Associations of Serum Perfluoroalkyl Substances and Placental Human Chorionic Gonadotropin in Early Pregnancy, Measured in the UPSIDE Study in Rochester, New York.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are widely detected in pregnant women and associated with adverse outcomes related to impaired placental function. Human chorionic gonadotropin (hCG) is a dimeric glycoprotein hormone that can indicate placental toxicity. OBJECTIVES: Our aim was to quantify the association of serum PFAS with placental hCG, measured as an intact molecule (hCG), as free alpha-(hCGα) and beta-subunits (hCGß), and as a hyperglycosylated form (h-hCG), and evaluate effect measure modification by social determinants and by fetal sex. METHODS: Data were collected from 326 pregnant women enrolled from 2015 to 2019 in the UPSIDE study in Rochester, New York. hCG forms were normalized for gestational age at the time of blood draw in the first trimester [multiple of the median (MoM)]. Seven PFAS were measured in second-trimester maternal serum. Multivariate imputation by chained equations and inverse probability weighting were used to evaluate robustness of linear associations. PFAS mixture effects were estimated by Bayesian kernel machine regression. RESULTS: Perfluorohexane sulfonic acid (PFHxS) [hCGß: 0.29 log MoM units per log PFHxS; 95% confidence interval (CI): 0.08, 0.51] and perfluorodecanoic acid (PFDA) (hCG: -0.09; 95% CI: -0.16, -0.02) were associated with hCG in the single chemical and mixture analyses. The PFAS mixture was negatively associated with hCGα and positively with hCGß. Subgroup analyses revealed that PFAS associations with hCG differed by maternal race/ethnicity and education. Perfluoropentanoic acid (PFPeA) was associated with hCGß only in Black participants (-0.23; 95% CI: -0.37, -0.09) and in participants with high school education or less (-0.14; 95% CI: -0.26, -0.02); conversely, perfluorononanoic acid (PFNA) was negatively associated with hCGα only in White participants (-0.15; 95% CI: -0.27, -0.03) and with hCGß only in participants with a college education or greater (-0.19; 95% CI: -0.36, -0.01). These findings were robust to testing for selection bias, confounding bias, and left truncation bias where PFAS detection frequency was <100%. Two associations were negative in male (and null in female) pregnancies: Perfluoroundecanoic acid (PFUnDA) with hCGα, and PFNA with h-hCG. CONCLUSIONS: Evidence was strongest for the association between PFHxS and PFDA with hCG in all participants and for PFPeA and PFNA within subgroups defined by social determinants and fetal sex. PFAS mixture associations with hCGα and hCGß differed, suggesting subunit-specific types of toxicity and/or regulation. Future studies will evaluate the biological, clinical and public health significance of these findings. https://doi.org/10.1289/EHP12950.

Evaluating contamination of seafood purchased from U.S. retail stores by persistent environmental pollutants, pesticides and veterinary drugs.

Studies have reported health risks associated with seafood contamination, but few data exist on levels in commercially available seafood in the US. To better understand, the magnitude of foodborne exposure and identify vulnerable populations in the US, we measured concentrations of veterinary drugs, persistent organic pollutants (POPs) (polycyclic aromatic hydrocarbons [PAHs], polybrominated diphenyl ethers [PBDEs] and polychlorinated biphenyls [PCBs]), and legacy and current-use pesticides in 46 seafood samples purchased from retail outlets. Measured levels were used to estimate risk based on available maximum residue limits (MRLs) and toxic equivalence (TEQ) factors for analytes. Only seventeen of the 445 analytes were detected, at low substance frequencies. However, half of the samples tested positive for one or more analyte, with total concentrations ranging from below the limit of detection (LOD) to as high as 156 µg/kg wet weight. Based on the risk assessment for individual pesticides and veterinary drugs, the hazard quotients (HQ) were all <1, indicating no risk. However, for the sum of PCB126 and PCB167, two dioxin-like PCBs detected in our samples, the TEQ was nearly two orders of magnitude higher than the WHO limits in one catfish sample. Moreover, vulnerable groups with higher rates of consumption of specific fish types may face higher risks.

Characterization of per- and polyfluoroalkyl substances (PFAS) concentrations in a community-based sample of infants from Samoa.

