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Several decades after selenium impacts on wild fish populations were observed in freshwater reservoirs receiving fly ash effluents from electric power facilities at Belews Lake and Hyco Reservoir (North Carolina, USA), developments in selenium (Se) toxicology have led to a greater understanding of Se effects on freshwater fish. These latter advancements have allowed regulatory agencies in several jurisdictions to develop tissue-based toxicity benchmarks for the protection of aquatic life. These benchmarks were generally derived from datasets encompassing multiple fish species and designed to protect the most sensitive species (US Environmental Protection Agency [EPA] water quality criteria). Safety factors have been applied in the development of some Canadian guidelines (British Columbia [BC]), resulting in guidelines that appear to be overly conservative. The present study addresses the question, "Are current tissue-based selenium guidelines and criteria overly protective of freshwater fish populations?" A literature review was conducted of studies in which Se was the primary constituent of concern, to compare tissue concentrations and results of fish population metrics and deformity assessment studies with current regulatory thresholds for the protection of aquatic life in the United States and Canada. EPA fish tissue-based Se criteria were found to be protective of fish populations and, at times, overly protective. Canadian water quality guidelines for Se (BC Ministry of Environment and Climate Change Strategy [BCMOECCS], Environment and Climate Change Canada [ECCC]) were consistently found to be overly protective, especially for benchmarks in which safety factors were used to derive those guidelines. In addition to a synthesis of the results of these studies, various limitations of the reviewed studies are discussed, and recommendations for future studies are proposed. Integr Environ Assess Manag 2022;18:622-630. © 2021 SETAC.

Multiple linear regression (MLR) models for predicting chronic aluminum toxicity to a cladoceran (Ceriodaphnia dubia) and a fish (Pimephales promelas) as a function of 3 toxicity-modifying factors (TMFs)-dissolved organic carbon (DOC), pH, and hardness-have been published previously. However, the range over which data for these TMFs were available was somewhat limited. To address this limitation, additional chronic toxicity tests with these species were subsequently conducted to expand the DOC range up to 12 mg/L, the pH range up to 8.7, and the hardness range up to 428 mg/L. The additional toxicity data were used to update the chronic MLR models. The adjusted R

The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) database, the authoritative source of U.S. risk assessment toxicity factors, currently lacks an oral reference dose (RfD) for copper. In the absence of such a value, various health-based reference values for copper are available for use in risk assessment. We summarize the scientific bases and differences in assumptions among key reference values for ingested copper to guide selection of appropriate values for risk assessment. A comprehensive review of the scientific literature best supports the oral RfD of 0.04 mg/kg body weight/day derived by EPA from their Drinking Water Action Level. This value is based on acute gastrointestinal effects but is further supported by broader analysis of copper deficiency and toxicity.

Decades of study indicate that copper oral exposures are typically not a human health concern. Ingesting high levels of soluble copper salts can cause acute gastrointestinal symptoms and, in uncommon cases, liver toxicity in susceptible individuals with repeated exposure. This focused toxicological review evaluated the current literature since the last comprehensive reviews (2007–2010). Our review identified limitations in the existing United States and international guidance for determining an oral reference dose (RfD) for essential metals like copper. Instead, an alternative method using categorical regression analysis to develop an optimal dose that considers deficiency, toxicity, and integrates information from human and animal studies was reviewed for interpreting an oral RfD for copper. We also considered subchronic or chronic toxicity from genetic susceptibility to copper dysregulation leading to rare occurrences of liver and other organ toxicity with elevated copper exposure. Based on this approach, an oral RfD of 0.04 mg Cu/kg/day would be protective of acute or chronic toxicity in adults and children. This RfD is also protective for possible genetic susceptibility to elevated copper exposure and allows for background dietary exposures. This dose is not intended to be protective of patients with rare genetic disorders for copper sensitivity within typical nutritional intake ranges, nor is it protective for those with excessive supplement intake. Less soluble mineral forms of copper in soil have reduced bioavailability as compared with more soluble copper in water and diet, which should be considered in using this RfD for risk assessments of copper.

Analyses of natural waters frequently show elevated levels of total aluminum (Al) attributable to acid extraction of Al from the total suspended solids (TSS) minerals. Hence, there is a need for an analytical method that measures only bioavailable Al. Natural waters high in TSS were collected to study the chronic effects of Al on Ceriodaphnia dubia. In the collected waters TSS ranged from 30 to 411 mg/L; total Al concentrations ranged from 2.0 to 44.8 mg/L. The TSS in natural waters inhibited reproduction of C. dubia up to 40% in comparison to the same filtered waters. This inhibition did not correlate with the concentration of TSS or total Al; it was attributed to nutritional deficiency and was prevented by increasing the food supply. To demonstrate that toxicity can be measured in natural waters, samples with elevated TSS were spiked with soluble Al, and survival and reproduction were measured in chronic studies performed at pH 6.3 and 8.0. To properly characterize the Al concentrations in the toxicity studies, a method was needed that could discriminate bioavailable Al from mineral forms of Al. An extraction method at pH 4 for bioavailable Al was developed and evaluated using C. dubia chronic toxicity studies in the presence of TSS. It is concluded that the proposed method is better able to discriminate chronic toxicity effects attributable to bioavailable Al from mineralized nontoxic forms of Al compared with existing methods using total or total recoverable Al (i.e., extraction at pH ≤ 1.5). We propose that this new method be used when assessing the potential for Al in natural surface waters to cause toxicity. Environ Toxicol Chem 2019;38:1668–1681. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

