbN&md5=0334b08ad3d3b87cc0a47f6e768b8289
    50. 50
      Escher, B. I.; Neale, P. A.; Villeneuve, D. The advantages of linear concentration-response curves for in vitro bioassays with environmental samples. Environ. Toxicol. Chem. 2018, 37, 2273– 2280,  DOI: 10.1002/etc.4178
      50
      The advantages of linear concentration-response curves for in vitro bioassays with environmental samples
      Escher, Beate I.; Neale, Peta A.; Villeneuve, Daniel L.
      Environmental Toxicology and Chemistry (2018), 37 (9), 2273-2280CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
      In vitro assays and high-throughput screening (HTS) tools are increasingly being employed as replacements for animal testing, but most concn.-response curves are still evaluated with models developed for animal testing. The authors argue that application of in vitro assays, particularly reporter gene assays, to environmental samples can benefit from a different approach to concn.-response modeling. First, cytotoxicity often occurs at higher concns., esp. for weakly acting compds. and in complex environmental mixts. with many components. In these cases, specific effects can be masked by cytotoxicity. Second, for many HTS assays, low effect levels can be precisely quantified because of the low variability of controls in cell-based assays and the opportunity to run many concns. and replicates when using high-d. well-plate formats (e.g., 384 or more wells per plate). Hence, the authors recommend focusing concn.-response modeling on the lower portion of the concn.-response curve, which is approx. linear. Effect concns. derived from low-effect level linear concn.-response models facilitate simple derivation of relative effect potencies and the correct application of mixt. toxicity models in the calcn. of bioanal. equiv. concns.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht12ltrvP&md5=4049489a714d0c5d9fcc59fa806dc778
    51. 51
      Qin, W.; Henneberger, L.; Huchthausen, J.; König, M.; Escher, B. I. Role of bioavailability and protein binding of four anionic perfluoroalkyl substances in cell-based bioassays for quantitative in vitro to in vivo extrapolations. Environ. Int. 2023, 173, 107857  DOI: 10.1016/j.envint.2023.107857
      51
      Role of bioavailability and protein binding of four anionic perfluoroalkyl substances in cell-based bioassays for quantitative in vitro to in vivo extrapolations
      Qin, Weiping; Henneberger, Luise; Huchthausen, Julia; Koenig, Maria; Escher, Beate I.
      Environment International (2023), 173 (), 107857CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
      Perfluoroalkyl substances (PFAS) are persistent and pose a risk to human health. High throughput screening (HTS) cell-based bioassays may inform risk assessment of PFAS provided that quant. in vitro to in vivo extrapolation (QIVIVE) can be developed. The QIVIVE ratio is the ratio of nominal (Cnom) or freely dissolved concn. (Cfree) in human blood to Cnom or Cfree in the bioassays. Considering that the concns. of PFAS in human plasma and in vitro bioassays may vary by orders of magnitude, we tested the hypothesis that anionic PFAS bind to proteins concn.-dependently and therefore the binding differs substantially between human plasma and bioassays, which has an impact on QIVIVE. Solid phase microextn. (SPME) with C18-coated fibers served to quantify the Cfree of four anionic PFAS (perfluorobutanoate (PFBA), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS)) in the presence of proteins and lipid, medium components, cells and human plasma over five orders of magnitude in concns. The C18-SPME method was used to quantify the non-linear binding to proteins, human plasma and medium, and the partition consts. to cells. These binding parameters were used to predict Cfree of PFAS in cell bioassays and human plasma by a concn.-dependent mass balance model (MBM). The approach was illustrated with a reporter gene assay indicating activation of the peroxisome proliferator-activated receptor gamma (PPARγ-GeneBLAzer). Blood plasma levels were collected from literature for occupational exposure and the general population. The QIVIVEnom ratios were higher than the QIVIVEfree ratios due to the strong affinity to proteins and large differences in protein contents between human blood and bioassays. For human health risk assessment, the QIVIVEfree ratios of many in vitro assays need to be combined to cover all health relevant endpoints. If Cfree cannot be measured, they can be estd. with the MBM and concn.-dependent distribution ratios.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXkvVOnurw%253D&md5=f798d07da6dc0365eb1fbdadf21eb82c
    52. 52
      Droge, S. T. J. Membrane-Water Partition Coefficients to Aid Risk Assessment of Perfluoroalkyl Anions and Alkyl Sulfates. Environ. Sci. Technol. 2019, 53, 760– 770,  DOI: 10.1021/acs.est.8b05052
      52
      Membrane-Water Partition Coefficients to Aid Risk Assessment of Perfluoroalkyl Anions and Alkyl Sulfates
      Droge, Steven T. J.
