Expanded Systematic Evidence Map for Hundreds of Per- and Polyfluoroalkyl Substances (PFAS) and Comprehensive PFAS Human Health Dashboard.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) encompass a class of chemically and structurally diverse compounds that are extensively used in industry and detected in the environment. The US Environmental Protection Agency (US EPA) 2021 PFAS Strategic Roadmap describes national research plans to address the challenge of PFAS. OBJECTIVES: Systematic Evidence Map (SEM) methods were used to survey and summarize available epidemiological and mammalian bioassay evidence that could inform human health hazard identification for a set of 345 PFAS that were identified by the US EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing and through interagency discussions on PFAS of interest. This work builds from the 2022 evidence map that collated evidence on a separate set of ∼150 PFAS. Like our previous work, this SEM does not include PFAS that are the subject of ongoing or completed assessments at the US EPA. METHODS: SEM methods were used to search, screen, and inventory mammalian bioassay and epidemiological literature from peer-reviewed and gray literature sources using manual review and machine-learning software. For each included study, study design details and health end points examined were summarized in interactive web-based literature inventories. Some included studies also underwent study evaluation and detailed extraction of health end point data. All underlying data is publicly available online as interactive visuals with downloadable metadata. RESULTS: More than 13,000 studies were identified from scientific databases. Screening processes identified 121 mammalian bioassay and 111 epidemiological studies that met screening criteria. Epidemiological evidence (available for 12 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Mammalian bioassay evidence (available for 30 PFAS) commonly assessed effects in the reproductive, whole-body, nervous, and hepatic systems. Overall, 41 PFAS had evidence across mammalian bioassay and epidemiology data streams (roughly 11% of searched chemicals). DISCUSSION: No epidemiological and/or mammalian bioassay evidence were identified for most of the PFAS included in our search. Results from this SEM, our 2022 SEM on ∼150 PFAS, and other PFAS assessment products from the US EPA are compiled into a comprehensive PFAS dashboard that provides researchers and regulators an overview of the current PFAS human health landscape including data gaps and can serve as a scoping tool to facilitate prioritization of PFAS-related research and/or risk assessment activities. https://doi.org/10.1289/EHP13423.

Why adverse outcome pathways need to be FAIR.

Adverse outcome pathways (AOPs) provide evidence for demonstrating and assessing causality between measurable toxicological mechanisms and human or environmental adverse effects. AOPs have gained increasing attention over the past decade and are believed to provide the necessary steppingstone for more effective risk assessment of chemicals and materials and moving beyond the need for animal testing. However, as with all types of data and knowledge today, AOPs need to be reusable by machines, i.e., machine-actionable, in order to reach their full impact potential. Machine-actionability is supported by the FAIR principles, which guide findability, accessibility, interoperability, and reusability of data and knowledge. Here, we describe why AOPs need to be FAIR and touch on aspects such as the improved visibility and the increased trust that FAIRification of AOPs provides.

New approach methodologies (NAMs) can detect biological phenomena that occur before they add up to serious problems like cancer, infertility, death, and others. NAMs detect key events (KE) along well-proven and agreed adverse outcome pathways (AOP). If a substance tests positive in a NAM for an upstream KE, this signals an early warning that actual adversity might follow. However, what if the knowledge about these AOPs is a well-kept secret? And what if decision-makers find AOPs too exotic to apply in risk assessment? This is where FAIR comes in! FAIR stands for making information findable, accessible, interoperable and re-useable. It aims to increase availability, usefulness, and trustworthiness of data. Here, we show that by interpreting the FAIR principles beyond a purely technical level, AOPs can ring in a new era of 3Rs applicability ‒ by increasing their visibility and making their creation process more transparent and reproducible.

Use of systematic evidence maps within the US environmental protection agency (EPA) integrated risk information system (IRIS) program: Advancements to date and looking ahead.

Systematic evidence maps (SEMs) are increasingly used to inform decision-making and risk management priority-setting and to serve as problem formulation tools to refine the focus of questions that get addressed in full systematic reviews. Within the U.S. Environmental Protection Agency (EPA) Office of Research and Development (ORD) Integrated Risk Information System (IRIS), SEMs have been used to inform data gaps, determine the need for updated assessments, inform assessment priorities, and inform development of study evaluation considerations, among other uses. Increased utilization of SEMs across the environmental health field has the potential to increase transparency and efficiency for data gathering, problem formulation, read-across, and evidence surveillance. Use of the SEM templates published in the companion text (Thayer et al.) can promote harmonization in the environmental health community and create more opportunities for sharing extracted content.

