Regulating PFAS as a Chemical Class under the California Safer Consumer Products Program

Background: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a group of manmade chemicals containing at least one fully fluorinated carbon atom. The widespread use, large number, and diverse chemical structures of PFAS pose challenges to any sufficiently protective regulation, emissions reduction, and remediation at contaminated sites. Regulating only a subset of PFAS has led to their replacement with other members of the class with similar hazards, that is, regrettable substitutions. Regulations that focus solely on perfluoroalkyl acids (PFAAs) are ineffective, given that nearly all other PFAS can generate PFAAs in the environment.Objectives: In this commentary, we present the rationale adopted by the State of California’s Department of Toxic Substances Control (DTSC) for regulating PFAS as a class in certain consumer products.Discussion: We at the California DTSC propose regulating certain consumer products if they contain any member of the class of PFAS because: a) all PFAS, or their degradation, reaction, or metabolism products, display at least one common hazard trait according to the California Code of Regulations, namely environmental persistence; and b) certain key PFAS that are the degradation, reaction or metabolism products, or impurities of nearly all other PFAS display additional hazard traits, including toxicity; are widespread in the environment, humans, and biota; and will continue to cause adverse impacts for as long as any PFAS continue to be used. Regulating PFAS as a class is thus logical, necessary, and forward-thinking. This technical position may be helpful to other regulatory agencies in comprehensively addressing this large class of chemicals with common hazard traits. https://doi.org/10.1289/EHP7431     

Genetic contributions of the serotonin transporter to social learning of fear and economic decision making

Serotonin (5-HT) modulates emotional and cognitive functions such as fear conditioning (FC) and decision making. This study investigated the effects of a functional polymorphism in the regulatory region (5-HTTLPR) of the human 5-HT transporter (5-HTT) gene on observational FC, risk taking and susceptibility to framing in decision making under uncertainty, as well as multidimensional anxiety and autonomic control of the heart in healthy volunteers. The present results indicate that in comparison to the homozygotes for the long (l) version of 5-HTTLPR, the carriers of the short (s) version display enhanced observational FC, reduced financial risk taking and increased susceptibility to framing in economic decision making. We also found that s-carriers have increased trait anxiety due to threat in social evaluation, and ambiguous threat perception. In addition, s-carriers also show reduced autonomic control over the heart, and a pattern of reduced vagal tone and increased sympathetic activity in comparison to l-homozygotes. This is the first genetic study that identifies the association of a functional polymorphism in a key neurotransmitter-related gene with complex social–emotional and cognitive processes. The present set of results suggests an endophenotype of anxiety disorders, characterized by enhanced social learning of fear, impaired decision making and dysfunctional autonomic activity.     

A novel <Emphasis Type="Italic">KCNA1</Emphasis> mutation in a family with episodic ataxia and malignant hyperthermia

Episodic ataxia type 1 (EA1) is an autosomal dominant channelopathy caused by mutations in KCNA1, which encodes the voltage-gated potassium channel, Kv1.1. Eleven members of an EA family were evaluated with molecular and functional studies. A novel c.746T>G (p.Phe249Cys) missense mutation of KCNA1 segregated in the family members with episodic ataxia, myokymia, and malignant hyperthermia susceptibility. No mutations were found in the known malignant hyperthermia genes RYR1 or CACNA1S. The Phe249Cys-Kv1.1 channels did not show any currents upon functional expression, confirming a pathogenic role of the mutation. Malignant hyperthermia may be a presentation of KCNA1 mutations, which has significant implications for the clinical care of these patients and illustrates the phenotypic heterogeneity of KCNA1 mutations.     

Using national electronic health care registries for comparing the risk of psychiatric re-hospitalisation in six European countries: Opportunities and limitations

Psychiatric re-hospitalisation rates have been of longstanding interest as health care quality metric for planners and policy makers, but are criticized for not being comparable across hospitals and countries due to measurement unclarities. The objectives of the present study were to explore the interoperability of national electronic routine health care registries of six European countries (Austria, Finland, Italy, Norway, Romania, Slovenia) and, by using variables found to be comparable, to calculate and compare re-hospitalisation rates and the associated risk factors. A “Methods Toolkit” was developed for exploring the interoperability of registry data and protocol led pilot studies were carried out. Problems encountered in this process are described. Using restricted but comparable data sets, up to twofold differences in psychiatric re-hospitalisation rates were found between countries for both a 30- and 365-day follow-up period. Cumulative incidence curves revealed noteworthy additional differences. Health system characteristics are discussed as potential causes for the differences. Multi-level logistic regression analyses showed that younger age and a diagnosis of schizophrenia/mania/bipolar disorder consistently increased the probability of psychiatric re-hospitalisation across countries. It is concluded that the advantage of having large unselected study populations of national electronic health care registries needs to be balanced against the considerable efforts to examine the interoperability of databases in cross-country comparisons.     

