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Perfluorooctane sulfonate (PFOS) is one of the dominant perfluoroalkyl substances (PFAS) detected in aquatic ecosystems. It has been used in a wide range of industrial and consumer products for decades. The unique properties of PFOS, including its stability and resistance to degradation, have made it highly persistent in the aquatic environment. Because of its persistence, potential toxicity, and occurrence in aquatic ecosystems, interest in PFOS has increased in recent decades. Despite this interest, current information on the environmental distribution of PFOS in ambient surface waters of the United States is fairly limited. This critical review summarizes the currently available literature on PFOS occurrence in surface waters across the United States and highlights existing data gaps. Available data are largely from a handful of study areas with known PFAS manufacturing or industrial uses, with much of the data collected from freshwater systems in eastern states and the upper Midwest. Measured PFOS concentrations in surface waters vary widely, over 8 orders of magnitude, with the highest concentrations occurring downstream from manufacturing and industrial use plants, areas near aqueous film-forming foam-use sites, and sites where PFOS precursors were used in textile treatment. Non-point source-related occurrences are highest near urbanized areas with high population densities. Current data illustrate the occurrence of PFOS in surface waters across multiple US states. Additional data are needed to better understand PFOS occurrence in US aquatic ecosystems, particularly in estuarine and marine systems and where monitoring data are not available (e.g., southwestern, central, and western United States). Additional PFOS occurrence data would provide valuable information on potential spatial and temporal variability in surface waters and possible risks posed to aquatic ecosystems. Environ Toxicol Chem 2021;40:2425-2442. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.

The potential for delayed mortality following short‐term episodic pollution events was evaluated by exposing cladocerans (Ceriodaphnia dubia) and rainbow trout (Oncorhynchus mykiss) to zinc (Zn) in various 1‐ to 48‐h and 1‐ to 96‐h exposures, respectively, followed by transferring the exposed organisms to clean water for up to 47 h for C. dubia and up to 95 h for trout for additional observation. For C. dubia, 1‐h exposures of up to 3790 µg Zn/L never resulted in mortality during the actual Zn exposures, but by 48 h, a 1‐h exposure to 114 µg/L, a concentration similar to the present US national water quality acute criterion for the test water conditions, ultimately killed 70% of C. dubia. With C. dubia, the speed of action of Zn toxicity was faster for intermediate concentrations than for the highest concentrations tested. For rainbow trout, pronounced delayed mortalities by 96 h only occurred following ≥8‐h exposures. For both species, ultimate mortalities from Zn exposures ≤8 h mostly presented as delayed mortalities, whereas for exposures ≥24 h, almost all ultimate mortalities presented during the actual exposure periods. With Zn, risks of delayed mortality following exposures to all concentrations tested were much greater for the more sensitive, small‐bodied invertebrate (C. dubia) than for the less sensitive, larger‐bodied fish (rainbow trout). These results, along with previous studies, show that delayed mortality is an important consideration in evaluating risks to aquatic organisms from brief, episodic exposures to some substances. Environ Toxicol Chem 2021;40:2484–2498. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA., Rainbow trout could withstand extreme Zn pulses of 1 to 3 h, with few subsequent deaths. Few Ceriodaphnia dubia died during 1‐ to 3‐h Zn pulses, but after 48 h, most were dead. Time to effects decreased as expected as rainbow trout were exposed to increasing Zn concentrations. Not so with C. dubia: time to effects was fastest in intermediate Zn exposures, with longer survivals in higher Zn exposures.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in CF is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n=16) or GIP (n=16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions with either incretin or placebo infused by randomized, double-blind, cross-over fashion. Another 4 adults with PI-CF and normal glucose tolerance (NGT) and 4 matched non-CF controls underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion, but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in non-CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP’s insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

CF related diabetes is common with pancreatic insufficient CF (PI-CF) . Highly effective modulator therapy enhances aberrant CF transmembrane conductance regulator (CFTR) function and improves pulmonary and nutritional status. Ivacaftor therapy for indicated CFTR mutations enhanced insulin secretion to glucose-potentiated arginine (GPA) testing; however the effects of elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta™) on β-cell function have not been assessed. We retrospectively compared changes in GPA measures performed on two visits in individuals with PI-CF without diabetes and who were 1) initiated on ETI after the baseline visit (ETI group) vs. 2) not treated with CFTR modulator therapy (controls) . ETI participants (mean±SD age 27±9 years) and 8 matched controls were followed up after a median (IQR) 5.8 (3.7-6.7) and 2.7 (1.9-3.0) years, respectively (p=0.001) , with ETI initiation 1.1 (0.2-1.2) years before the follow-up visit. Weight increased in both groups, but by more in the ETI group (p Acute insulin and C-peptide responses to glucose-potentiated arginine deteriorated in controls (p ETI therapy appears to preserve β-cell function in CF through effects on glucose-dependent insulin secretion and proinsulin processing. Further work should determine whether early intervention with ETI can prevent deterioration of glucose tolerance in PI-CF. Disclosure A.Flatt: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. A.Kelly: Research Support; vTv Therapeutics. S.Sheikh: None. A.J.Peleckis: None. K.Gallagher: None. P.Alvarado: None. D.Hadjiliadis: Advisory Panel; AstraZeneca, Research Support; Mylan N.V. D.Stefanovski: None. R.J.Gallop: None. R.C.Rubenstein: None. Funding Public Health Service research grants (RDK97830; K23 DK107937; UL1 TR001878) and National Institutes of Health (P30 DK19525) .