Per- and polyfluoroalkyl substances (PFAS) are persistent contaminants with documented harmful health effects. Despite increasing research, little attention has been given to studying PFAS contamination in low- and middle-income countries, including Samoa. Using data and biosamples collected through the Foafoaga o le Ola ("Beginning of Life") Study, which recruited a sample of mothers and infants from Samoa, we conducted an exploratory study to describe concentrations of 40 PFAS analytes in infant cord blood collected at birth (n = 66) and infant dried blood spots (DBS) collected at 4 months post-birth (n = 50). Of the 40 PFAS analytes tested, 19 were detected in cord blood, with 10 detected in >50% of samples (PFBA, PFPeA, PFOA, PFNA, PFDA, PFUnA, PFTrDA, PFHxS, PFOS, and 9Cl-PF3ONS); and 12 analytes were detected in DBS, with 3 detected in >50% of samples (PFBA, PFHxS, and PFOS). PFAS concentrations were generally lower than those reported in existing literature, with the exception of PFHxS, which was detected at higher concentrations. In cord blood, we noted suggestive (p < 0.05) or significant (p < 0.006) associations between higher PFHxS and male sex; higher PFPeA and residence in Northwest 'Upolu (NWU) compared to the Apia Urban Area (AUA); lower PFUnA and 9Cl-PF3ONS and greater socioeconomic resources; lower PFOA and higher parity; higher PFDA and higher maternal age; and lower PFUnA, PFTrDA, and 9Cl-PF3ONS and higher maternal BMI. In DBS, we found suggestive (p < 0.05) or significant (p < 0.025) associations between lower PFBA and residence in NWU versus AUA; lower PFBA and PFHxS and higher maternal age; and higher PFBA and higher maternal BMI. Finally, we observed associations between nutrition source at 4 months and DBS PFBA and PFHxS, with formula- or mixed-fed infants having higher concentrations compared to exclusively breastfed infants. This study represents the first characterization of PFAS contamination in Samoa. Additional work in larger samples is needed to identify potentially modifiable determinants of PFAS concentrations, information that is critical for informing environmental and health policy measures.

Mechanisms and Opportunities for Rational In Silico Design of Enzymes to Degrade Per- and Polyfluoroalkyl Substances (PFAS).

Per and polyfluoroalkyl substances (PFAS) present a unique challenge to remediation techniques because their strong carbon-fluorine bonds make them difficult to degrade. This review explores the use of in silico enzymatic design as a potential PFAS degradation technique. The scope of the enzymes included is based on currently known PFAS degradation techniques, including chemical redox systems that have been studied for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) defluorination, such as those that incorporate hydrated electrons, sulfate, peroxide, and metal catalysts. Bioremediation techniques are also discussed, namely the laccase and horseradish peroxidase systems. The redox potential of known reactants and enzymatic radicals/metal-complexes are then considered and compared to potential enzymes for degrading PFAS. The molecular structure and reaction cycle of prospective enzymes are explored. Current knowledge and techniques of enzyme design, particularly radical-generating enzymes, and application are also discussed. Finally, potential routes for bioengineering enzymes to enable or enhance PFAS remediation are considered as well as the future outlook for computational exploration of enzymatic in situ bioremediation routes for these highly persistent and globally distributed contaminants.

Characterization of Per- and Polyfluoroalkyl Substance (PFAS) concentrations in a community-based sample of infants from Samoa.

Per- and polyfluoroalkyl substances (PFAS) are persistent contaminants with documented harmful health effects. Despite increasing research, little attention has been given to studying PFAS contamination in low- and middle-income countries, including Samoa, where there is more recent modernization and potential window to examine earlier stages of PFAS exposure and consequences. Using data and biosamples collected through the Foafoaga o le Ola ("Beginning of Life") Study, which recruited a sample of mothers and infants from Samoa, we conducted an exploratory study to describe concentrations of 40 PFAS analytes in infant cord blood collected at birth (n=66) and dried blood spots (DBS) collected at 4 months post-birth (n=50). Of the 40 PFAS analytes tested, 19 were detected in cord blood, with 11 detected in >10% of samples (PFBA, PFPeA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFTrDA, PFHxS, PFOS, and 9Cl-PF3ONS); 12 analytes were detected in DBS, with 3 detected in >10% of samples (PFBA, PFHxS, and PFOS). PFAS concentrations were generally lower than those reported in existing literature, with the exception of PFHxS, which was detected at higher concentrations. In cord blood, we noted associations between higher PFHxS and male sex, higher PFPeA and residence in Northwest 'Upolu (NWU) compared to the Apia Urban Area (AUA), and lower PFUnA and 9Cl-PF3ONS with greater socioeconomic resources. In DBS, we found associations between higher PFBA and greater socioeconomic resources, and between lower PFBA and PFHxS and residence in NWU versus AUA. However, the latter association did not hold when controlling for socioeconomic resources. Finally, we observed associations between nutrition source at 4 months and DBS PFBA and PFHxS, with formula- or mixed-fed infants having higher concentrations compared to exclusively breastfed infants. This study presents the first evidence of PFAS contamination in Samoa. Additional work in larger samples is needed to identify potentially modifiable determinants of PFAS concentrations, information that is critical for informing environmental and health policy measures.

