An automated computational data pipeline to rapidly acquire, score, and rank toxicological data for ecological hazard assessment.

Biological Evaluations support Endangered Species Act (ESA) consultation with the US Fish and Wildlife Service and National Marine Fisheries Service by federal action agencies, such as the USEPA, regarding impacts of federal activities on threatened or endangered species. However, they are often time-consuming and challenging to conduct. The identification of pollutant benchmarks or guidance to protect taxa for states and tribes when USEPA has not yet developed criteria recommendations is also of importance to ensure a streamlined approach to Clean Water Act program implementation.

Projection of Interspecific Competition (PIC) Matrices: A Conceptual Framework for Inclusion in Population Risk Assessments.

Accounting for intraspecific and interspecific competition when assessing the effects of chemical and nonchemical stressors is an important uncertainty in ecological risk assessments. We developed novel projection of interspecific competition (PIC) matrices that allow for analysis of population dynamics of two or more species exposed to a given stressor(s) that compete for shared resources within a landscape. We demonstrate the application of PIC matrices to investigate the population dynamics of two hypothetical fish species that compete with one another and have differences in net reproductive rate and intrinsic rate of population increase.

Towards Precision Ecotoxicology: Leveraging Evolutionary Conservation of Pharmaceutical and Personal Care Product Targets to Understand Adverse Outcomes Across Species and Life Stages.

Translation of environmental science to the practice aims to protect biodiversity and ecosystem services, and our future ability to do so relies on the development of a precision ecotoxicology approach wherein we leverage the genetics and informatics of species to better understand and manage the risks of global pollution. A little over a decade ago, a workshop focusing on the risks of pharmaceuticals and personal care products (PPCPs) in the environment identified a priority research question, "What can be learned about the evolutionary conservation of PPCP targets across species and life stages in the context of potential adverse outcomes and effects?" We review the activities in this area over the past decade, consider prospects of more recent developments, and identify future research needs to develop next-generation approaches for PPCPs and other global chemicals and waste challenges. Environ Toxicol Chem 2024;43:526-536.

Cross-species applicability of an adverse outcome pathway network for thyroid hormone system disruption.

Thyroid hormone system disrupting compounds are considered potential threats for human and environmental health. Multiple adverse outcome pathways (AOPs) for thyroid hormone system disruption (THSD) are being developed in different taxa. Combining these AOPs results in a cross-species AOP network for THSD which may provide an evidence-based foundation for extrapolating THSD data across vertebrate species and bridging the gap between human and environmental health.

Putative adverse outcome pathway development based on physiological responses of female fathead minnows to model estrogen versus androgen receptor agonists.

Several adverse outcome pathways (AOPs) have linked molecular initiating events like aromatase inhibition, androgen receptor (AR) agonism, and estrogen receptor (ER) antagonism to reproductive impairment in adult fish. Estrogen receptor agonists can also cause adverse reproductive effects, however, the early key events (KEs) in an AOP leading to this are mostly unknown. The primary aim of this study was to develop hypotheses regarding the potential mechanisms through which exposure to ER agonists might lead to reproductive impairment in female fish.

Weight of evidence for cross-species conservation of androgen receptor-based biological activity.

The U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP) is tasked with assessing chemicals for their potential to perturb endocrine pathways, including those controlled by androgen receptor (AR).

Demonstration of the Sequence Alignment to Predict Across Species Susceptibility Tool for Rapid Assessment of Protein Conservation.

The US Environmental Protection Agency Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool is a fast, freely available, online screening application that allows researchers and regulators to extrapolate toxicity information across species. For biological targets in model systems such as human cells, mice, rats, and zebrafish, toxicity data are available for a variety of chemicals. Through the evaluation of protein target conservation, this tool can be used to extrapolate data generated from such model systems to thousands of other species lacking toxicity data, yielding predictions of relative intrinsic chemical susceptibility.

Combining In Vitro and In Silico New Approach Methods to Investigate Type 3 Iodothyronine Deiodinase Chemical Inhibition Across Species.