An emerging Multi-Ion Toxicity (MIT) model for assessment of environmental salt pollution is based on the premise that major ion toxicity to aquatic organisms is related to a critical disturbance of the trans-epithelial potential across the gills (ΔTEP), which can be predicted by electrochemical theory. However, the model has never been evaluated physiologically. We directly tested key assumptions by examining the individual effects of eight different salts (NaCl, Na2SO4, MgCl2, MgSO4, KCl, K2SO4, CaCl2, and CaSO4) on measured TEP in three different fish species (fathead minnow, Pimephales promelas = FHM; channel catfish, Ictalurus punctatus = CC; bluegill, Lepomis macrochirus = BG). A geometric concentration series based on previously reported 96-h LC50 values for FHM was used. All salts caused concentration-dependent increases in TEP to less negative/more positive values in a pattern well-described by the Michaelis-Menten equation. The ΔTEP responses for different salts were similar to one another within each species when concentrations were expressed as a percentage of the FHM LC50. A plateau was reached at or before 100 % of the LC50 where the ΔTEP values were remarkably consistent, with only 1.4 to 2.2-fold variation. This relative uniformity in the ΔTEP responses contrasts with 28-fold variation in salt concentration (in mmol L−1), 9.6-fold in total dissolved solids, and 7.9-fold in conductivity at the LC50. The Michaelis-Menten Km values (salt concentrations causing 50 % of the ΔTEPmax) were positively related to the 96-h LC50 values. ΔTEP responses were not a direct effect of osmolarity in all species and were related to specific cation rather than specific anion concentrations in FHM. These responses were stable for up to 24 h in CC. The results provide strong physiological support for the assumptions of the MIT model, are coherent with electrochemical theory, and point to areas for future research.

Urban regions of the world are expanding rapidly, placing additional stress on water resources. Urban water bodies serve many purposes, from washing and sources of drinking water to transport and conduits for storm drainage and effluent discharge. These water bodies receive chemical emissions arising from either single or multiple point sources, diffuse sources which can be continuous, intermittent, or seasonal. Thus, aquatic organisms in these water bodies are exposed to temporally and compositionally variable mixtures. We have delineated source-specific signatures of these mixtures for diffuse urban runoff and urban point source exposure scenarios to support risk assessment and management of these mixtures. The first step in a tiered approach to assessing chemical exposure has been developed based on the event mean concentration concept, with chemical concentrations in runoff defined by volumes of water leaving each surface and the chemical exposure mixture profiles for different urban scenarios. Although generalizations can be made about the chemical composition of urban sources and event mean exposure predictions for initial prioritization, such modeling needs to be complemented with biological monitoring data. It is highly unlikely that the current paradigm of routine regulatory chemical monitoring alone will provide a realistic appraisal of urban aquatic chemical mixture exposures. Future consideration is also needed of the role of nonchemical stressors in such highly modified urban water bodies. Environ Toxicol Chem 2018;37:703-714. © 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

The chemistry, bioavailability, and toxicity of aluminum (Al) in the aquatic environment are complex and affected by a wide range of water quality characteristics (including pH, hardness, and dissolved organic carbon). Data gaps in Al ecotoxicology exist for pH ranges representative of natural surface waters (pH 6-8). To address these gaps, a series of chronic toxicity tests were performed at pH 6 with 8 freshwater species, including 2 fish (Pimephales promelas and Danio rerio), an oligochaete (Aeolosoma sp.), a rotifer (Brachionus calyciflorus), a snail (Lymnaea stagnalis), an amphipod (Hyalella azteca), a midge (Chironomus riparius), and an aquatic plant (Lemna minor). The 10% effect concentrations (EC10s) ranged from 98 μg total Al/L for D. rerio to 2175 μg total Al/L for L. minor. From these data and additional published data, species-sensitivity distributions (SSDs) were developed to derive concentrations protective of 95% of tested species (i.e., 50% lower confidence limit of a 5th percentile hazard concentration [HC5-50]). A generic HC5-50 (not adjusted for bioavailability) of 74.4 μg total Al/L was estimated using the SSD. An Al-specific biotic ligand model (BLM) was used to develop SSDs normalized for bioavailability based on site-specific water quality characteristics. Normalized HC5-50s ranged from 93.7 to 534 μg total Al/L for waters representing a range of European ecoregions, whereas a chronic HC5 calculated using US Environmental Protection Agency aquatic life criteria methods (i.e., a continuous criterion concentration [CCC]) was 125 μg total Al/L when normalized to Lake Superior water in the United States. The HC5-50 and CCC values for site-specific waters other than those in the present study can be obtained using the Al BLM. Environ Toxicol Chem 2018;37:36-48. © 2017 SETAC.

Aluminum (Al) toxicity to aquatic organisms is strongly affected by water chemistry. Toxicity-modifying factors such as pH, dissolved organic carbon (DOC), hardness, and temperature have a large impact on the bioavailability and toxicity of Al to aquatic organisms. The importance of water chemistry on the bioavailability and toxicity of Al suggests that interactions between Al and chemical constituents in exposures to aquatic organisms can affect the form and reactivity of Al, thereby altering the extent to which it interacts with biological membranes. These types of interactions have previously been observed in the toxicity data for other metals, which have been well described by the biotic ligand model (BLM) framework. In BLM applications to other metals (including cadmium, cobalt, copper, lead, nickel, silver, and zinc), these interactions have focused on dissolved metal. A review of Al toxicity data shows that concentrations of Al that cause toxicity are frequently in excess of solubility limitations. Aluminum solubility is strongly pH dependent, with a solubility minimum near pH 6 and increasing at both lower and higher pH values. For the Al BLM, the mechanistic framework has been extended to consider toxicity resulting from a combination of dissolved and precipitated Al to recognize the solubility limitation. The resulting model can effectively predict toxicity to fish, invertebrates, and algae over a wide range of conditions. Environ Toxicol Chem 2018;37:70-79. © 2017 SETAC.