      Environmental Science & Technology (2019), 53 (2), 760-770CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
      This study detd. the sorption affinity to artificial phospholipid membranes (KmW) for series of perfluorinated carboxylates (PFCAs), perfluorinated sulfonates (PFSAs), alkyl sulfates (CxSO4), and 1-alkanesulfonates (CxSO3). A sorbent diln. assay with solid supported lipid membranes (SSLM) showed consistent CF2 unit increments of 0.59, and CH2 unit increments of 0.53, for the log KmW of perfluorinated and hydrogenated anions, resp. PFSAs sorbed 0.90 log units stronger than analog PFCAs; CxSO4 sorbed 0.75 log units stronger than analog CxSO3 anions. The log KmW values for the octyl analogs increase in the order H(CH2)8SO3- (1.74) < H(CH2)8SO4- (2.58) < F(CF2)8CO2- (PFNA, 4.04) < F(CF2)8SO3- (PFOS, 4.88). Intrinsic partition ratios detd. on a phospholipid coated HPLC column (IAM-HPLC) closely aligned with SSLM KmW values. COSMO-RS based mol. calcns. of KmW aligned with SSLM KmW values for hydrogenated anions with C8-C14 alkyl chains but strongly underestimated CF2 and CH2 unit increments for C4-C8 based anions. Dividing the crit. narcotic membrane burden of 100 mmol/kg by the exptl. KmW predicts lethal baseline toxicity concns. (LC50,narc). The LC50,narc coincides with the lowest reported acute LC50 values for several anionic surfactants but were on av. about an order of magnitude lower.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFOks7zN&md5=4bf9f4f1a42c91e66dd4865d8f94af73
    53. 53
      Ebert, A.; Allendorf, F.; Berger, U.; Goss, K. U.; Ulrich, N. Membrane/Water Partitioning and Permeabilities of Perfluoroalkyl Acids and Four of their Alternatives and the Effects on Toxicokinetic Behavior. Environ. Sci. Technol. 2020, 54, 5051– 5061,  DOI: 10.1021/acs.est.0c00175
      53
      Membrane/Water Partitioning and Permeabilities of Perfluoroalkyl Acids and Four of their Alternatives and the Effects on Toxicokinetic Behavior
      Ebert, Andrea; Allendorf, Flora; Berger, Urs; Goss, Kai-Uwe; Ulrich, Nadin
      Environmental Science & Technology (2020), 54 (8), 5051-5061CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
      The search for alternatives to bioaccumulative perfluoroalkyl acids (PFAAs) is ongoing. New, still highly fluorinated alternatives are produced in hopes of reducing bioaccumulation. To better est. this bioaccumulative behavior, we performed dialysis expts. and detd. membrane/water partition coeffs., Kmem/w, of six perfluoroalkyl carboxylic acids (PFCAs), three perfluoroalkanesulfonic acids, and four alternatives. We also investigated how passive permeation might influence the uptake kinetics into cells, measuring the passive anionic membrane permeability Pion through planar lipid bilayers for six PFAAs and three alternatives. Exptl. Kmem/w and Pion were both predicted well by the COSMO-RS theory (log RMSE 0.61 and 0.46, resp.). Kmem/w values were consistent with the literature data, and alternatives showed similar sorption behavior as PFAAs. Exptl. Pion values were high enough to explain obsd. cellular uptake by passive diffusion with no need to postulate the existence of active uptake processes. However, predicted pKa and neutral permeabilities suggest that also the permeation of the neutral species should be significant in case of PFCAs. This can have direct consequences on the steady-state distribution of PFAAs across cell membranes and thus toxicity. Consequently, we propose a model to predict pH-dependent baseline toxicity based on Kmem/w, which considers the permeation of both neutral and anionic species.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvVGms7c%253D&md5=5888488c435b3f603b14beb2a96a6af6
    54. 54
      Altenburger, R.; Boedeker, W.; Faust, M.; Grimme, L. H. Regulations for combined effects of pollutants: consequences from risk assessment in aquatic toxicology. Food. Chem. Toxicol. 1996, 34, 1155– 1157,  DOI: 10.1016/S0278-6915(97)00088-4
      54
      Regulations for combined effects of pollutants: consequences from risk assessment in aquatic toxicology
      Altenburger R; Boedeker W; Faust M; Grimme L H
      Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (1996), 34 (11-12), 1155-7 ISSN:0278-6915.
