Quantitative Structure Use Relationships: Highlights from a technical summit meeting.

The Quantitative Structure Use Relationship (QSUR) Summit, held on November 2-4, 2022, focused on advancing the development, refinement, and use of QSURs to support chemical substance prioritization and risk assessment and mitigation. QSURs utilize chemical structures to predict the function of a chemical within a formulated product or an industrial process. This presumed function can then be used to develop chemical use categories or other information necessary to refine exposure assessments. The invited expert meeting was attended by 38 scientists from Canada, Finland, France, the UK, and the USA, representing government, business, and academia, with expertise in exposure science, chemical engineering, risk assessment, formulation chemistry, and machine learning. Workshop discussions emphasized the importance of collection and sharing of data and quantification of relative chemical quantities to progress QSUR development. Participants proposed collaborative approaches to address key challenges, including mechanisms for aggregating information while still protecting proprietary product composition and other confidential business information. Discussions also led to proposals for applications beyond exposure and risk modeling, including sustainable formulation discovery. In addition, discussions continue to construct, conduct, and circulate case studies tied to various specific problem formulations in which QSURs supply or derive information on chemical functions, concentrations, and exposures.

Construction of an In Silico Structural Profiling Tool Facilitating Mechanistically Grounded Classification of Aquatic Toxicants.

The performance of chemical safety assessment within the domain of environmental toxicology is often impeded by a shortfall of appropriate experimental data describing potential hazards across the many compounds in regular industrial use. In silico schemes for assigning aquatic-relevant modes or mechanisms of toxic action to substances, based solely on consideration of chemical structure, have seen widespread employment─including those of Verhaar, Russom, and later Bauer (MechoA). Recently, development of a further system was reported by Sapounidou, which, in common with MechoA, seeks to ground its classifications in understanding and appreciation of molecular initiating events. Until now, this Sapounidou scheme has not seen implementation as a tool for practical screening use. Accordingly, the primary purpose of this study was to create such a resource─in the form of a computational workflow. This exercise was facilitated through the formulation of 183 structural alerts/rules describing molecular features associated with narcosis, chemical reactivity, and specific mechanisms of action. Output was subsequently compared relative to that of the three aforementioned alternative systems to identify strengths and shortcomings as regards coverage of chemical space.

A scheme to evaluate structural alerts to predict toxicity - Assessing confidence by characterising uncertainties.

Structure-activity relationships (SARs) in toxicology have enabled the formation of structural rules which, when coded as structural alerts, are essential tools in in silico toxicology. Whilst other in silico methods have approaches for their evaluation, there is no formal process to assess the confidence that may be associated with a structural alert. This investigation proposes twelve criteria to assess the uncertainty associated with structural alerts, allowing for an assessment of confidence. The criteria are based around the stated purpose, description of the chemistry, toxicology and mechanism, performance and coverage, as well as corroborating and supporting evidence of the alert. Alerts can be given a confidence assessment and score, enabling the identification of areas where more information may be beneficial. The scheme to evaluate structural alerts was placed in the context of various use cases for industrial and regulatory applications. The analysis of alerts, and consideration of the evaluation scheme, identifies the different characteristics an alert may have, such as being highly specific or generic. These characteristics may determine when an alert can be used for specific uses such as identification of analogues for read-across or hazard identification.

Development of an Enhanced Mechanistically Driven Mode of Action Classification Scheme for Adverse Effects on Environmental Species.

This study developed a novel classification scheme to assign chemicals to a verifiable mechanism of (eco-)toxicological action to allow for grouping, read-across, and in silico model generation. The new classification scheme unifies and extends existing schemes and has, at its heart, direct reference to molecular initiating events (MIEs) promoting adverse outcomes. The scheme is based on three broad domains of toxic action representing nonspecific toxicity (e.g., narcosis), reactive mechanisms (e.g., electrophilicity and free radical action), and specific mechanisms (e.g., associated with enzyme inhibition). The scheme is organized at three further levels of detail beyond broad domains to separate out the mechanistic group, specific mechanism, and the MIEs responsible. The novelty of this approach comes from the reference to taxonomic diversity within the classification, transparency, quality of supporting evidence relating to MIEs, and that it can be updated readily.

HFSA/SAEM/ISHLT Clinical Expert Consensus Document on the Emergency Management of Patients with Ventricular Assist Devices.