Systematic evidence map (SEM) template: Report format and methods used for the US EPA Integrated Risk Information System (IRIS) program, Provisional Peer Reviewed Toxicity Value (PPRTV) program, and other "fit for purpose" literature-based human health analyses.

BACKGROUND: Systematic evidence maps (SEMs) are gaining visibility in environmental health for their utility to serve as problem formulation tools and assist in decision-making, especially for priority setting. SEMs are now routinely prepared as part of the assessment development process for the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) and Provisional Peer Reviewed Toxicity Value (PPRTV) assessments. SEMs can also be prepared to explore the available literature for an individual chemical or groups of chemicals of emerging interest. OBJECTIVES: This document describes the typical methods used to produce SEMs for the IRIS and PPRTV Programs, as well as "fit for purpose" applications using a variety of examples drawn from existing analyses. It is intended to serve as an example base template that can be adapted as needed for the specific SEM. The presented methods include workflows intended to facilitate rapid production. The Populations, Exposures, Comparators and Outcomes (PECO) criteria are typically kept broad to identify mammalian animal bioassay and epidemiological studies that could be informative for human hazard identification. In addition, a variety of supplemental content is tracked, e.g., studies presenting information on in vitro model systems, non-mammalian model systems, exposure-level-only studies in humans, pharmacokinetic models, and absorption, distribution, metabolism, and excretion (ADME). The availability of New Approach Methods (NAMs) evidence is also tracked (e.g., high throughput, transcriptomic, in silico, etc.). Genotoxicity studies may be considered as PECO relevant or supplemental material, depending on the topic and context of the review. Standard systematic review practices (e.g., two independent reviewers per record) and specialized software applications are used to search and screen the literature and may include the use of machine learning software. Mammalian bioassay and epidemiological studies that meet the PECO criteria after full-text review are briefly summarized using structured web-based extraction forms with respect to study design and health system(s) assessed. Extracted data is available in interactive visual formats and can be downloaded in open access formats. Methods for conducting study evaluation are also presented which is conducted on a case-by-case basis, depending on the usage of the SEM.

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS).

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS. OBJECTIVE: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing. METHODS: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement-only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata. RESULTS: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams. DISCUSSION: Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343.

Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks.

The workshop titled "Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks" was co-organized by the Evidence-based Toxicology Collaboration and the European Food Safety Authority (EFSA) and hosted by EFSA at its headquarters in Parma, Italy on October 2 and 3, 2019. The goal was to explore integration of systematic review with mechanistic evidence evaluation. Participants were invited to work on concrete products to advance the exploration of how evidence-based approaches can support the development and application of adverse outcome pathways (AOP) in chemical risk assessment. The workshop discussions were centered around three related themes: 1) assessing certainty in AOPs, 2) literature-based AOP development, and 3) integrating certainty in AOPs and non-animal evidence into decision frameworks. Several challenges, mostly related to methodology, were identified and largely determined the workshop recommendations. The workshop recommendations included the comparison and potential alignment of processes used to develop AOP and systematic review methodology, including the translation of vocabulary of evidence-based methods to AOP and vice versa, the development and improvement of evidence mapping and text mining methods and tools, as well as a call for a fundamental change in chemical risk and uncertainty assessment methodology if to be conducted based on AOPs and new approach methodologies (NAM). The usefulness of evidence-based approaches for mechanism-based chemical risk assessments was stressed, particularly the potential contribution of the rigor and transparency inherent to such approaches in building stakeholders' trust for implementation of NAM evidence and AOPs into chemical risk assessment.

Health Effects of Naphthalene Exposure: A Systematic Evidence Map and Analysis of Potential Considerations for Dose-Response Evaluation.