      In the analysis of combined effects two reference concepts are currently considered as equally valid for the assessment of mixture toxicities: these are LOEWE additivity (concentration addition) and BLISS independence (response addition) (Greco et al., 1995). The aim of this study of 137 binary mixtures of pesticides and surfactants using an algal biotest was to find rational procedures for the assessment of mixture toxicities in the aquatic environment. By introducing an index on prediction quality the quantitative relationships between predicted and observed effects are evaluated for each concept. It is shown that LOEWE additivity leads to good predictions of mixture toxicities for most combinations, whereas BLISS independence tends to underestimate mixture toxicities. By this it is reaffirmed that there is a solid basis for forthcoming regulatory activities on mixtures of chemicals.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaK2s3ktVansg%253D%253D&md5=13a713e23c3986e0621968a128c169d3
    55. 55
      Mann, A.; Tyndale, R. F. Cytochrome P450 2D6 enzyme neuroprotects against 1-methyl-4-phenylpyridinium toxicity in SH-SY5Y neuronal cells. Eur. J. Neurosci. 2010, 31, 1185– 1193,  DOI: 10.1111/j.1460-9568.2010.07142.x
      There is no corresponding record for this reference.
    56. 56
      Fernandez-Abascal, J.; Ripullone, M.; Valeri, A.; Leone, C.; Valoti, M. β-Naphtoflavone and Ethanol Induce Cytochrome P450 and Protect towards MPP+ Toxicity in Human Neuroblastoma SH-SY5Y Cells. Int. J. Mol. Sci. 2018, 19, 3369,  DOI: 10.3390/ijms19113369
      There is no corresponding record for this reference.
    57. 57
      Fischer, F. C.; Abele, C.; Henneberger, L.; Klüver, N.; König, M.; Mühlenbrink, M.; Schlichting, R.; Escher, B. I. Characterizing cellular metabolism in high-throughput in vitro reporter gene assays. Chem. Res. Toxicol. 2020, 33, 1770– 17797,  DOI: 10.1021/acs.chemrestox.0c00037
      There is no corresponding record for this reference.
    58. 58
      Warne, M. S. J.; Hawker, D. W. The number of components in a mixture determines whether synergistic and antagonistic or additive toxicity predominate - the funnel hypothesis. Ecotoxicol. Environ. Saf. 1995, 31, 23– 28,  DOI: 10.1006/eesa.1995.1039
      There is no corresponding record for this reference.
    59. 59
      CHEM Trust, Chemical cocktails - The neglected threat from toxic mixtures and how to fix it. https://chemtrust.org/chemicalcocktails/ (accessed June 1, 2024).
      There is no corresponding record for this reference.