There is consensus that fish are the most sensitive aquatic organisms to selenium (Se) and that Se concentrations in fish tissue are the most reliable indicators of potential toxicity. Differences in Se speciation, biological productivity, Se concentration, and parameters that affect Se bioavailability (e.g., sulfate) may influence the relationship between Se concentrations in water and fish tissue. It is desirable to identify environmentally protective waterborne Se guidelines that, if not exceeded, reduce the need to directly measure Se concentrations in fish tissue. Three factors that should currently be considered in developing waterborne Se screening guidelines are 1) differences between lotic and lentic sites, 2) the influence of exposure concentration on Se partitioning among compartments, and 3) the influence of sulfate on selenate bioavailability. Colocated data sets of Se concentrations in 1) water and particulates, 2) particulates and invertebrates, and 3) invertebrates and fish tissue were compiled; and a quantile regression approach was used to derive waterborne Se screening guidelines. Use of a regression-based approach for describing relationships in Se concentrations between compartments reduces uncertainty associated with selection of partitioning factors that are generally not constant over ranges of exposure concentrations. Waterborne Se screening guidelines of 6.5 and 3.0 μg/L for lotic and lentic water bodies were derived, and a sulfate-based waterborne Se guideline equation for selenate-dominated lotic waters was also developed. Environ Toxicol Chem 2017;36:2503-2513. © 2017 SETAC.

Many metals (aluminum, cadmium, cobalt, copper, nickel, lead, zinc) are widely studied environmental contaminants because of their ubiquity, potential toxicity to aquatic life, and tendency for toxicity to vary widely as a function of water chemistry. The interactions between metal and water chemistry influence metal "bioavailability," an index of the rate and extent to which the metal reaches the site of toxic action. The implications of metal bioavailability for ecological risk assessment are large, with as much as a 100-fold variability across a range of water chemistries in surface waters. Beginning as early as the 1930s, considerable research effort was expended toward documenting and understanding metal bioavailability as a function of total and dissolved metal, water hardness, natural organic matter, pH, and other water characteristics. The understanding of these factors and improvements in both analytical and computational chemistry led to the development of modeling approaches intended to describe and predict the relationship between water chemistry and metal toxicity, including the free ion activity model, the gill surface interaction model, the biotic ligand model, and additional derivatives and regression models that arose from similar knowledge. The arc of these scientific advances can also be traced through the evolution of the US Environmental Protection Agency's ambient water quality criteria over the last 50 yr, from guidance in the "Green Book" (1968) to metal-specific criteria produced in the last decade. Through time, water quality criteria in many jurisdictions have incorporated increasingly sophisticated means of addressing metal bioavailability. The present review discusses the history of scientific understanding of metal bioavailability and the development and application of models to incorporate this knowledge into regulatory practice. Environ Toxicol Chem 2019;39:48-59. (c) 2019 SETAC

The complex chemistry of iron (Fe) at circumneutral pH in oxygenated waters and the poor correlation between ecotoxicity results in laboratory and natural waters, has led to regulatory approaches for iron based on field studies (United States Environmental Protection Agency Water Quality Criteria and European Union Water Framework Directive proposal for Fe). The results of the present study account for the observed differences between laboratory and field observations for Fe toxicity to algae (Pseudokirchneriella subcapitata). Results from standard 72 hours assays with Fe at pH 6.3 and pH 8 resulted in similar toxicity values measured as algal biomass, with 50% effect concentration (EC50s) of 3.28 and 4.95 mg/L total Fe(III), respectively. However, at the end of the 72 h exposure, dissolved Fe concentrations were lower than 30 µg/L for all test concentrations, making a direct toxic effect of dissolved iron on algae unlikely. Analysis of nutrient concentrations in the artificial test media detected phosphorus depletion in a dose dependent manner that correlated well with algal toxicity. Subsequent experiments adding excess phosphorus after Fe precipitation eliminated the toxicity. These results strongly suggest that observed Fe(III) toxicity on algae in laboratory conditions is a secondary effect of phosphorous depletion. This article is protected by copyright. All rights reserved

Mechanical stresses on the myocyte nucleus have been associated with several diseases and potentially transduce mechanical stimuli into cellular responses. Although a number of physical links between the nuclear envelope and cytoplasmic filaments have been identified, previous studies have focused on the mechanical properties of individual components of the nucleus, such as the nuclear envelope and lamin network. The mechanical interaction between the cytoskeleton and chromatin on nuclear deformability remains elusive. Here, we investigated how cytoskeletal and chromatin structures influence nuclear mechanics in cardiac myocytes. Rapid decondensation of chromatin and rupture of the nuclear membrane caused a sudden expansion of DNA, a consequence of prestress exerted on the nucleus. To characterize the prestress exerted on the nucleus, we measured the shape and the stiffness of isolated nuclei and nuclei in living myocytes during disruption of cytoskeletal, myofibrillar, and chromatin structure. We found that the nucleus in myocytes is subject to both tensional and compressional prestress and its deformability is determined by a balance of those opposing forces. By developing a computational model of the prestressed nucleus, we showed that cytoskeletal and chromatin prestresses create vulnerability in the nuclear envelope. Our studies suggest the cytoskeletal–nuclear–chromatin interconnectivity may play an important role in mechanics of myocyte contraction and in the development of laminopathies by lamin mutations.