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP’s insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Insulin pump therapy in pediatric type 1 diabetes has been associated with better glycemic control than multiple daily injections. However, insulin pump use remains limited. This article describes an initiative from the T1D Exchange Quality Improvement Collaborative aimed at increasing insulin pump use in patients aged 12–26 years with type 1 diabetes from a baseline of 45% in May 2018 to >50% by February 2020. Interventions developed by participating centers included increasing in-person and telehealth education about insulin pump technology, creating and distributing tools to assist in informed decision-making, facilitating insulin pump insurance approval and onboarding processes, and improving clinic staff knowledge about insulin pumps. These efforts yielded a 13% improvement in pump use among the five participating centers, from 45 to 58% over 22 months.

Many studies have demonstrated the clinical benefit of continuous glucose monitoring (CGM) in type 1 diabetes (T1D). Although favorable insurance policy changes have gradually increased the access of CGM nationally, widespread uptake has been slow. The T1DX-QI is a national type 1 diabetes learning collaborative coordinated by the T1D Exchange in Boston, MA. This work describes how 10 diabetes centers in the T1DX-QI used QI principles including the Plan - Do - Study - Act (PDSA) cycles to test and expand different interventions to increase CGM use in their respective centers. Successful efforts include the redesign of relevant workflows, assessing and removing barriers to adoption, developing CGM patient education classes, and advocating for state Medicaid coverage of CGM. The centers piloted these changes in 12 - 26 year olds with T1D. The coordinating center used statistical process control charts to evaluate the effectiveness of the interventions (Figure 1). Eight of 10 participating centers improved CGM use significantly. There was a 12% improvement from over 20 months across the entire cohort of centers (range 7-34%). This demonstrates that by using QI principles to test interventions and cross-learning, the T1D community can increase use of CGM devices. Figure 1. Disclosure O. Ebekozien: None. N. Rioles: None. D. DeSalvo: Consultant; Self; Dexcom, Inc., Insulet Corporation. K. Gallagher: None. J.M. Lee: Advisory Panel; Self; Goodrx. Consultant; Self; T1D Exchange. Research Support; Self; Lenovo. R. McDonough: None. K. Obrynba: None. P. Prahalad: None. S. Thomas: None. R.S. Weinstock: Board Member; Self; JDRF. Consultant; Self; Insulogic LLC. Research Support; Self; Boehringer Ingelheim International GmbH, Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Insulet Corporation, Jaeb Center for Health Research, Kowa Research Institute, Inc., Medtronic, Tolerion, Inc. S. Corathers: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust

There is an increased risk of complications among “high risk” patients (having elevated HbA1c scores). Social, racial, and economic factors contribute to the difficulty in reducing HbA1c. The T1DX-QI is a type 1 diabetes learning health system with over 10 endocrinology centers working collaboratively on the goal of improving outcomes for people with type 1 diabetes. The program is coordinated by the T1D Exchange in Boston, MA. “High-risk” patients are defined as having two clinic visits in the preceding 12 months and two HbA1cs above 9%. Centers shared data monthly with the coordinating office which used statistical process control charts to evaluate the effectiveness of the interventions. (Figure 1). This abstract describes how 10 centers used QI principles and interventions to reduce the proportion of high-risk patients. Successful efforts include: utilizing a patient navigator, workflow redesign, developing insulin pump and CGM education classes, depression screening, and addressing social determinants of health. The Collaborative set a goal to decrease percentage of high risk patients by 5% from baseline and made a significant 3% improvement; data is projected to meet goal by June 2020. Six of 10 centers met the goal, impacting over 200 patients. Continued efforts are needed to expand interventions to additional sites to reduce the number of high-risk patients. Disclosure N. Rioles: None. C. Bunker: None. M.A. Clements: Consultant; Self; Glooko, Inc. Other Relationship; Self; Glooko, Inc. K. Gallagher: None. A. Garrity: None. N. Jones: None. M.K. Kamboj: Research Support; Self; Type 1 Diabetes TrialNet, Unitio, Inc. S. Majidi: Advisory Panel; Self; Companion Medical. P. Prahalad: None. R.Y. Sonabend: None. K. Thivener: None. O. Ebekozien: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust

A Society of Environmental Toxicology and Chemistry technical workshop was held in December 2017 to critically evaluate the current state of the science of metal bioavailability modeling. The availability of mechanistic models such as the biotic ligand model and the rapid development of empirical models such as multiple linear regressions means that choices are available in terms of bioavailability normalization approaches that can be used in metal risk assessments and the development of risk-based protective values for aquatic life. A key goal of the workshop was to provide potential users of metal bioavailability models with the information required to make appropriate decisions when choosing among mechanistic and empirical models. Workshop participants focused on the state of the science of metal bioavailability modeling, mechanistic and empirical model frameworks, validation of bioavailability models, and application of bioavailability models in risk-based decision-making approaches. The output of this workshop provides the necessary scientific information to incorporate bioavailability normalization in regulations pertaining to metals in freshwater systems. Environ Toxicol Chem 2019;39:42-47. © 2019 SETAC.