Assessing per- and polyfluoroalkyl substances in globally sourced food packaging.

The purpose of this study was to investigate the presence and levels of per- and polyfluoroalkyl substances (PFAS) in food packaging originating from different geographic locations. Food packaging samples were extracted and analyzed by targeted analysis with liquid chromatography-mass spectrometry (LC-MS/MS) before and after a total oxidizable precursor (TOP) assay. Additionally, full-scan high resolution MS (HRMS) was used to screen for PFAS not included in the targeted list. Of the 88 food packaging samples, 84% had detectable levels of at least one PFAS prior to oxidation with a TOP assay, with 6:2 fluorotelomer phosphate diester (6:2 diPAP) found most frequently and at the highest levels (224 ng/g). Other frequently detected substances (in 15-17% of samples) were PFHxS, PFHpA and PFDA. Shorter chain perfluorinated carboxylic acids PFHpA (C7), PFPeA (C5) and PFHxS (C6) were present at levels up to 51.3, 24.1 and 18.2 ng/g, respectively. Average ∑PFAS levels were 28.3 ng/g and 381.9 ng/g before and after oxidation with the TOP assay. The 25 samples with highest frequency of detection and amounts of measured PFAS were selected for migration experiments with food simulants to better understand potential dietary exposure. PFHxS, PFHpA, PFHxA and 6:2 diPAP were measured in the food simulants of five samples at concentrations ranging from 0.04 to 12.2 ng/g and at increasing concentrations over the 10-day migration period. To estimate potential exposure to PFAS that had migrated from food packaging samples, weekly intake was calculated and ranged from 0.0006 ng/kg body weight/week for PFHxA exposure in tomato packaging to 1.1200 ng/kg body weight/week for PFHxS exposure in cake paper. These values were below the established EFSA maximum tolerable weekly intake (TWI) of 4.4 ng/kg body weight/week for the sum of PFOA, PFNA, PFHxS and PFOS.

A State-of-the-Science Review of Interactions of Per- and Polyfluoroalkyl Substances (PFAS) with Renal Transporters in Health and Disease: Implications for Population Variability in PFAS Toxicokinetics.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and have been shown to cause various adverse health impacts. In animals, sex- and species-specific differences in PFAS elimination half-lives have been linked to the activity of kidney transporters. However, PFAS molecular interactions with kidney transporters are still not fully understood. Moreover, the impact of kidney disease on PFAS elimination remains unclear. OBJECTIVES: This state-of-the-science review integrated current knowledge to assess how changes in kidney function and transporter expression from health to disease could affect PFAS toxicokinetics and identified priority research gaps that should be addressed to advance knowledge. METHODS: We searched for studies that measured PFAS uptake by kidney transporters, quantified transporter-level changes associated with kidney disease status, and developed PFAS pharmacokinetic models. We then used two databases to identify untested kidney transporters that have the potential for PFAS transport based on their endogenous substrates. Finally, we used an existing pharmacokinetic model for perfluorooctanoic acid (PFOA) in male rats to explore the influence of transporter expression levels, glomerular filtration rate (GFR), and serum albumin on serum half-lives. RESULTS: The literature search identified nine human and eight rat kidney transporters that were previously investigated for their ability to transport PFAS, as well as seven human and three rat transporters that were confirmed to transport specific PFAS. We proposed a candidate list of seven untested kidney transporters with the potential for PFAS transport. Model results indicated PFOA toxicokinetics were more influenced by changes in GFR than in transporter expression. DISCUSSION: Studies on additional transporters, particularly efflux transporters, and on more PFAS, especially current-use PFAS, are needed to better cover the role of transporters across the PFAS class. Remaining research gaps in transporter expression changes in specific kidney disease states could limit the effectiveness of risk assessment and prevent identification of vulnerable populations. https://doi.org/10.1289/EHP11885.