Mechanical circulatory support is now widely accepted as a viable long-term treatment option for patients with end-stage heart failure (HF). As the range of indications for the implantation of ventricular assist devices grows, so does the number of patients living in the community with durable support. Because of their underlying disease and comorbidities, in addition to the presence of mechanical support, these patients are at a high risk for medical urgencies and emergencies (Table 1). Thus, it is the responsibility of clinicians to understand the basics of their emergency care. This consensus document represents a collaborative effort by the Heart Failure Society of America, the Society for Academic Emergency Medicine, and the International Society for Heart and Lung Transplantation (ISHLT) to educate practicing clinicians about the emergency management of patients with ventricular assist devices. The target audience includes HF specialists and emergency medicine physicians, as well as general cardiologists and community-based providers.

The effect of completeness of revascularization during CABG with single versus multiple arterial grafts.

INTRODUCTION: Incomplete coronary revascularization is associated with suboptimal outcomes. We investigated the long-term effects of Incomplete, Complete, and Supra-complete revascularization and whether these effects differed in the setting of single-arterial and multi-arterial coronary artery bypass graft (CABG). METHODS: We analyzed 15-year mortality in 7157 CABG patients (64.1 ± 10.5 years; 30% women). All patients received a left internal thoracic artery to left anterior descending coronary artery graft with additional venous grafts only (single-arterial) or with at least one additional arterial graft (multi-arterial) and were grouped based on a completeness of revascularization index (CRI = number of grafts minus the number of diseased principal coronary arteries): Incomplete (CRI ≤ -1 [N = 320;4.5%]); Complete (CRI = 0 [N = 2882;40.3%]; reference group); and two Supra-complete categories (CRI = +1[N = 3050; 42.6%]; CRI ≥ + 2 [N = 905; 12.6%]). Risk-adjusted mortality hazard ratios (AHR) were calculated using comprehensive propensity score adjustment by Cox regression. RESULTS: Incomplete revascularization was rare (4.5%) but associated with increased mortality in all patients (AHR [95% confidence interval] = 1.53 [1.29-1.80]), those undergoing single-arterial CABG (AHR = 1.27 [1.04-1.54]) and multi-arterial CABG (AHR = 2.18 [1.60-2.99]), as well as in patients with 3-Vessel (AHR = 1.37 [1.16-1.62]) and, to a lesser degree, with 2-Vessel (AHR = 1.67 [0.53-5.23]) coronary disease. Supra-complete revascularization was generally associated with incrementally decreased mortality in all patients (AHR [CRI = +1] = 0.94 [0.87-1.03]); AHR [CRI ≥ +2] = 0.74 [0.64-0.85]), and was driven by a significantly decreased mortality risk in single-arterial CABG (AHR [CRI = +1] = 0.90 [0.81-0.99]; AHR [CRI ≥ +2] = 0.64 [0.53-0.78]); and 3-Vessel disease patients (AHR [CRI = +1] = 0.94 [0.86-1.04]; and AHR [CRI ≥ +2] = 0.75 [0.63-0.88]) with no impact in multi-arterial CABG (AHR [CRI = +1] = 1.07 [0.91-1.26]; AHR [CRI ≥ +2] = 0.93 [0.73-1.17]). CONCLUSIONS: Incomplete revascularization is associated with decreased late survival, irrespective of grafting strategy. Alternatively, supra-complete revascularization is associated with improved survival in patients with 3-Vessel CAD, and in single-arterial but not multi-arterial CABG.

Use of Extracorporeal Membrane Oxygenation and Surgical Embolectomy for Massive Pulmonary Embolism in the Emergency Department.

BACKGROUND: Massive pulmonary embolism (PE) carries significant morbidity and mortality with current standard of care modalities. CASE REPORT: We present the case of a 63-year-old male status post abdominal surgery 2 weeks before presenting to the emergency department with a massive pulmonary embolism and subsequent acute cardiopulmonary failure. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Here we describe a case of extracorporeal membrane oxygenation (ECMO) deployed in the emergency department as a bridge to embolectomy to successfully treat massive pulmonary embolism. This provided the opportunity to establish a "Code ECMO" protocol and algorithm for PE with cardiopulmonary instability so that patients can be rapidly triaged to the appropriate treatment modality.