The fate and biological effects of chemical mixtures in the environment are receiving increased attention from the scientific and regulatory communities. Understanding the behavior and toxicity of metal mixtures poses unique challenges for incorporating metal-specific concepts and approaches, such as bioavailability and metal speciation, in multiple-metal exposures. To avoid the use of oversimplified approaches to assess the toxicity of metal mixtures, a collaborative 2-yr research project and multistakeholder group workshop were conducted to examine and evaluate available higher-tiered chemical speciation-based metal mixtures modeling approaches. The Metal Mixture Modeling Evaluation project and workshop achieved 3 important objectives related to modeling and interpretation of biological effects of metal mixtures: 1) bioavailability models calibrated for single-metal exposures can be integrated to assess mixture scenarios; 2) the available modeling approaches perform consistently well for various metal combinations, organisms, and endpoints; and 3) several technical advancements have been identified that should be incorporated into speciation models and environmental risk assessments for metals.

Standard static-exposure acute lethality tests were conducted with Daphnia magna neonates exposed to binary or ternary mixtures of Cd, Cu, and Zn in moderately hard reconstituted water that contained 3 mg dissolved organic carbon/L added as Suwannee River fulvic acid. These experiments were conducted to test for additive toxicity (i.e., the response to the mixture can be predicted by combining the responses obtained in single-metal toxicity tests) or nonadditive toxicity (i.e., the response is less than or greater than additive). Based on total metal concentrations (>90% dissolved) the toxicity of the tested metal mixtures could be categorized into all 3 possible additivity categories: less-than-additive toxicity (e.g., Cd–Zn and Cd–Cu–Zn mixtures and Cd–Cu mixtures when Cu was titrated into Cd-containing waters), additive toxicity (e.g., some Cu–Zn mixtures), or more-than-additive toxicity (some Cu–Zn mixtures and Cd–Cu mixtures when Cd was titrated into Cu-containing waters). Exposing the organisms to a range of sublethal to supralethal concentrations of the titrated metal was especially helpful in identifying nonadditive interactions. Geochemical processes (e.g., metal–metal competition for binding to dissolved organic matter and/or the biotic ligand, and possibly supersaturation of exposure waters with the metals in some high-concentration exposures) can explain much of the observed metal–metal interactions. Therefore, bioavailability models that incorporate those geochemical (and possibly some physiological) processes might be able to predict metal mixture toxicity accurately. Environ Toxicol Chem 2015;34:799–808. © 2014 SETAC

Biotic Ligand Models (BLMs) for metals are widely applied in ecological risk assessments and in the development of regulatory water quality guidelines in Europe, and in 2007 the United States Environmental Protection Agency (USEPA) recommended BLM-based water quality criteria (WQC) for Cu in freshwater. However, to-date, few states have adopted BLM-based Cu criteria into their water quality standards on a state-wide basis, which appears to be due to the perception that the BLM is too complicated or requires too many input variables. Using the mechanistic BLM framework to first identify key water chemistry parameters that influence Cu bioavailability, namely dissolved organic carbon (DOC), pH, and hardness, we developed Cu criteria using the same basic methodology used by the USEPA to derive hardness-based criteria but with the addition of DOC and pH. As an initial proof of concept, we developed stepwise multiple linear regression (MLR) models for species that have been tested over wide ranges of DOC, pH, and hardness conditions. These models predicted acute Cu toxicity values that were within a factor of ±2 in 77% to 97% of tests (5 species had adequate data) and chronic Cu toxicity values that were within a factor of ±2 in 92% of tests (1 species had adequate data). This level of accuracy is comparable to the BLM. Following USEPA guidelines for WQC development, the species data were then combined to develop a linear model with pooled slopes for each independent parameter (i.e., DOC, pH, and hardness) and species-specific intercepts using Analysis of Covariance. The pooled MLR and BLM models predicted species-specific toxicity with similar precision; adjusted R

The bioavailability of aluminum (Al) to freshwater aquatic organisms varies as a function of several water chemistry parameters, including pH, dissolved organic carbon (DOC), and water hardness. We evaluated the ability of multiple linear regression (MLR) models to predict chronic Al toxicity to a green alga (Pseudokirchneriella subcapitata), a cladoceran (Ceriodaphnia dubia), and a fish (Pimephales promelas) as a function of varying DOC, pH, and hardness conditions. The MLR models predicted toxicity values that were within a factor of 2 of observed values in 100% of the cases for P. subcapitata (10 and 20% effective concentrations [EC10s and EC20s]), 91% of the cases for C. dubia (EC10s and EC20s), and 95% (EC10s) and 91% (EC20s) of the cases for P. promelas. The MLR models were then applied to all species with Al toxicity data to derive species and genus sensitivity distributions that could be adjusted as a function of varying DOC, pH, and hardness conditions (the P. subcapitata model was applied to algae and macrophytes, the C. dubia model was applied to invertebrates, and the P. promelas model was applied to fish). Hazardous concentrations to 5% of the species or genera were then derived in 2 ways: 1) fitting a log-normal distribution to species-mean EC10s for all species (following the European Union methodology), and 2) fitting a triangular distribution to genus-mean EC20s for animals only (following the US Environmental Protection Agency methodology). Overall, MLR-based models provide a viable approach for deriving Al water quality guidelines that vary as a function of DOC, pH, and hardness conditions and are a significant improvement over bioavailability corrections based on single parameters. Environ Toxicol Chem 2018;37:80-90. © 2017 SETAC.

