Recommended Reference Values for Risk Assessment of Oral Exposure to Copper.

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.

The Role of the Plantaris in Intramuscular Gastrocnemius Equinus Correction.

Equinus deformity is a common cause of foot and ankle pathology. The purpose of our study was to evaluate the role of the plantaris in equinus. Secondary aims were to describe the role of the plantaris in intramuscular gastrocnemius recession and to determine the prevalence of the plantaris in our patient population. We measured ankle dorsiflexion during the steps of a Baumann-type intramuscular gastrocnemius recession. Eighty-nine patients were enrolled in our study. Fourteen of 89 (15.7%) patients did not have a plantaris. A mean dorsiflexion of 9 (interquartile range 6-12)° was obtained after transection of the plantaris tendon and an additional mean 8 (interquartile range 5-10)° was obtained after recession of the gastrocnemius aponeurosis. There was a strong positive correlation (rs = 0.842) of dorsiflexion increase after plantaris transection and dorsiflexion increase after gastrocnemius recession (p < .00). Linear regression showed that for every one-degree of dorsiflexion increase with plantaris transection, there was a predicted dorsiflexion increase of 0.69° with gastrocnemius recession. These results indicate that the plantaris is a component of equinus deformity.

Critical Review of Exposure and Effects: Implications for Setting Regulatory Health Criteria for Ingested Copper.

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.

Use of Multiple Linear Regression Models for Setting Water Quality Criteria for Copper: A Complementary Approach to the Biotic Ligand Model.

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 R2 and R2 values ranged from 0.56 to 0.86 and 0.66-0.85, respectively. Graphical exploration of relationships between predicted and observed toxicity, residuals and observed toxicity, and residuals and concentrations of key input parameters revealed many similarities and a few key distinctions between the performances of the two models. The pooled MLR model was then applied to the species sensitivity distribution to derive acute and chronic criteria equations similar in form to the USEPA's current hardness-based criteria equations but with DOC, pH, and hardness as the independent variables. Overall, the MLR is less responsive to DOC than the BLM across a range of hardness and pH conditions but more responsive to hardness than the BLM. Additionally, at low and intermediate hardness, the MLR model is less responsive than the BLM to pH, but the two models respond comparably at high hardness. The net effect of these different response profiles is that under many typical water quality conditions, MLR- and BLM-based criteria are quite comparable. Indeed, conditions where the two models differ most (high pH/low hardness and low pH/high hardness) are relatively rare in natural aquatic systems. We suggest that this MLR-based approach, which includes the mechanistic foundation of the BLM but is also consistent with widely accepted hardness-dependent WQC in terms of development and form, may facilitate adoption of updated state-wide Cu criteria that more accurately account for the parameters influencing Cu bioavailability than current hardness-based criteria.

Long-term monitoring of arsenic, copper, selenium, and other elements in Great Salt Lake (Utah, USA) surface water, brine shrimp, and brine flies.

This paper presents long-term monitoring data for 19 elements with a focus on arsenic (As), copper (Cu), and selenium (Se), in surface water (2002-2011), brine shrimp (2001-2011), and brine flies (1995-1996) collected from Great Salt Lake (GSL, Utah, USA). In open surface waters, mean (±standard deviation [SD]; range; n) As concentrations were 112 (±22.1; 54.0-169; 47) and 112 µg/L (±35.6; 5.1-175; 68) in filtered and unfiltered surface water samples, respectively, and 16.3 µg/g (±5.6; 5.1-35.2; 62) dry weight (dw) in brine shrimp. Mean (±SD; range; n) Cu concentrations were 4.2 (±2.1; 1.3-12.5; 47) and 6.9 µg/L (±6.6; 1.9-38.1; 68) in filtered and unfiltered surface water samples, respectively, and 20.6 µg/g (±18.4; 5.4-126; 62) dw in brine shrimp. Finally, mean (±SD; range; n) dissolved and total recoverable Se concentrations were 0.6 (±0.1; 0.4-1.2; 61) and 0.9 µg/L (±0.7; 0.5-3.6; 89), respectively, and 3.6 µg/g (±2.2; 1.1-14.9; 98) dw in brine shrimp. Thus, Se in open lake surface waters was most often in the range of 0.5-1 µg/L, and concentrations in both surface water and brine shrimp were comparable to concentrations measured in other monitoring programs for the GSL. Temporally, the statistical significance of differences in mean dissolved or total recoverable As, Cu, and Se concentrations between years was highly variable depending which test statistic was used, and there was no clear evidence of increasing or decreasing trends. In brine shrimp, significant differences in annual mean concentrations of As, Cu, and Se were observed using both parametric and nonparametric statistical approaches, but, as for water, there did not appear to be a consistent increase or decrease in concentrations of these elements over time.