New approach methodologies (NAMs) are being developed to reduce and replace vertebrate animal testing in support of ecotoxicology and risk assessment. The US Environmental Protection Agency's Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) bioinformatic tool was used to evaluate amino acid sequence conservation of the type 3 iodothyronine deiodinase (DIO3) enzyme across species to demonstrate NAM applications for understanding effects of chemical interactions with a specific protein target. Existing literature was used to identify critical amino acids for thyroid hormone binding and interaction with a reducing cofactor.

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.

Evaluation of Complex Mixture Toxicity in the Milwaukee Estuary (WI, USA) Using Whole-Mixture and Component-Based Evaluation Methods.

Anthropogenic activities introduce complex mixtures into aquatic environments, necessitating mixture toxicity evaluation during risk assessment. There are many alternative approaches that can be used to complement traditional techniques for mixture assessment. Our study aimed to demonstrate how these approaches could be employed for mixture evaluation in a target watershed.

From Protein Sequence to Structure: The Next Frontier in Cross-Species Extrapolation for Chemical Safety Evaluations.

Computational screening for potentially bioactive molecules using advanced molecular modeling approaches including molecular docking and molecular dynamic simulation is mainstream in certain fields like drug discovery. Significant advances in computationally predicting protein structures from sequence information have also expanded the availability of structures for nonmodel species. Therefore, the objective of the present study was to develop an analysis pipeline to harness the power of these bioinformatics approaches for cross-species extrapolation for evaluating chemical safety.

Defining the Biologically Plausible Taxonomic Domain of Applicability of an Adverse Outcome Pathway: A Case Study Linking Nicotinic Acetylcholine Receptor Activation to Colony Death.

For the majority of developed adverse outcome pathways (AOPs), the taxonomic domain of applicability (tDOA) is typically narrowly defined with a single or a handful of species. Defining the tDOA of an AOP is critical for use in regulatory decision-making, particularly when considering protection of untested species. Structural and functional conservation are two elements that can be considered when defining the tDOA.

Linking Mechanistic Effects of Pharmaceuticals and Personal Care Products to Ecologically Relevant Outcomes: A Decade of Progress.

There are insufficient toxicity data to assess the ecological risks of many pharmaceuticals and personal care products (PPCPs). While data limitations are not uncommon for contaminants of environmental concern, PPCPs are somewhat unique in that an a priori understanding of their biological activities in conjunction with measurements of molecular, biochemical, or histological responses could provide a foundation for understanding mode(s) of action and predicting potential adverse apical effects. Over the past decade significant progress has been made in the development of new approach methodologies (NAMs) to efficiently quantify these types of endpoints using computational models and pathway-based in vitro and in vivo assays.

Current ecotoxicity testing needs among selected U.S. federal agencies.

U.S. regulatory and research agencies use ecotoxicity test data to assess the hazards associated with substances that may be released into the environment, including but not limited to industrial chemicals, pharmaceuticals, pesticides, food additives, and color additives.

Leveraging ToxCast data and protein sequence conservation to complement aquatic life criteria derivation.

The USEPA's 1985 guidelines for the derivation of aquatic life criteria (ALC) are robust but data-intensive. For many chemicals, the extensive in vivo data sets required for ALC derivation are not available. Thus, alternative analyses and processes that can provide provisional values to guide states, tribes, and other stakeholders while data accumulate and more rigorous criteria are derived would be beneficial.

The ECOTOXicology Knowledgebase: A Curated Database of Ecologically Relevant Toxicity Tests to Support Environmental Research and Risk Assessment.

The need for assembled existing and new toxicity data has accelerated as the amount of chemicals introduced into commerce continues to grow and regulatory mandates require safety assessments for a greater number of chemicals. To address this evolving need, the ECOTOXicology Knowledgebase (ECOTOX) was developed starting in the 1980s and is currently the world's largest compilation of curated ecotoxicity data, providing support for assessments of chemical safety and ecological research through systematic and transparent literature review procedures. The recently released version of ECOTOX (Ver 5, www.