BACKGROUND: Naphthalene is a polycyclic aromatic hydrocarbon that has been associated with health effects, including cancer. As the state of the science on naphthalene toxicity continues to evolve, updated toxicity reference value(s) may be required to support human health risk assessment. OBJECTIVES: We present a systematic evidence map of studies that could be used to derive toxicity reference value(s) for naphthalene. METHODS: Human and animal health effect studies and physiologically based pharmacokinetic (PBPK) models were identified from a literature search based on populations, exposures, comparators, and outcomes (PECO) criteria. Human and animal studies meeting PECO criteria were refined to a smaller subset considered most informative for deriving chronic reference value(s), which are preferred for assessing risk to the general public. This subset was evaluated for risk of bias and sensitivity, and the suitability of each study for dose-response analysis was qualitatively assessed. Lowest observed adverse effect levels (LOAELs) were extracted and summarized. Other potentially relevant studies (e.g., mechanistic and toxicokinetic studies) were tracked as supplemental information but not evaluated further. Existing reference values for naphthalene are also summarized. RESULTS: We identified 26 epidemiology studies and 16 animal studies that were considered most informative for further analysis. Eleven PBPK models were identified. The available epidemiology studies generally had significant risk of bias and/or sensitivity concerns and were mostly found to have low suitability for dose-response analysis due to the nature of the exposure measurements. The animal studies had fewer risk of bias and sensitivity concerns and were mostly found to be suitable for dose-response analysis. CONCLUSION: Although both epidemiological and animal studies of naphthalene provide weight of evidence for hazard identification, the available animal studies appear more suitable for reference value derivation. PBPK models and mechanistic and toxicokinetic data can be applied to extrapolate these animal data to humans, considering mode of action and interspecies metabolic differences. https://doi.org/10.1289/EHP7381.

Applying evidence-based methods to the development and use of adverse outcome pathways

The workshop "Application of evidence-based methods to construct mechanistic frameworks for the development and use of non-animal toxicity tests" was organized by the Evidence-based Toxicology Collaboration and hosted by the Grading of Recommendations Assessment, Development and Evaluation Working Group on June 12, 2019. The purpose of the workshop was to bring together international regulatory bodies, risk assessors, academic scientists, and industry to explore how systematic review methods and the adverse outcome pathway framework could be combined to develop and use mechanistic test methods for predicting the toxicity of chemical substances in an evidence-based manner. The meeting covered the history of biological frameworks, the way adverse outcome pathways are currently developed, the basic principles of systematic methodology, including systematic reviews and evidence maps, and assessment of cer­tainty in models, and adverse outcome pathways in particular. Specific topics were discussed via case studies in small break-out groups. The group concluded that adverse outcome pathways provide an important framework to support mechanism-based assessment in environmental health. The process of their development has a few challenges that could be addressed with systematic methods and automation tools. Addressing these challenges will increase the transparency of the evidence behind adverse outcome pathways and the consistency with which they are defined; this in turn will increase their value for supporting public health decisions. It was suggested to explore the details of applying systematic methods to adverse outcome pathway development in a series of case studies and workshops.

Human exposure pathways to poly- and perfluoroalkyl substances (PFAS) from indoor media: A systematic review protocol.

BACKGROUND: Human exposure to per- and polyfluoroalkyl substances (PFAS) has been primarily attributed to contaminated food and drinking water. However, additional PFAS exposure pathways have been raised by a limited number of studies reporting correlations between commercial and industrial products and PFAS levels in human media and biomonitoring. Systematic review (SR) methodologies have been widely used to evaluate similar questions using an unbiased approach in the fields of clinical medicine, epidemiology, and toxicology, but the deployment in exposure science is ongoing. Here we present a systematic review protocol that adapts existing systematic review methodologies and study evaluation tools to exposure science studies in order to investigate evidence for important PFAS exposure pathways from indoor media including consumer products, household articles, cleaning products, personal care products, plus indoor air and dust. OBJECTIVES: We will systematically review exposure science studies that present both PFAS concentrations from indoor exposure media and PFAS concentrations in blood serum or plasma. Exposure estimates will be synthesized from the evidence to answer the question, "For the general population, what effect does exposure from PFAS chemicals via indoor media have on blood, serum or plasma concentrations of PFAS?" We adapt existing systematic review methodologies and study evaluation tools from the U.S. EPA's Systematic Review Protocol for the PFBA, PFHxA, PFHxS, PFNA, and PFDA IRIS Assessments and the Navigation Guide for exposure science studies, as well as present innovative developments of exposure pathway-specific search strings for use in artificial intelligence screening software. DATA SOURCES: We will search electronic databases for potentially relevant literature, including Web of Science, PubMed, and ProQuest. Literature search results will be stored in EPA's Health and Environmental Research Online (HERO) database. STUDY ELIGIBILITY AND CRITERIA: Included studies will present exposure measures from indoor media including consumer products, household articles, cleaning products, personal care products, plus indoor air and dust, paired with PFAS concentrations in blood, serum or plasma from adults and/or children in the general population. We focus on a subset of PFAS chemicals including perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), perfluorobutanoic acid (PFBA), perfluorobutane sulfonate (PFBS), perfluorodecanoic acid (PFDA), perfluorohexanoic acid (PFHxA), perfluorohexanesulfonate (PFHxS), and perfluorononanoic acid (PFNA). STUDY APPRAISAL AND SYNTHESIS METHODS: Studies will be prefiltered at the title and abstract level using computationally intelligent search strings to expedite the screening process for reviewers. Two independent reviewers will screen the prefiltered studies against inclusion criteria at the title/abstract level and then full-text level, after which the reviewers will assess the studies' risk of bias using an approach modified from established systematic review tools for exposure studies. Exposure estimates will be calculated to investigate the proportion of blood, serum or plasma) PFAS concentrations that can be explained by exposure to PFAS in indoor media.