Heart Failure in Non-Caucasians, Women, and Older Adults: A White Paper on Special Populations From the Heart Failure Society of America Guideline Committee.

The presentation, natural history, clinical outcomes, and response to therapy in patients with heart failure differ in some ways across populations. Women, older adults, and non-Caucasian racial or ethnic groups compose a substantial proportion of the overall heart failure population, but they have typically been underrepresented in clinical trials. As a result, uncertainty exists about the efficacy of some guideline-directed medical therapies and devices in specific populations, which may result in the under- or overtreatment of these patients. Even when guideline-based treatments are prescribed, socioeconomic, physical, or psychologic factors may affect non-Caucasian and older adult patient groups to a different extent and affect the application, effectiveness, and tolerability of these therapies. Individualized therapy based on tailored biology (genetics, proteomics, metabolomics), socioeconomic and cultural considerations, and individual goals and preferences may be the optimal approach for managing diverse patients. This comprehensive approach to personalized medicine is evolving, but in the interim, the scientific community should continue efforts focused on intensifying research in special populations, prescribing guideline-directed medical therapy unless contraindicated, and implementing evidence-based strategies including patient and family education and multidisciplinary team care in the management of patients.

Advanced (stage D) heart failure: a statement from the Heart Failure Society of America Guidelines Committee.

We propose that stage D advanced heart failure be defined as the presence of progressive and/or persistent severe signs and symptoms of heart failure despite optimized medical, surgical, and device therapy. Importantly, the progressive decline should be primarily driven by the heart failure syndrome. Formally defining advanced heart failure and specifying when medical and device therapies have failed is challenging, but signs and symptoms, hemodynamics, exercise testing, biomarkers, and risk prediction models are useful in this process. Identification of patients in stage D is a clinically important task because treatments are inherently limited, morbidity is typically progressive, and survival is often short. Age, frailty, and psychosocial issues affect both outcomes and selection of therapy for stage D patients. Heart transplant and mechanical circulatory support devices are potential treatment options in select patients. In addition to considering indications, contraindications, clinical status, and comorbidities, treatment selection for stage D patients involves incorporating the patient's wishes for survival versus quality of life, and palliative and hospice care should be integrated into care plans. More research is needed to determine optimal strategies for patient selection and medical decision making, with the ultimate goal of improving clinical and patient centered outcomes in patients with stage D heart failure.

Transmural heterogeneity of cellular level power output is reduced in human heart failure.

Heart failure is associated with pump dysfunction and remodeling but it is not yet known if the condition affects different transmural regions of the heart in the same way. We tested the hypotheses that the left ventricles of non-failing human hearts exhibit transmural heterogeneity of cellular level contractile properties, and that heart failure produces transmural region-specific changes in contractile function. Permeabilized samples were prepared from the sub-epicardial, mid-myocardial, and sub-endocardial regions of the left ventricular free wall of non-failing (n=6) and failing (n=10) human hearts. Power, an in vitro index of systolic function, was higher in non-failing mid-myocardial samples (0.59±0.06µWmg(-1)) than in samples from the sub-epicardium (p=0.021) and the sub-endocardium (p=0.015). Non-failing mid-myocardial samples also produced more isometric force (14.3±1.33kNm(-2)) than samples from the sub-epicardium (p=0.008) and the sub-endocardium (p=0.026). Heart failure reduced power (p=0.009) and force (p=0.042) but affected the mid-myocardium more than the other transmural regions. Fibrosis increased with heart failure (p=0.021) and mid-myocardial tissue from failing hearts contained more collagen than matched sub-epicardial (p<0.001) and sub-endocardial (p=0.043) samples. Power output was correlated with the relative content of actin and troponin I, and was also statistically linked to the relative content and phosphorylation of desmin and myosin light chain-1. Non-failing human hearts exhibit transmural heterogeneity of contractile properties. In failing organs, region-specific fibrosis produces the greatest contractile deficits in the mid-myocardium. Targeting fibrosis and sarcomeric proteins in the mid-myocardium may be particularly effective therapies for heart failure.

Using membrane-water partition coefficients in a critical membrane burden approach to aid the identification of neutral and ionizable chemicals that induce acute toxicity below narcosis levels.