Assessing effects of aromatase inhibition on fishes with group-synchronous oocyte development using western mosquitofish (Gambusia affinis) as a model.

Exposure to certain anthropogenic chemicals can inhibit the activity to cytochrome P450 aromatase (CYP19) in fishes leading to decreased plasma 17β-estradiol (E2), plasma vitellogenin (VTG), and egg production. Reproductive dysfunction resulting from exposure to aromatase inhibitors has been extensively investigated in several laboratory model species of fish. These model species have ovaries that undergo asynchronous oocyte development, but many fishes have ovaries with group-synchronous oocyte development.

Conversion of Estrone to 17β-Estradiol: A Potential Confounding Factor in Assessing Risks of Environmental Estrogens to Fish.

Feminization of male fish and the role of endocrine-active chemicals in this phenomenon has been an area of intense study for many years. Estrone (E1), a natural steroid, is found in aquatic environments sometimes at high concentrations relative to the estrogenic steroids 17β-estradiol (E2) and 17α-ethynylestradiol. However, E1 has been less thoroughly studied than E2 or 17α-ethynylestradiol due in part to a relatively lower potency in metabolically limited estrogen receptor (ER) binding/activation assays.

Toxicology Advances for 21 Century Chemical Pollution.

Pollution represents a leading threat to global health and ecosystems. Systems-based initiatives, including Planetary Health, EcoHealth, and One Health, require theoretical and translational platforms to address chemical pollution. Comparative and predictive toxicology are providing integrative approaches for identifying problematic contaminants, designing less hazardous alternatives, and reducing the impacts of chemical pollution.

Nontarget Screening of Per- and Polyfluoroalkyl Substances Binding to Human Liver Fatty Acid Binding Protein.

More than 1000 per- and polyfluoroalkyl substances (PFASs) have been discovered by nontarget analysis (NTA), but their prioritization for health concerns is challenging. We developed a method by incorporating size-exclusion column co-elution (SECC) and NTA, to screen PFASs binding to human liver fatty acid binding protein (L-FABP). Of 74 PFASs assessed, 20 were identified as L-FABP ligands in which eight of them have high binding affinities.

Adverse Outcome Pathway Network-Based Assessment of the Interactive Effects of an Androgen Receptor Agonist and an Aromatase Inhibitor on Fish Endocrine Function.

Predictive approaches to assessing the toxicity of contaminant mixtures have been largely limited to chemicals that exert effects through the same biological molecular initiating event. However, by understanding specific pathways through which chemicals exert effects, it may be possible to identify shared "downstream" nodes as the basis for forecasting interactive effects of chemicals with different molecular initiating events. Adverse outcome pathway (AOP) networks conceptually support this type of analysis.

Quantitative Response-Response Relationships Linking Aromatase Inhibition to Decreased Fecundity are Conserved Across Three Fishes with Asynchronous Oocyte Development.

Quantitative adverse outcome pathways (qAOPs) describe quantitative response-response relationships that can predict the probability or severity of an adverse outcome for a given magnitude of chemical interaction with a molecular initiating event. However, the taxonomic domain of applicability for these predictions is largely untested. The present study began defining this applicability for a previously described qAOP for aromatase inhibition leading to decreased fecundity developed using data from fathead minnow ().

Adverse Outcome Pathways: Moving from a Scientific Concept to an Internationally Accepted Framework.

The adverse outcome pathway (AOP) framework has gained significant international traction as a systematic approach for capturing toxicological knowledge to transparently link mechanistic data to apical endpoints that inform research and regulatory decision-making. While the framework has evolved significantly since its introduction in 2010, it was recognized that a survey of the broader scientific community would be useful in identifying shortcomings and guiding further development. In 2016 we reached out to this community through an international horizon scanning exercise to gather information on key outstanding challenges that must be addressed in order to realize the full potential of the AOP framework.