Diets enriched with coconut, fish, or olive oil modify peripheral metabolic effects of ozone in rats.

Dietary factors may modulate metabolic effects of air pollutant exposures. We hypothesized that diets enriched with coconut oil (CO), fish oil (FO), or olive oil (OO) would alter ozone-induced metabolic responses. Male Wistar-Kyoto rats (1-month-old) were fed normal diet (ND), or CO-, FO-, or OO-enriched diets. After eight weeks, animals were exposed to air or 0.8 ppm ozone, 4 h/day for 2 days. Relative to ND, CO- and OO-enriched diet increased body fat, serum triglycerides, cholesterols, and leptin, while all supplements increased liver lipid staining (OO > FO > CO). FO increased n-3, OO increased n-6/n-9, and all supplements increased saturated fatty-acids. Ozone increased total cholesterol, low-density lipoprotein, branched-chain amino acids (BCAA), induced hyperglycemia, glucose intolerance, and changed gene expression involved in energy metabolism in adipose and muscle tissue in rats fed ND. Ozone-induced glucose intolerance was exacerbated by OO-enriched diet. Ozone increased leptin in CO- and FO-enriched groups; however, BCAA increases were blunted by FO and OO. Ozone-induced inhibition of liver cholesterol biosynthesis genes in ND-fed rats was not evident in enriched dietary groups; however, genes involved in energy metabolism and glucose transport were increased in rats fed FO and OO-enriched diet. FO- and OO-enriched diets blunted ozone-induced inhibition of genes involved in adipose tissue glucose uptake and cholesterol synthesis, but exacerbated genes involved in adipose lipolysis. Ozone-induced decreases in muscle energy metabolism genes were similar in all dietary groups. In conclusion, CO-, FO-, and OO-enriched diets modified ozone-induced metabolic changes in a diet-specific manner, which could contribute to altered peripheral energy homeostasis.

Knowledge Organization Systems for Systematic Chemical Assessments.

BACKGROUND: Although the implementation of systematic review and evidence mapping methods stands to improve the transparency and accuracy of chemical assessments, they also accentuate the challenges that assessors face in ensuring they have located and included all the evidence that is relevant to evaluating the potential health effects an exposure might be causing. This challenge of information retrieval can be characterized in terms of "semantic" and "conceptual" factors that render chemical assessments vulnerable to the streetlight effect. OBJECTIVES: This commentary presents how controlled vocabularies, thesauruses, and ontologies contribute to overcoming the streetlight effect in information retrieval, making up the key components of Knowledge Organization Systems (KOSs) that enable more systematic access to assessment-relevant information than is currently achievable. The concept of Adverse Outcome Pathways is used to illustrate what a general KOS for use in chemical assessment could look like. DISCUSSION: Ontologies are an underexploited element of effective knowledge organization in the environmental health sciences. Agreeing on and implementing ontologies in chemical assessment is a complex but tractable process with four fundamental steps. Successful implementation of ontologies would not only make currently fragmented information about health risks from chemical exposures vastly more accessible, it could ultimately enable computational methods for chemical assessment that can take advantage of the full richness of data described in natural language in primary studies. https://doi.org/10.1289/EHP6994.

Advancing systematic-review methodology in exposure science for environmental health decision making.