The risk assessment of thousands of chemicals used in our society benefits from adequate grouping of chemicals based on the mode and mechanism of toxic action (MoA). We measure the phospholipid membrane-water distribution ratio (DMLW) using a chromatographic assay (IAM-HPLC) for 121 neutral and ionized organic chemicals and screen other methods to derive DMLW. We use IAM-HPLC based DMLW as a chemical property to distinguish between baseline narcosis and specific MoA, for reported acute toxicity endpoints on two separate sets of chemicals. The first set comprised 94 chemicals of US EPA's acute fish toxicity database: 47 categorized as narcosis MoA, 27 with specific MoA, and 20 predominantly ionic chemicals with mostly unknown MoA. The narcosis MoA chemicals clustered around the median narcosis critical membrane burden (CMBnarc) of 140 mmol kg-1 lipid, with a lower limit of 14 mmol kg-1 lipid, including all chemicals labelled Narcosis_I and Narcosis_II. This maximum 'toxic ratio' (TR) between CMBnarc and the lower limit narcosis endpoint is thus 10. For 23/28 specific MoA chemicals a TR >10 was derived, indicative of a specific adverse effect pathway related to acute toxicity. For 10/12 cations categorized as "unsure amines", the TR <10 suggests that these affect fish via narcosis MoA. The second set comprised 29 herbicides, including 17 dissociated acids, and evaluated the TR for acute toxic effect concentrations to likely sensitive aquatic plant species (green algae and macrophytes Lemna and Myriophyllum), and non-target animal species (invertebrates and fish). For 21/29 herbicides, a TR >10 indicated a specific toxic mode of action other than narcosis for at least one of these aquatic primary producers. Fish and invertebrate TRs were mostly <10, particularly for neutral herbicides, but for acidic herbicides a TR >10 indicated specific adverse effects in non-target animals. The established critical membrane approach to derive the TR provides for useful contribution to the weight of evidence to bin a chemical as having a narcosis MoA or less likely to have acute toxicity caused by a more specific adverse effect pathway. After proper calibration, the chromatographic assay provides consistent and efficient experimental input for both neutral and ionizable chemicals to this approach.

New Approach Methodologies for the Endocrine Activity Toolbox: Environmental Assessment for Fish and Amphibians.

Multiple in vivo test guidelines focusing on the estrogen, androgen, thyroid, and steroidogenesis pathways have been developed and validated for mammals, amphibians, or fish. However, these tests are resource-intensive and often use a large number of laboratory animals. Developing alternatives for in vivo tests is consistent with the replacement, reduction, and refinement principles for animal welfare considerations, which are supported by increasing mandates to move toward an "animal-free" testing paradigm worldwide. New approach methodologies (NAMs) hold great promise to identify molecular, cellular, and tissue changes that can be used to predict effects reliably and more efficiently at the individual level (and potentially on populations) while reducing the number of animals used in (eco)toxicological testing for endocrine disruption. In a collaborative effort, experts from government, academia, and industry met in 2020 to discuss the current challenges of testing for endocrine activity assessment for fish and amphibians. Continuing this cross-sector initiative, our review focuses on the current state of the science regarding the use of NAMs to identify chemical-induced endocrine effects. The present study highlights the challenges of using NAMs for safety assessment and what work is needed to reduce their uncertainties and increase their acceptance in regulatory processes. We have reviewed the current NAMs available for endocrine activity assessment including in silico, in vitro, and eleutheroembryo models. New approach methodologies can be integrated as part of a weight-of-evidence approach for hazard or risk assessment using the adverse outcome pathway framework. The development and utilization of NAMs not only allows for replacement, reduction, and refinement of animal testing but can also provide robust and fit-for-purpose methods to identify chemicals acting via endocrine mechanisms. Environ Toxicol Chem 2023;42:757-777. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Right Ventricular Dysfunction and Short-Term Outcomes Following Left-Sided Valvular Surgery: An Echocardiographic Study.