Selenium-mercury interactions and relationship to aquatic toxicity: A review.

A review of the literature pertaining to selenium-mercury (Se/Hg) interactions in aquatic species was performed to provide insight into the mechanisms allowing for the reported changes in bioaccumulation and toxicity that have been observed when the two elements occur at elevated concentrations. Selenium (Se) has been shown to protect against mercury (Hg) toxicity in all animal models evaluated (fish, birds, mammals, and plants). To explore the interaction between the two elements, data are presented on concentrations of both elements in wild-caught fish at numerous locations. The data show that most fish have Se/Hg ratios >1.0. The importance of this ratio has been reported, with suggestions that the protective interaction is due in large part to the formation of HgSe. Data show that when the Se/Hg molar ratio is <1.0 in the diet of fish and animals, Hg toxicity will be expressed, provided that the Hg concentration is sufficiently high. This toxicity is likely the result of Se deficiency leading to an excess of reactive oxygen species. Laboratory fish toxicity studies reviewed show that Se toxicity can be reduced or eliminated when Hg is added to the diet in moderate amounts. Field studies have shown reduced accumulation of Hg when Se concentrations are increased. When Hg in the diet is significantly elevated (usually >10 µg/g), toxicity is expressed regardless of the Se present. Likewise, amelioration of Se toxicity by Hg occurs over a limited range. Tissue thresholds for Se toxicity have been derived primarily from studies where fish eggs were extracted from wild fish and embryo deformities were observed; however, the amount of Hg in the fish or ovaries was not considered, which could lead to uncertainty in the toxicity threshold. It is recommended that both elements be measured and evaluated when performing risk assessments and setting water quality criteria. Integr Environ Assess Manag 2024;00:1-11. © 2024 SETAC.

Myocyte shape regulates lateral registry of sarcomeres and contractility.

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.

Do Cd, Cu, Ni, Pb, and Zn biomagnify in aquatic ecosystems?

In this review, we sought to assess from a study of the literature whether five in organic metals (viz., cadmium, copper, lead, nickel, and zinc) bio magnify in aquatic food webs. We also examined whether accumulated metals were toxic to consumers/predators and whether the essential metals (Cu and Zn and possibly Ni) behaved differently from non-essential ones (Cd and Pb). Biomagnification potential was indexed by the magnitude of single and multiple trophic transfers in food chains. In this analysis, we used three lines of evidence-laboratory empirical, biokinetic modeling, and field studies-to make assessments. Trophic transfer factors, calculatedfrom lab studies, field studies, and biokinetic modeling, were generally congruent.Results indicated that Cd, Cu, Pb, and Zn generally do not biomagnify in food chains consisting of primary producers, macro invertebrate consumers, and fish occupying TL 3 and higher. However, bio magnification of Zn (TTFs of 1-2) is possible for circumstances in which dietary Zn concentrations are below those required for metabolism. Cd, Cu, Ni, and Zn may biomagnify in specific marine food chains consisting of bivalves, herbivorous gastropods, and barnacles at TL2 and carnivorous gastropods at TL3. There was an inverse relationship between TTF and exposure concentration for Cd, Cu, Pb, and Zn, a finding that is consistent with previous reviews of bioconcentration factors and bioaccumulation factors for metals. Our analysis also failed to demonstrate a relationship between the magnitude of TTFsand dietary toxicity to consumer organisms. Consequently, we conclude that TTFs for the metals examined are not an inherently useful predictor of potential hazard(i.e., toxic potential) to aquatic organisms. This review identified several uncertainties or data gaps, such as the relatively limited data available for nickel, reliance upon highly structured food chains in laboratory studies compared to the unstructured food webs found in nature, and variability in TTFs between the organisms found in different habitats, and years sampled.

Recommended updates to the USEPA Framework for Metals Risk Assessment: Aquatic ecosystems.

In 2007, the USEPA issued its "Framework for Metals Risk Assessment." The framework provides technical guidance to risk assessors and regulators when performing human health and environmental risk assessments of metals. This article focuses on advances in the science including assessing bioavailability in aquatic ecosystems, short- and long-term fate of metals in aquatic ecosystems, and advances in risk assessment of metals in sediments. Notable advances have occurred in the development of bioavailability models for assessing toxicity as a function of water chemistry in freshwater ecosystems. The biotic ligand model (BLM), the multiple linear regression model, and multimetal BLM now exist for most of the common mono- and divalent metals. Species sensitivity distributions for many metals exist, making it possible for many jurisdictions to develop or update their water quality criteria or guidelines. The understanding of the fate of metals in the environment has undergone significant scrutiny over the past 20 years. Transport and toxicity models have evolved including the Unit World Model allowing for estimation of concentrations of metals in various compartments as a function of loading and time. There has been significant focus on the transformation of metals in sediments into forms that are less bioavailable and on understanding conditions that result in resolubilization or redistribution of metals in and from sediments. Methods for spiking sediments have advanced such that the resulting chemistry in the laboratory mimics that in natural systems. Sediment bioavailability models are emerging including models that allow for prediction of toxicity in sediments for copper and nickel. Biodynamic models have been developed for several organisms and many metals. The models allow for estimates of transport of metals from sediments to organisms via their diet as well as their water exposure. All these advances expand the tool set available to risk assessors. Integr Environ Assess Manag 2023;00:1-28. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Development of Multiple Linear Regression Models for Predicting Chronic Iron Toxicity to Aquatic Organisms.