    60. 60
      Escher, B. I.; Braun, G.; Zarfl, C. Exploring the concepts of concentration addition and independent action using a linear low-effect mixture model. Environ. Toxicol. Chem. 2020, 39, 2552– 2559,  DOI: 10.1002/etc.4868
      60
      Exploring the Concepts of Concentration Addition and Independent Action Using a Linear Low-Effect Mixture Model
      Escher, Beate; Braun, Georg; Zarfl, Christiane
      Environmental Toxicology and Chemistry (2020), 39 (12), 2552-2559CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
      Chems. emitted into the environment are typically present at low concns. but may act together in mixts. Concn.-response curves of in vitro bioassays were often linear for effect levels <30%, and the predictions for concn. addn. (CA) of similarly acting chems. and for independent action (IA) of dissimilarly acting chems. overlapped. We derived a joint CA/IA mixt. model for the low-effect level portion of concn.-response curves. In a first case study, we evaluated the cytotoxicity of over 200 mixts. of up to 17 components that were mixed in concn. ratios as they occurred in river water. The predictions of the full IA model were indistinguishable from the predictions of the full CA model up to 10% effect, confirming the applicability of the joint CA/IA mixt. model at low effect levels. In a second case study, we evaluated if environmental concns. trigger effects at levels low enough for the joint CA/IA mixt. model to apply. The detected concns. were scaled by their toxic potencies to est. the mixt. effect of the detected chems. in a complex mixt. In 86% of 156 samples the effects fell in the validity range of the joint CA/IA mixt. model (<10% effect level), confirming the CA assumption for toxic unit summation. The joint CA/IA mixt. model is not suitable for testing specific mixt. hypotheses and interactions of chems. in mixts., where more refined models are required; but it is helpful for the interpretation of effects of complex (multicomponent) environmental mixts., esp. for water samples with relatively low effect level. Environ Toxicol Chem 2020;00:1-8. 2020 The Authors. Environmental Toxicol. and Chem. published by Wiley Periodicals LLC on behalf of SETAC.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFWis7fJ&md5=4c2ddddc298f9d28c965d46d8444c4c0
    61. 61
      Kim, S.; Kang, K.; Kim, H.; Seo, M. In Vitro Toxicity Screening of Fifty Complex Mixtures in HepG2 Cells. Toxics 2024, 12, 126,  DOI: 10.3390/toxics12020126
      There is no corresponding record for this reference.
    62. 62
      Cedergreen, N. Quantifying synergy: A systematic review of mixture toxicity studies within environmental toxicology. PLoS One 2014, 9, e96580  DOI: 10.1371/journal.pone.0096580
      62
      Quantifying synergy: a systematic review of mixture toxicity studies within environmental toxicology
      Cedergreen, Nina
      PLoS One (2014), 9 (5), e96580/1-e96580/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      A review. Cocktail effects and synergistic interactions of chems. in mixts. are an area of great concern to both the public and regulatory authorities. The main concern is whether some chems. can enhance the effect of other chems., so that they jointly exert a larger effect than predicted. This phenomenon is called synergy. Here we present a review of the scientific literature on three main groups of environmentally relevant chem. toxicants: pesticides, metal ions and antifouling compds. The aim of the review is to det. 1) the frequency of synergy, 2) the extent of synergy, 3) whether any particular groups or classes of chems. tend to induce synergy, and 4) which physiol. mechanisms might be responsible for this synergy. Synergy is here defined as mixts. with min. two-fold difference between obsd. and predicted effect concns. using Concn. Addn. (CA) as a ref. model and including both lethal and sub-lethal endpoints. The results showed that synergy occurred in 7%, 3% and 26% of the 194, 21 and 136 binary pesticide, metal and antifoulants mixts. included in the data compilation on frequency. The difference between obsd. and predicted effect concns. was rarely more than 10-fold. For pesticides, synergistic mixts. included cholinesterase inhibitors or azole fungicides in 95% of 69 described cases. Both groups of pesticides are known to interfere with metabolic degrdn. of other xenobiotics. For the four synergistic metal and 47 synergistic antifoulant mixts. the pattern in terms of chem. groups inducing synergy was less clear. Hypotheses in terms of mechanisms governing these interactions are discussed. It was concluded that true synergistic interactions between chems. are rare and often occur at high concns. Addressing the cumulative rather than synergistic effect of co-occurring chems., using std. models as CA, is therefore regarded as the most important step in the risk assessment of chem. cocktails.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVKgsL%252FJ&md5=6a8cbc65fb2485c16d95e5d4d4aee7fe
    63. 63
      Bil, W.; Govarts, E.; Zeilmaker, M. J.; Woutersen, M.; Bessems, J.; Ma, Y.; Thomsen, C.; Haug, L. S.; Lignell, S.; Gyllenhammar, I.; Murinova, L. P.; Fabelova, L.; Tratnik, J. S.; Kosjek, T.; Gabriel, C.; Sarigiannis, D.; Pedraza-Diaz, S.; Esteban-Lopez, M.; Castano, A.; Rambaud, L.; Riou, M.; Franken, C.; Colles, A.; Vogel, N.; Kolossa-Gehring, M.; Halldorsson, T. I.; Uhl, M.; Schoeters, G.; Santonen, T.; Vinggaard, A. M. Approaches to mixture risk assessment of PFASs in the European population based on human hazard and biomonitoring data. Int. J. Hyg. Environ. Health 2023, 247, 114071  DOI: 10.1016/j.ijheh.2022.114071
      There is no corresponding record for this reference.