Systematic review (SR) is a rigorous methodology applied to synthesize and evaluate a body of scientific evidence to answer a research or policy question. Effective use of systematic-review methodology enables use of research evidence by decision makers. In addition, as reliance on systematic reviews increases, the required standards for quality of evidence enhances the policy relevance of research. Authoritative guidance has been developed for use of SR to evaluate evidence in the fields of medicine, social science, environmental epidemiology, toxicology, as well as ecology and evolutionary biology. In these fields, SR is typically used to evaluate a cause-effect relationship, such as the effect of an intervention, procedure, therapy, or exposure on an outcome. However, SR is emerging to be a useful methodology to transparently review and integrate evidence for a wider range of scientifically informed decisions and actions across disciplines. As SR is being used more broadly, there is growing consensus for developing resources, guidelines, ontologies, and technology to make SR more efficient and transparent, especially for handling large amounts of diverse data being generated across multiple scientific disciplines. In this article, we advocate for advancing SR methodology as a best practice in the field of exposure science to synthesize exposure evidence and enhance the value of exposure studies. We discuss available standards and tools that can be applied and extended by exposure scientists and highlight early examples of SRs being developed to address exposure research questions. Finally, we invite the exposure science community to engage in further development of standards and guidance to grow application of SR in this field and expand the opportunities for exposure science to inform environment and public health decision making.

Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization.

Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health safety evaluation by informing screening-level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals. PODs derived from new approach methodologies (NAMs) were obtained for this comparison using the 50th (PODNAM, 50) and the 95th (PODNAM, 95) percentile credible interval estimates for the steady-state plasma concentration used in in vitro to in vivo extrapolation of administered equivalent doses. Of the 448 substances, 89% had a PODNAM, 95 that was less than the traditional POD (PODtraditional) value. For the 48 substances for which PODtraditional < PODNAM, 95, the PODNAM and PODtraditional were typically within a factor of 10 of each other, and there was an enrichment of chemical structural features associated with organophosphate and carbamate insecticides. When PODtraditional < PODNAM, 95, it did not appear to result from an enrichment of PODtraditional based on a particular study type (eg, developmental, reproductive, and chronic studies). Bioactivity:exposure ratios, useful for identification of substances with potential priority, demonstrated that high-throughput exposure predictions were greater than the PODNAM, 95 for 11 substances. When compared with threshold of toxicological concern (TTC) values, the PODNAM, 95 was greater than the corresponding TTC value 90% of the time. This work demonstrates the feasibility, and continuing challenges, of using in vitro bioactivity as a protective estimate of POD in screening-level assessments via a case study.

Predicting the Probability that a Chemical Causes Steatosis Using Adverse Outcome Pathway Bayesian Networks (AOPBNs).

Adverse outcome pathway Bayesian networks (AOPBNs) are a promising avenue for developing predictive toxicology and risk assessment tools based on adverse outcome pathways (AOPs). Here, we describe a process for developing AOPBNs. AOPBNs use causal networks and Bayesian statistics to integrate evidence across key events. In this article, we use our AOPBN to predict the occurrence of steatosis under different chemical exposures. Since it is an expert-driven model, we use external data (i.e., data not used for modeling) from the literature to validate predictions of the AOPBN model. The AOPBN accurately predicts steatosis for the chemicals from our external data. In addition, we demonstrate how end users can utilize the model to simulate the confidence (based on posterior probability) associated with predicting steatosis. We demonstrate how the network topology impacts predictions across the AOPBN, and how the AOPBN helps us identify the most informative key events that should be monitored for predicting steatosis. We close with a discussion of how the model can be used to predict potential effects of mixtures and how to model susceptible populations (e.g., where a mutation or stressor may change the conditional probability tables in the AOPBN). Using this approach for developing expert AOPBNs will facilitate the prediction of chemical toxicity, facilitate the identification of assay batteries, and greatly improve chemical hazard screening strategies.

Progress in data interoperability to support computational toxicology and chemical safety evaluation.

New approach methodologies (NAMs) in chemical safety evaluation are being explored to address the current public health implications of human environmental exposures to chemicals with limited or no data for assessment. For over a decade since a push toward "Toxicity Testing in the 21st Century," the field has focused on massive data generation efforts to inform computational approaches for preliminary hazard identification, adverse outcome pathways that link molecular initiating events and key events to apical outcomes, and high-throughput approaches to risk-based ratios of bioactivity and exposure to inform relative priority and safety assessment. Projects like the interagency Tox21 program and the US EPA ToxCast program have generated dose-response information on thousands of chemicals, identified and aggregated information from legacy systems, and created tools for access and analysis. The resulting information has been used to develop computational models as viable options for regulatory applications. This progress has introduced challenges in data management that are new, but not unique, to toxicology. Some of the key questions require critical thinking and solutions to promote semantic interoperability, including: (1) identification of bioactivity information from NAMs that might be related to a biological process; (2) identification of legacy hazard information that might be related to a key event or apical outcomes of interest; and, (3) integration of these NAM and traditional data for computational modeling and prediction of complex apical outcomes such as carcinogenesis. This work reviews a number of toxicology-related efforts specifically related to bioactivity and toxicological data interoperability based on the goals established by Findable, Accessible, Interoperable, and Reusable (FAIR) Data Principles. These efforts are essential to enable better integration of NAM and traditional toxicology information to support data-driven toxicology applications.