We developed multiple linear regression (MLR) models for predicting iron (Fe) toxicity to aquatic organisms for use in deriving site-specific water quality guidelines (WQGs). The effects of dissolved organic carbon (DOC), hardness, and pH on Fe toxicity to three representative taxa (Ceriodaphnia dubia, Pimephales promelas, and Raphidocelis subcapitata) were evaluated. Both DOC and pH were identified as toxicity-modifying factors (TMFs) for P. promelas and R. subcapitata, whereas only DOC was a TMF for C. dubia. The MLR models based on effective concentration 10% and 20% values were developed and performed reasonably well, with adjusted R2 of 0.68-0.89 across all species and statistical endpoints. Differences among species in the MLR models precluded development of a pooled model. Instead, the species-specific models were assumed to be representative of invertebrates, fish, and algae and were applied accordingly to normalize toxicity data. The species sensitivity distribution (SSD) included standard laboratory toxicity data and effects data from mesocosm experiments on aquatic insects, with aquatic insects being the predominant taxa in the lowest quartile of the SSD. Using the European Union approach for deriving WQGs, application of MLR models to this SSD resulted in WQGs ranging from 114 to 765 µg l-1 Fe across the TMF conditions evaluated (DOC: 0.5-10 mg l-1 ; pH: 6.0-8.4), with slightly higher WQGs (199-910 µg l-1 ) derived using the US Environmental Protection Agency (USEPA) methodology. An important uncertainty in these derivations is the applicability of the C. dubia MLR model (no pH parameter) to aquatic insects, and understanding the pH sensitivity of aquatic insects to Fe toxicity is a research priority. An Excel-based tool for calculating Fe WQGs using both European Union and USEPA approaches across a range of TMF conditions is provided. Environ Toxicol Chem 2023;42:1386-1400. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Chronic Toxicity of Iron to Aquatic Organisms under Variable pH, Hardness, and Dissolved Organic Carbon Conditions.

A series of chronic toxicity tests was conducted exposing three aquatic species to iron (Fe) in laboratory freshwaters. The test organisms included the green algae Raphidocelis subcapitata, the cladoceran Ceriodaphnia dubia, and the fathead minnow Pimephales promelas. They were exposed to Fe (as Fe (III) sulfate) in waters under varying pH (5.9-8.5), hardness (10.3-255 mg/L CaCO3 ), and dissolved organic carbon (DOC; 0.3-10.9 mg/L) conditions. Measured total Fe was used for calculations of biological effect concentrations because dissolved Fe was only a fraction of nominal and did not consistently increase as total Fe increased. This was indicative of the high concentrations of Fe required to elicit a biological response and that Fe species that did not pass through a 0.20- or 0.45-µm filter (dissolved fraction) contributed to Fe toxicity. The concentrations frequently exceeded the solubility limits of Fe(III) under circumneutral pH conditions relevant to most natural surface waters. Chronic toxicity endpoints (10% effect concentrations [EC10s]) ranged from 442 to 9607 µg total Fe/L for R. subcapitata growth, from 383 to 15 947 µg total Fe/L for C. dubia reproduction, and from 192 to 58,308 µg total Fe/L for P. promelas growth. Toxicity to R. subcapitata was variably influenced by all three water quality parameters, but especially DOC. Toxicity to C. dubia was influenced by DOC, less so by hardness, but not by pH. Toxicity to P. promelas was variable, but greatest under low hardness, low pH, and low DOC conditions. These data were used to develop an Fe-specific, bioavailability-based multiple linear regression model as part of a companion publication. Environ Toxicol Chem 2023;42:1371-1385. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Self-organization of muscle cell structure and function.

The organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomere to the muscle bundle. One possible strategy for solving this multiscale coupling problem is to physically constrain the muscle cells in microenvironments that potentiate the organization of their intracellular space. We hypothesized that boundary conditions in the extracellular space potentiate the organization of cytoskeletal scaffolds for directed sarcomeregenesis. We developed a quantitative model of how the cytoskeleton of neonatal rat ventricular myocytes organizes with respect to geometric cues in the extracellular matrix. Numerical results and in vitro assays to control myocyte shape indicated that distinct cytoskeletal architectures arise from two temporally-ordered, organizational processes: the interaction between actin fibers, premyofibrils and focal adhesions, as well as cooperative alignment and parallel bundling of nascent myofibrils. Our results suggest that a hierarchy of mechanisms regulate the self-organization of the contractile cytoskeleton and that a positive feedback loop is responsible for initiating the break in symmetry, potentiated by extracellular boundary conditions, is required to polarize the contractile cytoskeleton.

Are current tissue-based selenium guidelines and criteria overly protective of freshwater fish populations? A critical review with recommendations.

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.

The potential for salt toxicity: Can the trans-epithelial potential (TEP) across the gills serve as a metric for major ion toxicity in fish?

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.

Updated Multiple Linear Regression Models for Predicting Chronic Aluminum Toxicity to Freshwater Aquatic Organisms and Developing Water Quality Guidelines.

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 R2 for the C. dubia 20% effect concentration (EC20) model increased from 0.71 to 0.92 with the additional toxicity data, and the predicted R2 increased from 0.57 to 0.89. For P. promelas, the adjusted R2 increased from 0.87 to 0.92 and the predicted R2 increased from 0.72 to 0.87. The high predicted R2 relative to the adjusted R2 indicates that the models for both species are not overly parameterized. When data for C. dubia and P. promelas were pooled, the adjusted R2 values were comparable to the species-specific models (0.90 and 0.88 for C. dubia and P. promelas, respectively). This indicates that chronic aluminum EC20s for C. dubia and P. promelas respond similarly to variation in DOC, pH, and hardness. Overall, the pooled model predicted EC20s that were within a factor of 2 of observed in 100% of the C. dubia tests and 94% of the P. promelas tests. Environ Toxicol Chem 2020;39:1724-1736. © 2020 SETAC.

10th Anniversary Critical Review: The tissue-residue approach for toxicity assessment: concepts, issues, application, and recommendations.

The tissue-residue approach for toxicity assessment (TRA) is simply the use of tissue concentrations as the dose metric for characterizing toxicant potency. There are several advantages to using tissue residues over exposure concentrations (e.g., water, sediment, and diet) to calculate toxicity metrics. These include a large reduction in toxic response variability among all species for a given compound, an improved ability to address mixture toxicity, an increased use of information on modes and mechanisms of toxic action, a likely reduction in the number of species needed to characterize toxicant potency, the potential to improve ecological risk assessments, and the generation of more scientifically defensible tissue, water, and sediment toxicity guidelines or criteria. A keystone concept for the TRA is that the body/tissue residue reflects the target "dose" better than the traditional dose (e.g., water, air, soil/sediment, or diet) because the closer the dose surrogate is to the actual site of toxic action the less it is influenced by myriad modifying factors. Our goal for this review is to present the concepts and issues associated with the TRA and discuss some of the potential applications and expected improvements to the field of environmental toxicology that we believe will promote enhanced protection for species and ecosystems.

Multiple linear regression models for predicting chronic aluminum toxicity to freshwater aquatic organisms and developing water quality guidelines.

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.

Evaluating the effects of pH, hardness, and dissolved organic carbon on the toxicity of aluminum to freshwater aquatic organisms under circumneutral conditions.

Although it is well known that increasing water hardness and dissolved organic carbon (DOC) concentrations mitigate the toxicity of aluminum (Al) to freshwater organisms in acidic water (i.e., pH < 6), these effects are less well characterized in natural waters at circumneutral pHs for which most aquatic life regulatory protection criteria apply (i.e., pH 6-8). The evaluation of Al toxicity under varying pH conditions may also be confounded by the presence of Al hydroxides and freshly precipitated Al in newly prepared test solutions. Aging and filtration of test solutions were found to greatly reduce toxicity, suggesting that toxicity from transient forms of Al could be minimized and that precipitated Al hydroxides contribute significantly to Al toxicity under circumneutral conditions, rather than dissolved or monomeric forms. Increasing pH, hardness, and DOC were found to have a protective effect against Al toxicity for fish (Pimephales promelas) and invertebrates (Ceriodaphnia dubia, Daphnia magna). For algae (Pseudokirchneriella subcapitata), the protective effects of increased hardness were only apparent at pH 6, less so at pH 7, and at pH 8, increased hardness appeared to increase the sensitivity of algae to Al. The results support the need for water quality-based aquatic life protection criteria for Al, rather than fixed value criteria, as being a more accurate predictor of Al toxicity in natural waters. Environ Toxicol Chem 2018;37:49-60. © 2017 SETAC.

Development and application of a biotic ligand model for predicting the chronic toxicity of dissolved and precipitated aluminum to aquatic organisms.

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.