Per- and polyfluoroalkyl substances (PFAS) measured in seafood from a cross-section of retail stores in the United States.

Seafood is a dominant source of human exposure to per- and polyfluoroalkyl substances (PFAS). Existing studies on foodborne PFAS exposure have focused on only a subset of these compounds. Here, we conducted a pilot study to screen 33 PFAS in 46 seafood samples from a cross-section of national and local stores in the US. Low levels of 8 PFAS were measured in 74% of the samples, predominated by PFHxS (59%). Total PFAS ranged between 0.12 and 20 ng/g; highest levels were measured in Estonia-sourced smelt. The highest median levels were of PFOA (0.84 ng/g) with elevated concentrations found in Chinese clams (2.4 ng/g), which exceeds the EU established maximum limits (MLs). Measured levels of PFHxS, PFOA, and PFNA also exceeded MLs in 24%, 7%, and 5% of the samples, respectively. For average consumption levels, exposures were below the EU established tolerable weekly intakes (TWIs). However, for more frequent consumption of flounder, catfish, and cod, exposures exceeded regulations, which warrants identifying vulnerable high seafood consuming populations. Accidental PFBS cross contamination from sample storage bags resulted in 100% detection in samples, highlighting the problem with post-purchase food handling practices such as storage and cooking that could also have a substantial impact on human exposure, potentially in larger amounts than the (sea)food itself.

Understanding impacts of organic contaminants from aquaculture on the marine environment using a chemical fate model.

As demand for sustainable marine aquaculture (mariculture) and marine food supply surges worldwide, there is a growing need for new tools to assess mariculture impacts on local ecosystems, including the cycling of toxic organic contaminants. With this in mind, we developed the Contaminant Fate in Aquaculture-Modified Ecosystems (CFAME) model. The current model was designed to explore the fate of mariculture-derived organic contaminants in the Marlborough Sounds, New Zealand, known for its Chinook salmon farming industry. Model evaluation indicated robust model design, with 80% of modeled concentrations falling within a factor of ten of measured ones for native biota. Model results showed that mariculture was a source of organic contaminants in the sediment even at the Marlborough Sounds regional level and in wild marine fishes with high trophic levels near the farm area. Future research attention should be directed toward measuring chemicals with low log KAW (<0) and high log KOW values (e.g., >3) in sediment, and chemicals with log KOW values of 3-9 in wild fish.

From Protein Sequence to Structure: The Next Frontier in Cross-Species Extrapolation for Chemical Safety Evaluations.

Computational screening for potentially bioactive molecules using advanced molecular modeling approaches including molecular docking and molecular dynamic simulation is mainstream in certain fields like drug discovery. Significant advances in computationally predicting protein structures from sequence information have also expanded the availability of structures for nonmodel species. Therefore, the objective of the present study was to develop an analysis pipeline to harness the power of these bioinformatics approaches for cross-species extrapolation for evaluating chemical safety. The Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool compares protein-sequence similarity across species for conservation of known chemical targets, providing an initial line of evidence for extrapolation of toxicity knowledge. However, with the development of structural models from tools like the Iterative Threading ASSEmbly Refinement (ITASSER), analyses of protein structural conservation can be included to add further lines of evidence and generate protein models across species. Models generated through such a pipeline could then be used for advanced molecular modeling approaches in the context of species extrapolation. Two case examples illustrating this pipeline from SeqAPASS sequences to I-TASSER-generated protein structures were created for human liver fatty acid-binding protein (LFABP) and androgen receptor (AR). Ninety-nine LFABP and 268 AR protein models representing diverse species were generated and analyzed for conservation using template modeling (TM)-align. The results from the structural comparisons were in line with the sequence-based SeqAPASS workflow, adding further evidence of LFABL and AR conservation across vertebrate species. The present study lays the foundation for expanding the capabilities of the web-based SeqAPASS tool to include structural comparisons for species extrapolation, facilitating more rapid and efficient toxicological assessments among species with limited or no existing toxicity data. Environ Toxicol Chem 2023;42:463-474. © 2022 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Understanding inter-individual variability in short-chain chlorinated paraffin concentrations in human blood.