Epigenetic Applications in Adverse Outcome Pathways and Environmental Risk Evaluation.

BACKGROUND: The epigenome may be an important interface between environmental chemical exposures and human health. However, the links between epigenetic modifications and health outcomes are often correlative and do not distinguish between cause and effect or common-cause relationships. The Adverse Outcome Pathway (AOP) framework has the potential to demonstrate, by way of an inference- and science-based analysis, the causal relationship between chemical exposures, epigenome, and adverse health outcomes. OBJECTIVE: The objective of this work is to discuss the epigenome as a modifier of exposure effects and risk, perspectives for integrating toxicoepigenetic data into an AOP framework, tools for the exploration of epigenetic toxicity, and integration of AOP-guided epigenetic information into science and risk-assessment processes. DISCUSSION: Organizing epigenetic information into the topology of a qualitative AOP network may help describe how a system will respond to epigenetic modifications caused by environmental chemical exposures. However, understanding the biological plausibility, linking epigenetic effects to short- and long-term health outcomes, and including epigenetic studies in the risk assessment process is met by substantive challenges. These obstacles include understanding the complex range of epigenetic modifications and their combinatorial effects, the large number of environmental chemicals to be tested, and the lack of data that quantitatively evaluate the epigenetic effects of environmental exposure. CONCLUSION: We anticipate that epigenetic information organized into AOP frameworks can be consistently used to support biological plausibility and to identify data gaps that will accelerate the pace at which epigenetic information is applied in chemical evaluation and risk-assessment paradigms. https://doi.org/10.1289/EHP2322.

Adverse outcome pathway networks II: Network analytics.

Toxicological responses to stressors are more complex than the simple one-biological-perturbation to one-adverse-outcome model portrayed by individual adverse outcome pathways (AOPs). Consequently, the AOP framework was designed to facilitate de facto development of AOP networks that can aid in the understanding and prediction of pleiotropic and interactive effects more common to environmentally realistic, complex exposure scenarios. The present study introduces nascent concepts related to the qualitative analysis of AOP networks. First, graph theory-based approaches for identifying important topological features are illustrated using 2 example AOP networks derived from existing AOP descriptions. Second, considerations for identifying the most significant path(s) through an AOP network from either a biological or risk assessment perspective are described. Finally, approaches for identifying interactions among AOPs that may result in additive, synergistic, or antagonistic responses (or previously undefined emergent patterns of response) are introduced. Along with a companion article (part I), these concepts set the stage for the development of tools and case studies that will facilitate more rigorous analysis of AOP networks, and the utility of AOP network-based predictions, for use in research and regulatory decision-making. The present study addresses one of the major themes identified through a Society of Environmental Toxicology and Chemistry Horizon Scanning effort focused on advancing the AOP framework. Environ Toxicol Chem 2018;37:1734-1748. © 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

Adverse outcome pathway networks I: Development and applications.

Based on the results of a Horizon Scanning exercise sponsored by the Society of Environmental Toxicology and Chemistry that focused on advancing the adverse outcome pathway (AOP) framework, the development of guidance related to AOP network development was identified as a critical need. This not only included questions focusing directly on AOP networks, but also on related topics such as mixture toxicity assessment and the implementation of feedback loops within the AOP framework. A set of two articles has been developed to begin exploring these concepts. In the present article (part I), we consider the derivation of AOP networks in the context of how it differs from the development of individual AOPs. We then propose the use of filters and layers to tailor AOP networks to suit the needs of a given research question or application. We briefly introduce a number of analytical approaches that may be used to characterize the structure of AOP networks. These analytical concepts are further described in a dedicated, complementary article (part II). Finally, we present a number of case studies that illustrate concepts underlying the development, analysis, and application of AOP networks. The concepts described in the present article and in its companion article (which focuses on AOP network analytics) are intended to serve as a starting point for further development of the AOP network concept, and also to catalyze AOP network development and application by the different stakeholder communities. Environ Toxicol Chem 2018;37:1723-1733. © 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.