Summary Vascular endothelium is a dynamic cellular interface that displays a unique phenotypic plasticity. This plasticity is critical for vascular function and when dysregulated is pathogenic in several diseases. Human genotype-phenotype studies of endothelium are limited by the unavailability of patient-specific endothelial cells. To establish a cellular platform for studying endothelial biology, we have generated vascular endothelium from human induced pluripotent stem cells (iPSCs) exhibiting the rich functional phenotypic plasticity of mature primary vascular endothelium. These endothelial cells respond to diverse proinflammatory stimuli, adopting an activated phenotype including leukocyte adhesion molecule expression, cytokine production, and support for leukocyte transmigration. They maintain dynamic barrier properties responsive to multiple vascular permeability factors. Importantly, biomechanical or pharmacological stimuli can induce pathophysiologically relevant atheroprotective or atheroprone phenotypes. Our results demonstrate that iPSC-derived endothelium possesses a repertoire of functional phenotypic plasticity and is amenable to cell-based assays probing endothelial contributions to inflammatory and cardiovascular diseases., Graphical Abstract, Highlights • Human iPSCs generate vascular ECs with a rich functional repertoire • iPSC-ECs can undergo endothelial activation and maintain dynamic permeability • Biomechanical forces direct iPSC-ECs to atheroprotective or atheroprone phenotypes • iPSC-ECs are directed to an atheroprotective phenotype via pharmacological stimulus

The heart actively remodels architecture in response to various physiological and pathological conditions. Gross structural change of the heart chambers is directly reflected at the cellular level by altering the morphological characteristics of individual cardiomyocytes. However, an understanding of the relationship between cardiomyocyte shape and the contractile function remains unclear. By using in vitro assays to analyze systolic stress of cardiomyocytes with controlled shape, we demonstrated that the characteristic morphological features of cardiomyocytes observed in a variety of pathophysiological conditions are correlated with mechanical performance. We found that cardiomyocyte contractility is optimized at the cell length/width ratio observed in normal hearts, and decreases in cardiomyocytes with morphological characteristics resembling those isolated from failing hearts. Quantitative analysis of sarcomeric architecture revealed that the change of contractility may arise from alteration of myofibrillar structure. Measurements of intracellular calcium in myocytes revealed unique characteristics of calcium metabolism as a function of myocyte shape. Our data suggest that cell shape is critical in determining contractile performance of single cardiomyocytes by regulating the intracellular structure and calcium handling ability.

There is consensus that fish are the most sensitive aquatic organisms to selenium (Se) and that Se concentrations in fish tissue are the most reliable indicators of potential toxicity. Differences in Se speciation, biological productivity, Se concentration, and parameters that affect Se bioavailability (e.g., sulfate) may influence the relationship between Se concentrations in water and fish tissue. It is desirable to identify environmentally protective waterborne Se guidelines that, if not exceeded, reduce the need to directly measure Se concentrations in fish tissue. Three factors that should currently be considered in developing waterborne Se screening guidelines are 1) differences between lotic and lentic sites, 2) the influence of exposure concentration on Se partitioning among compartments, and 3) the influence of sulfate on selenate bioavailability. Colocated data sets of Se concentrations in 1) water and particulates, 2) particulates and invertebrates, and 3) invertebrates and fish tissue were compiled; and a quantile regression approach was used to derive waterborne Se screening guidelines. Use of a regression-based approach for describing relationships in Se concentrations between compartments reduces uncertainty associated with selection of partitioning factors that are generally not constant over ranges of exposure concentrations. Waterborne Se screening guidelines of 6.5 and 3.0 μg/L for lotic and lentic water bodies were derived, and a sulfate-based waterborne Se guideline equation for selenate-dominated lotic waters was also developed. Environ Toxicol Chem 2017;36:2503-2513. © 2017 SETAC.

The complexity and diversity of many human diseases pose significant hurdles to the development of novel therapeutics. New scientific and technological advances, such as pharmacogenetics, provide valuable frameworks for understanding genetic predisposition to disease and tools for diagnosis and drug development. However, another framework is emerging based on recent scientific advances, one we suggest to call pharmacoempirics. Pharmacoempirics takes advantage of merging two nascent fields: first, the generation of induced pluripotent stem cells, which are differentiated into mature cell types and represent patient-specific genetic backgrounds, and, second, bioengineering advances allowing sophisticated re-creation of human pathophysiology in laboratory settings. The combination of these two innovative technologies should allow new experimentation on disease biology and drug discovery, efficacy, and toxicology unencumbered by hypothesis generation and testing. In this review, we discuss the challenges and promises of this exciting new type of discovery platform and outline its implementation for cardiovascular drug discovery.

Over the past few years, the "critical body residue" approach for assessing toxicity based on bioaccumulated chemicals has evolved into a more expansive consideration of tissue residues as the dose metric when defining dose-response relationships,evaluating mixtures, developing protective guidelines, and conducting risk assessments. Hence, scientists refer to "tissue residue approach for toxicity assessment" or "tissue residue-effects approach" (TRA) when addressing ecotoxicology issues pertaining to tissue (or internal) concentrations. This introduction provides an overview of a SETAC Pellston Workshop held in 2007 to review the state of the science for using tissue residues as the dose metric in environmental toxicology. The key findings of the workshop are presented, along with recommendations for research to enhance understanding of toxic responses within and between species, and to advance the use of the TRA in assessment and management of chemicals in the environment.