Chlorinated paraffins (CPs), particularly short-chain CPs (SCCPs), have been reported in human blood with high detection frequency and often high variation among individuals. However, factors associated with and their contributions to inter-individual variability in SCCP concentrations in human blood have not been assessed. In this study, we first measured SCCP concentrations in 57 human blood samples collected from individuals living in the same vicinity in China. We then used the PROduction-To-Exposure model to investigate the impacts of variations in sociodemographic data, biotransformation rates, dietary patterns, and indoor contamination on inter-individual variability in SCCP concentrations in human blood. Measured ∑SCCP concentrations varied by a factor of 10 among individuals with values ranging from 122 to 1230 ng/g, wet weight. Model results show that age, sex, body weight, and dietary composition played a minor role in causing variability in ∑SCCP concentrations in human blood given that modeled ∑SCCP concentrations ranged over a factor of 2 - 3 correlated to the variations of these factors. In contrast, variations in the modeled ΣSCCP concentrations increased to factors of 6 and 8 when variability in biotransformation rates and indoor contamination were considered, respectively, indicating these two factors could be the most influential on inter-individual variability in SCCP concentrations in human blood.

Evaluating the Thiessen polygon approach for efficient parameterization of urban stormwater models.

Catchment discretization plays a key role in constructing stormwater models. Traditional methods usually require aerial or topographic data to manually partition the catchment, but this approach is challenging in areas with poor data access. Here, we propose an alternative approach, by drawing Thiessen polygons around sewer nodes to construct a sewershed model. The utility of this approach is evaluated using the EPA's Storm Water Management Model (SWMM) to simulate pipe flow in a sewershed in the City of Pittsburgh. Parameter sensitivities and model uncertainties were explored via Monte Carlo simulations and a simple algorithm applied to calibrate the model. The calibrated model could reliably simulate pipe flow, with a Nash-Sutcliffe efficiency (NSE) of 0.82 when compared to measured flow. The potential influence of sewer data availability on model performance was tested as a function of the number of nodes used to build the model. No statistical differences were observed in model performance when randomly reducing the number of nodes used to build the model (up to 40%). Based on our analyses, the Thiessen polygon approach can be used to construct urban stormwater models and generate good pipe flow simulations even for sewer data limited scenarios.

Modeling the transplacental transfer of small molecules using machine learning: a case study on per- and polyfluorinated substances (PFAS).

BACKGROUND: Despite their large numbers and widespread use, very little is known about the extent to which per- and polyfluoroalkyl substances (PFAS) can cross the placenta and expose the developing fetus. OBJECTIVE: The aim of our study is to develop a computational approach that can be used to evaluate the of extend to which small molecules, and in particular PFAS, can cross to cross the placenta and partition to cord blood. METHODS: We collected experimental values of the concentration ratio between cord and maternal blood (RCM) for 260 chemical compounds and calculated their physicochemical descriptors using the cheminformatics package Mordred. We used the compiled database to, train and test an artificial neural network (ANN). And then applied the best performing model to predict RCM for a large dataset of PFAS chemicals (n = 7982). We, finally, examined the calculated physicochemical descriptors of the chemicals to identify which properties correlated significantly with RCM. RESULTS: We determined that 7855 compounds were within the applicability domain and 127 compounds are outside the applicability domain of our model. Our predictions of RCM for PFAS suggested that 3623 compounds had a log RCM > 0 indicating preferable partitioning to cord blood. Some examples of these compounds were bisphenol AF, 2,2-bis(4-aminophenyl)hexafluoropropane, and nonafluoro-tert-butyl 3-methylbutyrate. SIGNIFICANCE: These observations have important public health implications as many PFAS have been shown to interfere with fetal development. In addition, as these compounds are highly persistent and many of them can readily cross the placenta, they are expected to remain in the population for a long time as they are being passed from parent to offspring. IMPACT: Understanding the behavior of chemicals in the human body during pregnancy is critical in preventing harmful exposures during critical periods of development. Many chemicals can cross the placenta and expose the fetus, however, the mechanism by which this transport occurs is not well understood. In our study, we developed a machine learning model that describes the transplacental transfer of chemicals as a function of their physicochemical properties. The model was then used to make predictions for a set of 7982 per- and polyfluorinated alkyl substances that are listed on EPA's CompTox Chemicals Dashboard. The model can be applied to make predictions for other chemical categories of interest, such as plasticizers and pesticides. Accurate predictions of RCM can help scientists and regulators to prioritize chemicals that have the potential to cause harm by exposing the fetus.