Background The prognostic value of echocardiographic evaluation of right ventricular (RV) function in patients undergoing left-sided valvular surgery has not been well described. The objective of this study is to determine the role of broad echocardiographic assessment of RV function in predicting short-term outcomes after valvular surgery. Methods and Results Preoperative echocardiographic data, perioperative adverse outcomes, and 30-day mortality were analyzed in patients who underwent left-sided valvular surgery from 2006 to 2014. Echocardiographic parameters used to evaluate RV function include RV fractional area change, tricuspid annular plane systolic excursion, systolic movement of the RV lateral wall using tissue Doppler imaging (S'), RV myocardial performance index, and RV dP/dt. Subjects with at least 3 abnormal parameters out of the 5 aforementioned indices were defined as having significant RV dysfunction. The study included 269 patients with valvular surgery (average age: 67±15, 60.6% male, 148 aortic, and 121 mitral). RV dysfunction was found in 53 (19.7%) patients; 30-day mortality occurred in 20 patients (7.5%). Compared with normal RV function, patients with RV dysfunction had higher 30-day mortality (22.6% versus 3.8%; P=0.01) and were at risk for developing multisystem failure/shock (13.2% versus 3.2%; P=0.01). Multivariate analyses showed that preexisting RV dysfunction was the strongest predictor of increased 30-day mortality (odds ratio: 3.5; 95% CI, 1.1-11.1; P<0.05). Conclusions Preoperative RV dysfunction identified by comprehensive echocardiographic assessment is a strong predictor of adverse outcomes following left-sided valvular surgery.

An Emergency Medicine-focused Summary of the HFSA/SAEM/ISHLT Clinical Consensus Document on the Emergency Management of Patients With Ventricular Assist Devices.

Mechanical circulatory support is increasingly used as a long-term treatment option for patients with end-stage heart failure. Patients with implanted ventricular assist devices are at high risk for a range of diverse medical urgencies and emergencies. Given the increasing prevalence of mechanical circulatory support devices, this expert clinical consensus document seeks to help inform emergency medicine and prehospital providers regarding the approach to acute medical and surgical conditions encountered in these complex patients.

Orthopedic Principles to Facilitate Enhanced Recovery After Cardiac Surgery.

Enhanced recovery after surgery (ERAS) protocols recognize early postoperative mobilization as a driver of faster postoperative recovery, return to normal activities, and improved long-term patient outcomes. For patients undergoing open cardiac surgery, an opportunity for facilitating earlier mobilization and a return to normal activity lies in the use of improved techniques to stabilize the sternal osteotomy. By following the key orthopedic principles of approximation, compression, and rigid fixation, a more nuanced approach to sternal precaution protocols is possible, which may enable earlier patient mobilization, physical rehabilitation, and recovery.

A quantitative structure-activity relationship for predicting metabolic biotransformation rates for organic chemicals in fish.

An evaluated database of whole body in vivo biotransformation rate estimates in fish was used to develop a model for predicting the primary biotransformation half-lives of organic chemicals. The estimated biotransformation rates were converted to half-lives and divided into a model development set (n=421) and an external validation set (n=211) to test the model. The model uses molecular substructures similar to those of other biodegradation models. The biotransformation half-life predictions were calculated based on multiple linear regressions of development set data against counts of 57 molecular substructures, the octanol-water partition coefficient, and molar mass. The coefficient of determination (r2) for the development set was 0.82, the cross-validation (leave-one-out coefficient of determination, q2) was 0.75, and the mean absolute error (MAE) was 0.38 log units (factor of 2.4). Results for the external validation of the model using an independent test set were r2 = 0.73 and MAE = 0.45 log units (factor of 2.8). For the development set, 68 and 95% of the predicted values were within a factor of 3 and a factor of 10 of the expected values, respectively. For the test (or validation) set, 63 and 90% of the predicted values were within a factor of 3 and a factor of 10 of the expected values, respectively. Reasons for discrepancies between model predictions and expected values are discussed and recommendations are made for improving the model. This model can predict biotransformation rate constants from chemical structure for screening level bioaccumulation hazard assessments, exposure and risk assessments, comparisons with other in vivo and in vitro estimates, and as a contribution to testing strategies that reduce animal usage.

The state of in vitro science for use in bioaccumulation assessments for fish.