As part of a SETAC Pellston Workshop, we evaluated the potential use of metal tissue residues for predicting effects in aquatic organisms. This evaluation included consideration of different conceptual models and then development of several case studies on how tissue residues might be applied for metals, assessing the strengths and weaknesses of these different approaches. We further developed a new conceptual model in which metal tissue concentrations from metal-accumulating organisms (principally invertebrates) that are relatively insensitive to metal toxicity could be used as predictors of effects in metal-sensitive taxa that typically do not accumulate metals to a significant degree. Overall, we conclude that the use of tissue residue assessment for metals other than organometals has not led to the development of a generalized approach as in the case of organic substances. Species-specific and site-specific approaches have been developed for one or more metals (e.g., Ni). The use of gill tissue residues within the biotic ligand model is another successful application. Aquatic organisms contain a diverse array of homeostatic mechanisms that are both metal- and species-specific. As a result, use of whole-body measurements (and often specific organs) for metals does not lead to a defensible position regarding risk to the organism. Rather, we suggest that in the short term, with sufficient validation, species- and site-specific approaches for metals can be developed. In the longer term it may be possible to use metal-accumulating species to predict toxicity to metal-sensitive species with appropriate field validation.

We describe a design algorithm to build a cardiac myocyte with specific spatial dimensions and physiological function. Using a computational model of a cardiac muscle cell, we modeled calcium (Ca 2+ ) wave dynamics in a cardiac myocyte withcontrolledspatialdimensions.Themodeledmyocytewasreplicatedinvitrowhen primaryneonateratventricularmyocyteswereculturedonmicropatternedsubstrates. The myocytes remodel to conform to the two dimensional boundary conditions and assume the shape of the printed extracellular matrix island. Mechanical perturbation of the myocyte with an atomic force microscope results in calcium-induced calcium release from intracellular stores and the propagation of a Ca 2+ wave, as indicated by high speed video microscopy using fluorescent indicators of intracellular Ca 2+ .A nal- ysis and comparison of the measured wavefront dynamics with those simulated in the computer model reveal that the engineered myocyte behaves as predicted by the model. These results are important because they represent the use of computer mod- eling, computer-aided design, and physiological experiments to design and validate the performance of engineered cells. The ability to successfully engineer biological cells and tissues for assays or therapeutic implants will require design algorithms and tools for quality and regulatory assurance.

Previous studies have shown that biological noise may drive dynamic phenotypic mosaicism in isogenic unicellular organisms. However, there is no evidence for a similar mechanism operating in metazoans. Here we show that the endothelial-restricted gene, von Willebrand factor (VWF), is expressed in a mosaic pattern in the capillaries of many vascular beds and in the aorta. In capillaries, the mosaicism is dynamically regulated, with VWF switching between ON and OFF states during the lifetime of the animal. Clonal analysis of cultured endothelial cells reveals that dynamic mosaic heterogeneity is controlled by a low-barrier, noise-sensitive bistable switch that involves random transitions in the DNA methylation status of the VWF promoter. Finally, the hearts of VWF-null mice demonstrate an abnormal endothelial phenotype as well as cardiac dysfunction. Together, these findings suggest a novel stochastic phenotype switching strategy for adaptive homoeostasis in the adult vasculature., Spontaneous phenotypic heterogeneity confers a population-level advantage to cells that are exposed to fluctuating environments. Here the authors show that the endothelium of some organs displays a dynamic mosaicism in expression of Von Willebrand factor, suggesting bet hedging as a strategy for adaptive homeostasis.

Among unicellular organisms, stochastic phenotype switching is a documented strategy for survival. These populations "hedge their bets": while the majority of their cells are adapted to their present environment, a minority remains poised to thrive under drastically different conditions. Bet hedging has also been described in metazoan cells, primarily in vitro. However, its role in tissue homeostasis has yet to be established. Here, we show that von Willebrand factor (vWF) is expressed in a spatially heterogeneous manner in a small fraction of capillary endothelial cells in the heart, skeletal muscle, lung and brain. Moreover, these mosaic patterns are dynamic, in that vWF expression stochastically toggles ON/OFF over time. By contrast, expression of vWF in the aorta and liver is static in time. In cultured primary endothelial cells, biological noise resulted in mosaic vWF heterogeneity through a promoter-level DNA methylation switch. Finally, vWF-/- mice demonstrated extensive endothelial cell damage in capillaries of the heart and impaired cardiac function, but not kidney or aorta. Taken together, these findings suggest that dynamic mosaicism of vWF expression is functionally relevant and that bet hedging represents a previously unrecognized strategy for adaptive, organ-specific homeostasis.