Understanding the dynamics of physiological changes, protein expression, and PFAS in wildlife.

Per- and polyfluoroalkyl substances (PFAS) accumulation and elimination in both wildlife and humans is largely attributed to PFAS interactions with proteins, including but not limited to organic anion transporters (OATs), fatty acid binding proteins (FABPs), and serum proteins such as albumin. In wildlife, changes in the biotic and abiotic environment (e.g. salinity, temperature, reproductive stage, and health status) often lead to dynamic and responsive physiological changes that alter the prevalence and location of many proteins, including PFAS-related proteins. Therefore, we hypothesize that if key PFAS-related proteins are impacted as a result of environmentally induced as well as biologically programmed physiological changes (e.g. reproduction), then PFAS that associate with those proteins will also be impacted. Changes in tissue distribution across tissues of PFAS due to these dynamics may have implications for wildlife studies where these chemicals are measured in biological matrices (e.g., serum, feathers, eggs). For example, failure to account for factors contributing to PFAS variability in a tissue may result in exposure misclassification as measured concentrations may not reflect average exposure levels. The goal of this review is to share general information with the PFAS research community on what biotic and abiotic changes might be important to consider when designing and interpreting a biomonitoring or an ecotoxicity based wildlife study. This review will also draw on parallels from the epidemiological discipline to improve study design in wildlife research. Overall, understanding these connections between biotic and abiotic environments, dynamic protein levels, PFAS levels measured in wildlife, and epidemiology serves to strengthen study design and study interpretation and thus strengthen conclusions derived from wildlife studies for years to come.

Information Requirements under the Essential-Use Concept: PFAS Case Studies.

Per- and polyfluoroalkyl substances (PFAS) are a class of substances for which there are widespread concerns about their extreme persistence in combination with toxic effects. It has been argued that PFAS should only be employed in those uses that are necessary for health or safety or are critical for the functioning of society and where no alternatives are available ("essential-use concept"). Implementing the essential-use concept requires a sufficient understanding of the current uses of PFAS and of the availability, suitability, and hazardous properties of alternatives. To illustrate the information requirements under the essential-use concept, we investigate seven different PFAS uses, three in consumer products and four industrial applications. We investigate how much information is available on the types and functions of PFAS in these uses, how much information is available on alternatives, their performance and hazardous properties and, finally, whether this information is sufficient as a basis for deciding on the essentiality of a PFAS use. The results show (i) the uses of PFAS are highly diverse and information on alternatives is often limited or lacking; (ii) PFAS in consumer products often are relatively easy to replace; (iii) PFAS uses in industrial processes can be highly complex and a thorough evaluation of the technical function of each PFAS and of the suitability of alternatives is needed; (iv) more coordination among PFAS manufacturers, manufacturers of alternatives to PFAS, users of these materials, government authorities, and other stakeholders is needed to make the process of phasing out PFAS more transparent and coherent.

Bayesian Refinement of the Permeability-Limited Physiologically Based Pharmacokinetic Model for Perfluorooctanoic Acid in Male Rats.

Physiologically based pharmacokinetic (PBPK) modeling is a powerful technique to inform risk assessment of xenobiotic substances such as perfluorooctanoic acid (PFOA). In our previous study, a permeability-limited PBPK model was developed to simulate the toxicokinetics and tissue distribution of PFOA in male rats. However, due to limited information on some key model parameters (e.g., protein binding and active transport rates), the uncertainty of the permeability-limited PBPK model was quite high. To address this issue, a hierarchical Bayesian analysis with Markov chain Monte Carlo (MCMC) was applied to reduce the uncertainty of parameters and improve the performance of the PBPK model. With the optimized posterior parameters, the PBPK model was evaluated by comparing its prediction with experimental data from three different studies. The results show that the uncertainties of the posterior model parameters were reduced substantially. In addition, most of the PBPK model predictions were improved: with the posterior parameters, most of the predicted plasma toxicokinetics (e.g., half-life) and tissue distribution fell well within a factor of 2.0 of the experimental data. Finally, the Bayesian framework could provide insights into the molecular mechanisms driving PFOA toxicokinetics: PFOA-protein binding, membrane permeability, and active transport.