    64. 64
      Bil, W.; Zeilmaker, M.; Fragki, S.; Lijzen, J.; Verbruggen, E.; Bokkers, B. Risk Assessment of Per- and Polyfluoroalkyl Substance Mixtures: A Relative Potency Factor Approach. Environ. Toxicol. Chem. 2021, 40, 859,  DOI: 10.1002/etc.4835
      64
      Risk Assessment of Per- and Polyfluoroalkyl Substance Mixtures: A Relative Potency Factor Approach
      Bil, Wieneke; Zeilmaker, Marco; Fragki, Styliani; Lijzen, Johannes; Verbruggen, Eric; Bokkers, Bas
      Environmental Toxicology and Chemistry (2021), 40 (3), 859-870CODEN: ETOCDK; ISSN:0730-7268. (Wiley-Blackwell)
      Per- and polyfluoroalkyl substances (PFAS) often occur together as contamination in exposure media such as drinking water or food. The relative potency factor (RPF) methodol. facilitates the risk assessment of mixt. exposure. A database of liver endpoints was established for 16 PFAS, using data with the same species (rat), sex (male), and exposure route (oral) and comparable exposure duration (42-90 d). Dose-response anal. was applied to derive the relative potencies of 3 perfluoroalkyl sulfonic acids (perfluorobutane sulfonic acid, perfluorohexane sulfonic acid, perfluorooctane sulfonic acid), 8 perfluoroalkyl carboxylic acids (perfluorobutanoic acid, perfluorohexanoic acid, perfluorononanoic acid, perfluoroundecanoic acid, perfluorododecanoic acid, perfluorotetradecanoic acid, perfluorohexadecanoic acid, perfluorooctadecanoic acid), 2 perfluoroalkyl ether carboxylic acids (tetrafluoro-2-[heptafluoropropoxy]propanoic acid, 3H-perfluoro-3-[(3-methoxy-propoxy)propanoic acid]), and 2 fluorotelomer alcs. (6:2 FTOH, 8:2 FTOH) compared to perfluorooctanoic acid (PFOA), based on liver effects. In addn., the RPFs of 7 other perfluoroalkyl acids were estd. based on read-across. This resulted in the relative potencies of 22 PFAS compared to the potency of index compd. PFOA. The obtained RPFs can be applied to measured PFAS quantities, resulting in the sum of PFOA equiv. in a mixt. This sum can be compared with an established PFOA concn. limit (e.g., in drinking water or food) or an external health-based guidance value (e.g., tolerable daily intake, acceptable daily intake, or ref. dose) to est. the risk resulting from direct oral exposure to mixts. Assessing mixt. exposure is particularly relevant for PFAS, with omnipresent exposure in our daily lives.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhslKhurbF&md5=9bedd6f8f0ab0461bc151f98aeed87b5
    65. 65
      Colnot, T.; Dekant, W. Commentary: cumulative risk assessment of perfluoroalkyl carboxylic acids and perfluoralkyl sulfonic acids: what is the scientific support for deriving tolerable exposures by assembling 27 PFAS into 1 common assessment group?. Arch. Toxicol. 2022, 96, 3127– 3139,  DOI: 10.1007/s00204-022-03336-9
      There is no corresponding record for this reference.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.est.4c06017.

    • Additional information on chemicals, experimental details, concentration–response curves, additional analyses (PDF)


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.