Through the concerted evaluations of thousands of commercial substances for the qualities of persistence, bioaccumulation, and toxicity as a result of the United Nations Environment Program's Stockholm Convention, it has become apparent that fewer empirical data are available on bioaccumulation than other endpoints and that bioaccumulation models were not designed to accommodate all chemical classes. Due to the number of chemicals that may require further assessment, in vivo testing is cost prohibitive and discouraged due to the large number of animals needed. Although in vitro systems are less developed and characterized for fish, multiple high-throughput in vitro assays have been used to explore the dietary uptake and elimination of pharmaceuticals and other xenobiotics by mammals. While similar processes determine bioaccumulation in mammalian species, a review of methods to measure chemical bioavailability in fish screening systems, such as chemical biotransformation or metabolism in tissue slices, perfused tissues, fish embryos, primary and immortalized cell lines, and subcellular fractions, suggest quantitative and qualitative differences between fish and mammals exist. Using in vitro data in assessments for whole organisms or populations requires certain considerations and assumptions to scale data from a test tube to a fish, and across fish species. Also, different models may incorporate the predominant site of metabolism, such as the liver, and significant presystemic metabolism by the gill or gastrointestinal system to help accurately convert in vitro data into representative whole-animal metabolism and subsequent bioaccumulation potential. The development of animal alternative tests for fish bioaccumulation assessment is framed in the context of in vitro data requirements for regulatory assessments in Europe and Canada.

Creation of a Curated Aquatic Toxicology Database: EnviroTox.

Flexible, rapid, and predictive approaches that do not require the use of large numbers of vertebrate test animals are needed because the chemical universe remains largely untested for potential hazards. Development of robust new approach methodologies and nontesting approaches requires the use of existing information via curated, integrated data sets. The ecological threshold of toxicological concern (ecoTTC) represents one such new approach methodology that can predict a conservative de minimis toxicity value for chemicals with little or no information available. For the creation of an ecoTTC tool, a large, diverse environmental data set was developed from multiple sources, with harmonization, characterization, and information quality assessment steps to ensure that the information could be effectively organized and mined. The resulting EnviroTox database contains 91 217 aquatic toxicity records representing 1563 species and 4016 unique Chemical Abstracts Service numbers and is a robust, curated database containing high-quality aquatic toxicity studies that are traceable to the original information source. Chemical-specific information is also linked to each record and includes physico-chemical information, chemical descriptors, and mode of action classifications. Toxicity data are associated with the physico-chemical data, mode of action classifications, and curated taxonomic information for the organisms tested. The EnviroTox platform also includes 3 analysis tools: a predicted-no-effect concentration calculator, an ecoTTC distribution tool, and a chemical toxicity distribution tool. Although the EnviroTox database and tools were originally developed to support ecoTTC analysis and development, they have broader applicability to the field of ecological risk assessment. Environ Toxicol Chem 2019;9999:1-12. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Mode of Action Classifications in the EnviroTox Database: Development and Implementation of a Consensus MOA Classification.

Multiple mode of action (MOA) frameworks have been developed in aquatic ecotoxicology, mainly based on fish toxicity. These frameworks provide information on a key determinant of chemical toxicity, but the MOA categories and level of specificity remain unique to each of the classification schemes. The present study aimed to develop a consensus MOA assignment within EnviroTox, a curated in vivo aquatic toxicity database, based on the following MOA classification schemes: Verhaar (modified) framework, Assessment Tool for Evaluating Risk, Toxicity Estimation Software Tool, and OASIS. The MOA classifications from each scheme were first collapsed into one of 3 categories: non-specifically acting (i.e., narcosis), specifically acting, or nonclassifiable. Consensus rules were developed based on the degree of concordance among the 4 individual MOA classifications to attribute a consensus MOA to each chemical. A confidence rank was also assigned to the consensus MOA classification based on the degree of consensus. Overall, 40% of the chemicals were classified as narcotics, 17% as specifically acting, and 43% as unclassified. Sixty percent of chemicals had a medium to high consensus MOA assignment. When compared to empirical acute toxicity data, the general trend of specifically acting chemicals being more toxic is clearly observed for both fish and invertebrates but not for algae. EnviroTox is the first approach to establishing a high-level consensus across 4 computationally and structurally distinct MOA classification schemes. This consensus MOA classification provides both a transparent understanding of the variation between MOA classification schemes and an added certainty of the MOA assignment. In terms of regulatory relevance, a reliable understanding of MOA can provide information that can be useful for the prioritization (ranking) and risk assessment of chemicals. Environ Toxicol Chem 2019;38:2294-2304. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.