A Classification Model to Identify Direct-Acting Mutagenic Polycyclic Aromatic Hydrocarbon Transformation Products.

Polycyclic aromatic hydrocarbons (PAHs) are a complex group of environmental contaminants, many having long environmental half-lives. As these compounds degrade, the changes in their structure can result in a substantial increase in mutagenicity compared to the parent compound. Over time, each individual PAH can potentially degrade into several thousand unique transformation products, creating a complex, constantly evolving set of intermediates. Microbial degradation is the primary mechanism of their transformation and ultimate removal from the environment, and this process can result in mutagenic activation similar to the metabolic activation that can occur in multicellular organisms. The diversity of the potential intermediate structures in PAH-contaminated environments renders hazard assessment difficult for both remediation professionals and regulators. A mixture of structural and energetic descriptors has proven effective in existing studies for classifying which PAH transformation products will be mutagenic. However, most existing studies of environmental PAH mutagens primarily focus on nitrogenated derivatives, which are prevalent in the atmosphere and not as relevant in soil. Additionally, PAH products commonly found in the environment can range from as large as five rings to as small as a single ring, requiring a broadly inclusive methodology to comprehensively evaluate mutagenic potential. We developed a combination of supervised and unsupervised machine learning methods to predict environmentally induced PAH mutagenicity with improved performance over currently available tools. K-means clustering with principal component analysis allows us to identify molecular clusters that we hypothesize to have similar mechanisms of action. Recursive feature elimination identifies the most influential descriptors. The cluster-specific regression outperforms available classifiers in predicting direct-acting mutagens resulting from the microbial biodegradation of PAHs and provides direction for future studies evaluating the environmental hazards resulting from PAH biodegradation.

Absorption, distribution, and toxicity of per- and polyfluoroalkyl substances (PFAS) in the brain: a review.

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals colloquially known as "forever chemicals" 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 experiments, 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.

Addressing Urgent Questions for PFAS in the 21st Century.

Despite decades of research on per- and polyfluoroalkyl substances (PFAS), fundamental obstacles remain to addressing worldwide contamination by these chemicals and their associated impacts on environmental quality and health. Here, we propose six urgent questions relevant to science, technology, and policy that must be tackled to address the "PFAS problem": (1) What are the global production volumes of PFAS, and where are PFAS used? (2) Where are the unknown PFAS hotspots in the environment? (3) How can we make measuring PFAS globally accessible? (4) How can we safely manage PFAS-containing waste? (5) How do we understand and describe the health effects of PFAS exposure? (6) Who pays the costs of PFAS contamination? The importance of each question and barriers to progress are briefly described, and several potential paths forward are proposed. Given the diversity of PFAS and their uses, the extreme persistence of most PFAS, the striking ongoing lack of fundamental information, and the inequity of the health and environmental impacts from PFAS contamination, there is a need for scientific and regulatory communities to work together, with cooperation from PFAS-related industries, to fill in critical data gaps and protect human health and the environment.

Finding essentiality feasible: common questions and misinterpretations concerning the "essential-use" concept.

The essential-use concept is a tool that can guide the phase-out of per- and polyfluoroalkyl substances (PFAS) and potentially other substances of concern. This concept is a novel approach to chemicals management that determines whether using substances of concern, such as PFAS, is truly essential for a given functionality. To assess the essentiality of a particular use case, three considerations need to be addressed: (1) the function (chemical, end use and service) that the chemical provides in the use case, (2) whether the function is necessary for health and safety and critical for the functioning of society and (3) if the function is necessary, whether there are viable alternatives for the chemical for this particular use. A few illustrative examples of the three-step process are provided for use cases of PFAS. The essential-use concept takes chemicals management away from a substance-by-substance approach to a group approach. For PFAS and other substances of concern, it offers a more rapid pathway toward effective management or phase-out. Parts of the concept of essential use have already been widely applied in global treaties and international regulations and it has also been recently used by product manufacturers and retailers to phase out substances of concern from supply chains. Herein some of the common questions and misinterpretations regarding the practical application of the essential-use concept are reviewed, and answers and further clarifications are provided.