The US Environmental Protection Agency is developing a new guidance that outlines best practice in the submission, quality assurance, analysis and management of genomics data for environmental applications.

Over the last decade, the introduction of microarray technology has had a profound impact on gene expression research. The publication of studies with dissimilar or altogether contradictory results, obtained using different microarray platforms to analyze identical RNA samples, has raised concerns about the reliability of this technology. The MicroArray Quality Control (MAQC) project was initiated to address these concerns, as well as other performance and data analysis issues. Expression data on four titration pools from two distinct reference RNA samples were generated at multiple test sites using a variety of microarray-based and alternative technology platforms. Here we describe the experimental design and probe mapping efforts behind the MAQC project. We show intraplatform consistency across test sites as well as a high level of interplatform concordance in terms of genes identified as differentially expressed. This study provides a resource that represents an important first step toward establishing a framework for the use of microarrays in clinical and regulatory settings.

Water samples from several ponds in Minnesota were evaluated for their capacity to induce malformations in embryos of Xenopus laevis. The FETAX assay was used to assess the occurrence of malformations following a 96-hr period of exposure to water samples. These studies were conducted following reports of high incidences of malformation in natural populations of frogs in Minnesota wetlands. The purpose of these studies was to determine if a biologically active agent(s) was present in the waters and could be detected using the FETAX assay. Water samples from ponds with high incidences of frog malformations (affected sites), along with water samples from ponds with unaffected frog populations (reference sites), were studied. Initial experiments clearly showed that water from affected sites induced mortality and malformation in Xenopus embryos, while water from reference sites had little or no effect. Induction of malformation was dose dependent and highly reproducible, both with stored samples and with samples taken at different times throughout the summer. The biological activity of the samples was reduced or eliminated when samples were passed through activated carbon. Limited evidence from these samples indicates that the causal factor(s) is not an infectious organism nor are ion concentrations or metals responsible for the effects observed. Results do indicate that the water matrix has a significant effect on the severity of toxicity. Based on the FETAX results and the occurrence of frog malformations observed in the field, these studies suggest that water in the affected sites contains one or more unknown agents that induce developmental abnormalities in Xenopus. These same factors may contribute to the increased incidence of malformation in native species.

The US Environmental Protection Agency (EPA) has developed a framework for human health risk assessment to inform decision making. The National Research Council, in Science and Decisions, recommended that EPA adopt a framework for risk-based decision making, which maximises the utility of risk assessment. The framework considers the NRC's recommendations and builds upon existing agency guidance by emphasising the need to design risk assessments to provide information most applicable to the decision-making process. The framework ties together existing human health guidance, is flexible to accommodate the range of assessments conducted across the agency as well as future advances in risk assessment science, and considers overarching themes including environmental justice and susceptible lifestage risk. The framework integrates the concepts of planning and scoping and problem formulation and provides for incorporation of stakeholder involvement and peer review.

/ High concentrations of an unusual, complex mixture of chlorinated compounds were discovered in sediments and oysters near a federal aeronautics facility during implementation of a pollutant screening protocol. The mixture was identified as Aroclor 5432, a polychlorinated terphenyl (PCT) formulation, produced in the US until 1972. PCTs, particularly low chlorinated mixtures, have rarely been reported in the environment, despite significant manufacture and usage. Releases were traced to two outfalls. Creek sediments downstream of one contained concentrations as high as 200,000 |gmg/kg (dry weight basis); those in indigenous oysters reached 35,000 |gmg/kg, indicating significant bioavailability and bioaccumulation potential. Subsequent work showed that PCTs were widely disseminated in marsh grass, crabs, and fish. PCTs, PCBs, and mercury were also detected in storm drain lines entering these outfalls. The lines received input from both storm water and research buildings. Historical hydraulic fluid leaks and in-service compressor fluids in some buildings contained PCTs and PCBs. Contaminated materials on-site were removed to minimize pollutant spread. Aroclor 5432 usage, most likely as compressor/hydraulic fluid additives, probably ended about ten years prior to its on-site detection. In terms of biological effects, intraperitoneal injection of fish with Aroclor 5432 induced cytochrome P-4501A (CYP1A) and ethoxyresorufin O-deethylase (EROD) activity to a similar degree as PCB Aroclor 1254 and to a greater extent than PCT Aroclor 5460. The presence of high concentrations of PCTs contributed to the facility being included on the National Priorities List. It subsequently became the first US federal facility to sign a Federal Facility Agreement, identifying cleanup responsibilities, prior to formal listing.KEY WORDS: Polychlorinated terphenyls; Aroclor; Contaminated sediments; Hydraulic fluid; Enzyme induction; Polychlorinated biphenyls