Time lapse in vivo microscopy reveals distinct dynamics of microglia‐tumor environment interactions—a new role for the tumor perivascular space as highway for trafficking microglia

Microglial cells are critical for glioma growth and progression. However, only little is known about intratumoral microglial behavior and the dynamic interaction with the tumor. Currently the scarce understanding of microglial appearance in malignant gliomas merely originates from histological studies and in vitro investigations. In order to understand the pattern of microglia activity, motility and migration we designed an intravital study in an orthotopic murine glioma model using CX3CR1‐eGFP^GFP/wt mice. We analysed the dynamics of intratumoral microglia accumulation and activity, as well as microglia/tumor blood vessel interaction by epi‐illumination and 2‐photon laser scanning microscopy. We further investigated cellular and tissue function, including the enzyme activity of intratumoral and microglial NADPH oxidase measured by in vivo fluorescence lifetime imaging. We identified three morphological phenotypes of tumor‐associated microglia cells with entirely different motility patterns. We found that NADPH oxidase activation is highly divergent in these microglia subtypes leading to different production levels of reactive oxygen species (ROS). We observed that microglia motility is highest within the perivascular niche, suggesting relevance of microglia/tumor blood vessel interactions. In line, reduction of tumor blood vessels by antivascular therapy confirmed the relevance of the tumor vessel compartment on microglia biology in brain tumors. In summary, we provide new insights into in vivo microglial behavior, regarding both morphology and function, in malignant gliomas. GLIA 2016;64:1210–1226     

Evaluation of knowledge-based reconstruction for magnetic resonance volumetry of the right ventricle after arterial switch operation for dextro-transposition of the great arteries

Right ventricular (RV) volume and function evaluation is essential in the follow-up of patients after arterial switch operation (ASO) for dextro-transposition of the great arteries (d-TGA). Cardiac magnetic resonance (CMR) imaging using the Simpson’s method is the gold-standard for measuring these parameters. However, this method can be challenging and time-consuming, especially in congenital heart disease. Knowledge-based reconstruction (KBR) is an alternative method to derive volumes from CMR datasets. It is based on the identification of a finite number of anatomical RV landmarks in various planes, followed by computer-based reconstruction of the endocardial contours by matching these landmarks with a reference library of representative RV shapes. The purpose of this study was to evaluate the feasibility, accuracy, reproducibility and labor intensity of KBR for RV volumetry in patients after ASO for d-TGA. The CMR datasets of 17 children and adolescents (males 11, median age 15) were studied for RV volumetry using both KBR and Simpson’s method. The intraobserver, interobserver and intermethod variabilities were assessed using Bland–Altman analyses. Good correlation between KBR and Simpson’s method was noted. Intraobserver and interobserver variability for KBR showed excellent agreement. Volume and function assessment using KBR was faster when compared with the Simpson’s method (5.1?±?0.6 vs. 6.7?±?0.9 min, p?<?0.001). KBR is a feasible, accurate, reproducible and fast method for measuring RV volumes and function derived from CMR in patients after ASO for d-TGA.     

In Vitro Study on the Adhesive Performance of Some Resin-Based Materials Used to Restore Class II Cavities

The study aimed to evaluate the adhesive performances of two ormocer materials and two micro-hybrid composites placed to restore class II cavities. We tested the null hypothesis, which considered that the adhesive behaviors of tested materials did not differ. On each extracted tooth, two class II cavities were prepared having an enamel located cervical margin and a cementum located cervical margin, respectively, and were restored using two different restoration techniques. The teeth followed a tooth impregnating protocol and were sectioned and evaluated by optical microscopy to highlight the marginal microleakage around restorations. Cervical and occlusal microleakage as well as microleakage ratios were calculated. The microleakage test showed that all tested materials exhibited some degree of dentinal microleakage both on cervical and occlusal areas irrespective of the restoration technique. Some significant differences were recorded in adhesion performance of the materials. The cervical microleakage ratio was significantly increased for one of the micro-hybrid resin composites in comparison with one of the ormocer materials (p = 0.0159). Significantly differences were observed in occlusal microleakage ratios when the two micro-hybrid composites were compared (p = 0.047). The results failed to reject the null hypothesis. The present study could not demonstrate the superiority of ormocer-materials relative to conventional composites.