This paper presents a 30+ year record of changes in benthic macroinvertebrate communities and fish populations associated with improving water quality in mining-influenced streams. Panther Creek, a tributary to the Salmon River in central Idaho, USA suffered intensive damage from mining and milling operations at the Blackbird Mine that released copper (Cu), arsenic (As), and cobalt (Co) into tributaries. From the 1960s through the 1980s, no fish and few aquatic invertebrates could be found in 40 km of mine-affected reaches of Panther Creek downstream of the metals contaminated tributaries, Blackbird and Big Deer Creeks. Efforts to restore water quality began in 1995, and by 2002 Cu levels had been reduced by about 90%, with incremental declines since. Rainbow Trout (Oncorhynchus mykiss) were early colonizers, quickly expanding their range as areas became habitable when Cu concentrations dropped below about 3X the U.S. Environmental Protection Agency’s biotic ligand model (BLM) based chronic aquatic life criterion. Anadromous Chinook Salmon (O. tshawytscha) and steelhead (O. mykiss) have also reoccupied Panther Creek. Full recovery of salmonid populations occurred within about 12-years after the onset of restoration efforts and about 4-years after the Cu chronic criteria had mostly been met, with recovery interpreted as similarity in densities, biomass, year class strength, and condition factors between reference sites and mining-influenced sites. Shorthead Sculpin (Cottus confusus) were slower than salmonids to disperse and colonize. While benthic macroinvertebrate biomass has increased, species richness has plateaued at about 70 to 90% of reference despite the Cu criterion having been met for several years. Different invertebrate taxa had distinctly different recovery trajectories. Among the slowest taxa to recover were Ephemerella, Cinygmula and Rhithrogena mayflies, Enchytraeidae oligochaetes, and Heterlimnius aquatic beetles. Potential reasons for the failure of some invertebrate taxa to recover include competition, and high sensitivity to Co and Cu.

Previous studies indicate that the hatching success of brine shrimp (Artemia franciscana) cysts is surprisingly sensitive to ambient metal concentrations. These studies estimated median effective concentrations (EC50s) of 7, 5, and 28 μg l−1 for Cd, Cu, and Zn, suggesting that the hatching end point for A. franciscana is the most sensitive tested to date for Cd and Zn in saline environments and comparable in sensitivity with the most sensitive tested to date for Cu. Furthermore, these data suggest that brine shrimp are at significant risk from Cu and Zn in Great Salt Lake (GSL), UT, where ambient concentrations as high as 10 and 14 μg l−1, respectively, have been measured. Given that brine shrimp appear to be successfully reproducing in GSL, we hypothesized that these toxicity values were either biased low as a result of an artifact of the test method used or that site-specific water-quality conditions in the lake had decreased metal bioavailability such that brine shrimp could successfully reproduce. To test these hypotheses, we initiated a step-wise series of experiments. First we investigated the effects of pretreatment of brine shrimp cysts with antibiotics on brine shrimp sensitivity to metals because previous investigators as part of their test methods have used antibiotics. Next we considered the effect of ionic composition of the artificial test media on sensitivity. Finally, we evaluated the effects of the site-specific water quality of the GSL on metal bioavailability and toxicity. Results indicate that pretreatment of cysts with antibiotics had no effect on sensitivity. However, we were unable to repeat the previous values for Cd and Zn, obtaining EC50s of 11,859 and 289 μg l−1 for Cd and Zn, respectively. For Cu, however, we estimated an EC50 of 12 μg l−1, so we conducted further testing on the artificial media, adjusting the media composition to better reflect the Ca2+ and HCO 3 − concentration of normal seawater. This increased the EC50 to 28 μg l−1. Finally we evaluated the toxicity of Cu in GSL water and obtained an EC50 of 68 μg l−1, suggesting that the increased dissolved organic carbon in GSL has a significant protective effect. Overall, the results of this study suggest that brine shrimp hatching success is not particularly sensitive to Cd and Zn, but it is sensitive to Cu. However, site-specific water-quality conditions ensure that brine shrimp cyst hatching success is not significantly affected by any of these metals at the normal background concentrations that occur in GSL (

We compared the composition and richness of acute and chronic toxicity datasets for Cd, Cu, Ni, Pb, and Zn to several natural aquatic communities. The richness of acute datasets was reasonably representative, with the largest toxicity datasets containing a higher number of genera than some natural aquatic communities. Acute datasets also had a reasonably diverse composition compared to natural aquatic communities, although insects were under-represented and cladocerans over-represented. Given this robustness, we suggest manipulation of large acute datasets (Cd, Cu, Zn) to account for site-specific differences in aquatic community composition can be accomplished with confidence and that this will not result in under-protection of sensitive taxa. In contrast, the chronic datasets were not representative of natural aquatic communities in terms of composition or richness. Chronic dataset richness is an order of magnitude less than natural aquatic communities. Chronic datasets have minimal representat...

To help guarantee a profit in a very risky industry, major motion picture studios have dramatically increased movie production and marketing budgets. While advertising is the traditional emphasis in the movie marketing mix, in recent years the budget for promotion has equaled the advertising budgets. This essay discusses two areas of movie promotion that studios have increasingly turned to for additional revenues: merchandising and promotional/partner tie-ins. These two elements of the promotion mix generate billions of dollars in revenue for studios each year, but they are generally overlooked by the general population and academic researchers.

In this paper, we critically evaluate the statistical approaches and datasets previously used to derive chronic egg selenium thresholds for mallard ducks (laboratory data) and black-necked stilts (field data). These effect concentration thresholds of 3%, 10% (EC10), or 20% have been used by regulatory agencies to set avian protection criteria and site remediation goals, thus the need for careful assessment of the data. The present review indicates that the stilt field dataset used to establish a frequently cited chronic avian egg selenium threshold of 6 mg/kg dry weight lacks statistical robustness (r2 = 0.19-0.28 based on generalized linear models), suggesting that stilt embryo sensitivity to selenium is highly variable or that factors other than selenium are principally responsible for the increase in effects observed at the lower range of this dataset. Hockey stick regressions used with the stilt field dataset improve the statistical relationship (r2 = 0.90-0.97) but result in considerably higher egg selenium thresholds (EC10 = 21-31 mg/kg dry wt). Laboratory-derived (for mallards) and field-derived (for stilts) teratogenicity EC10 values are quite similar (16-24 mg/kg dry wt). Laboratory data regarding mallard egg inviability and duckling mortality data provide the most sensitive and statistically robust chronic threshold (EC10) with logit, probit, and hockey stick regressions fitted to laboratory data, resulting in mean egg selenium EC10 values of 12 to 15 mg/kg dry weight (r2 = 0.75-0.90).

The bioconcentration factor (BCF) and bioaccumulation factor (BAF) are used as the criteria for bioaccumulation in the context of identifying and classifying substances that are hazardous to the aquatic environment. The BCF/BAF criteria, while developed as surrogates for chronic toxicity and/or biomagnification of anthropogenic organic substances, are applied to all substances including metals. This work examines the theoretical and experimental basis for the use of BCF/BAF in the hazard assessment of Zn, Cd, Cu, Pb, Ni, and Ag. As well, BCF/BAFs for Hg (methyl and inorganic forms) and hexachlorobenzene (HCB) were evaluated. The BCF/BAF data for Zn, Cd, Cu, Pb, Ni, and Ag were characterized by extreme variability in mean BCF/BAF values and a clear inverse relationship between BCF/BAF and aqueous exposure. The high variability persisted when even when data were limited to an exposure range where chronic toxicity would be expected. Mean BCF/BAF values for Hg were also variable, but the inverse relationship was equivocal, in contrast with HCB, which conformed to the BCF model. This study illustrates that the BCF/BAF criteria, as currently applied, are inappropriate for the hazard identification and classification of metals. Furthermore, using BCF and BAF data leads to conclusions that are inconsistent with the toxicological data, as values are highest (indicating hazard) at low exposure concentrations and are lowest (indicating no hazard) at high exposure concentrations, where impacts are likely. Bioconcentration and bioaccumulation factors do not distinguish between essential mineral nutrient, normal background metal bioaccumulation, the adaptive capabilities of animals to vary uptake and elimination within the spectrum of exposure regimes, nor the specific ability to sequester, detoxify, and store internalized metal from metal uptake that results in adverse effect. An alternative to BCF, the accumulation factor (ACF), for metals was assessed and, while providing an improvement, it did not provide a complete solution. A bioaccumulation criterion for the hazard identification of metals is required, and work directed at linking chronic toxicity and bioaccumulation may provide some solutions.

Using copper as an example, we present a method for assessing chemical risks to an aquatic community using species sensitivity distributions (SSDs) for different taxonomic groups. This method fits probability models to chemical exposure and effects data to estimate the percentage of aquatic species potentially at risk and expands on existing probabilistic risk assessment methodologies. Due to a paucity of chronic toxicity data for many chemicals, this methodology typically uses an acute-chronic ratio (ACR) to estimate the chronic effects distribution from the acute effects distribution. We expanded on existing methods in two ways. First, copper SSDs were developed for different organism groups (e.g., insects, fish) that share similar sensitivities or ecological functions. Integration of exposure and effects distributions provides an estimate of which organism groups may be at risk. These results were then compared with a site-specific food web, allowing an estimation of whether key food web components are potentially at risk and whether the overall aquatic community may be at risk from the perspective of ecosystem function. Second, chronic SSDs were estimated using the relationship between copper ACRs and acute toxicity (i.e., the less acutely sensitive a species, the larger the ACR). This correction in the ACR removes concerns previously identified with use of the ACR and allows evaluation of a significantly expanded chronic data set with the same approach as that for assessing acute risks.

This study evaluated the relationship between ambient sulfate concentrations and acute selenate toxicity to freshwater aquatic life. Previous studies indicated that increasing sulfate concentrations reduced selenate bioconcentration and toxicity. However, these studies generally were not conducted in a manner that was conducive to their use in deriving a water quality criterion. We compiled results from previous studies and generated additional data to help define a selenate-sulfate relationship for acute toxicity. Selenate toxicity was determined in standardized test waters with varying sulfate concentrations using Ceriodaphnia dubia, Gammarus pseudolimnaeus, Hyalella azteca, and Pimephales promelas as the test organisms. Analysis of test results indicated that a significant relationship does exist between acute selenate toxicity and ambient sulfate concentrations. Data from these tests and previous studies were combined to develop a statistical relationship sufficiently robust to derive a sulfate-dependent water quality criterion for selenate. The relationship is similar to those commonly derived between divalent metals and hardness to adjust water quality criteria.

With the average cost of a feature motion picture rapidly approaching the $100 million mark, major production studios are turning to greater use of promotions to help guarantee the success of their films. As an entertainment commodity, motion pictures offer unique challenges in terms of promotions. This article briefly reviews some of the major traditional promotional techniques as well as techniques more commonly used in the entertainment industry. The research presented in the second half of the article uses secondary data on critical reviews, awards and box office returns to determine the relationship between critical opinion and motion picture success. The results suggest that there appears to be little or no correlation between the opinion of critics and the success of a motion picture.

This study provides practical guidelines for public relations campaigns targeted at Arab and American audiences. The authors examine various cultural frameworks for conceptualizing differences and similarities in the Arab and American cultures. They conclude that both cultures suffer considerably from biases and stereotypes.