Workshop Report: Catalyzing Knowledge-Driven Discovery in Environmental Health Sciences through a Harmonized Language.

Harmonized language is essential to finding, sharing, and reusing large-scale, complex data. Gaps and barriers prevent the adoption of harmonized language approaches in environmental health sciences (EHS). To address this, the National Institute of Environmental Health Sciences and partners created the Environmental Health Language Collaborative (EHLC). The purpose of EHLC is to facilitate a community-driven effort to advance the development and adoption of harmonized language approaches in EHS. EHLC is a forum to pinpoint language harmonization gaps, to facilitate the development of, raise awareness of, and encourage the use of harmonization approaches and tools, and to develop new standards and recommendations. To ensure that EHLC's focus and structure would be sustainable long-term and meet the needs of the field, EHLC launched an inaugural workshop in September 2021 focused on "Developing Sustainable Language Solutions" and "Building a Sustainable Community". When the attendees were surveyed, 91% said harmonized language solutions would be of high value/benefit, and 60% agreed to continue contributing to EHLC efforts. Based on workshop discussions, future activities will focus on targeted collaborative use-case working groups in addition to offering education and training on ontologies, metadata, and standards, and developing an EHS language resource portal.

Clinical and functional characterization of germline PIK3CA variants in patients with PIK3CA-related overgrowth spectrum disorders.

Mosaic variants in the PIK3CA gene, encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), produce constitutive PI3K activation, which causes PIK3CA-related overgrowth spectrum disorders. To date, fewer than 20 patients have been described with germline alterations in PIK3CA. In this study, we describe three unrelated individuals with overgrowth and germline PIK3CA variants. These variants were discovered through whole-exome sequencing and confirmed as germline by testing multiple tissue types, when available. Functional analysis using Patient 1's fibroblast cell line and two previously reported patients' cell lines showed increased phosphorylation of AKT during cellular starvation revealing constitutive activation of the phosphoinositide-3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway. Alternatively, stimulation of the cells by fetal bovine serum produced a reduced response, indicating an activated status of the PI3K complex reducing the pathway response to further external stimulation. Additional studies utilizing Biolog Phenotype Microarray technology indicated reduced energy production when cells were exposed to growth factors stimulating the PI3K/AKT/mTOR pathway, confirming the trend observed in the AKT phosphorylation test after stimulation. Furthermore, treatment with inhibitors of the PI3K/AKT/mTOR pathway rescued the normal energy response in the patients' cells. Collectively, these data demonstrate that disease-causing germline PIK3CA variants have a functional consequence, similar to mosaic variants in the PI3K/AKT/mTOR pathway.

Advancing New Approach Methodologies (NAMs) for Tobacco Harm Reduction: Synopsis from the 2021 CORESTA SSPT-NAMs Symposium.

New approach methodologies (NAMs) are emerging chemical safety assessment tools consisting of in vitro and in silico (computational) methodologies intended to reduce, refine, or replace (3R) various in vivo animal testing methods traditionally used for risk assessment. Significant progress has been made toward the adoption of NAMs for human health and environmental toxicity assessment. However, additional efforts are needed to expand their development and their use in regulatory decision making. A virtual symposium was held during the 2021 Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) Smoke Science and Product Technology (SSPT) conference (titled "Advancing New Alternative Methods for Tobacco Harm Reduction"), with the goals of introducing the concepts and potential application of NAMs in the evaluation of potentially reduced-risk (PRR) tobacco products. At the symposium, experts from regulatory agencies, research organizations, and NGOs shared insights on the status of available tools, strengths, limitations, and opportunities in the application of NAMs using case examples from safety assessments of chemicals and tobacco products. Following seven presentations providing background and application of NAMs, a discussion was held where the presenters and audience discussed the outlook for extending the NAMs toxicological applications for tobacco products. The symposium, endorsed by the CORESTA In Vitro Tox Subgroup, Biomarker Subgroup, and NextG Tox Task Force, illustrated common ground and interest in science-based engagement across the scientific community and stakeholders in support of tobacco regulatory science. Highlights of the symposium are summarized in this paper.

Data curation to support toxicity assessments using the Integrated Chemical Environment.

Humans are exposed to large numbers of chemicals during their daily activities. To assess and understand potential health impacts of chemical exposure, investigators and regulators need access to reliable toxicity data. In particular, reliable toxicity data for a wide range of chemistries are needed to support development of new approach methodologies (NAMs) such as computational models, which offer increased throughput relative to traditional approaches and reduce or replace animal use. NAMs development and evaluation require chemically diverse data sets that are typically constructed by incorporating results from multiple studies into a single, integrated view; however, integrating data is not always a straightforward task. Primary study sources often vary in the way data are organized and reported. Metadata and information needed to support interoperability and provide context are often lacking, which necessitates literature research on the assay prior to attempting data integration. The Integrated Chemical Environment (ICE) was developed to support the development, evaluation, and application of NAMs. ICE provides curated toxicity data and computational tools to integrate and explore available information, thus facilitating knowledge discovery and interoperability. This paper describes the data curation workflow for integrating data into ICE. Data destined for ICE undergo rigorous harmonization, standardization, and formatting processes using both automated and manual expert-driven approaches. These processes improve the utility of the data for diverse analyses and facilitate application within ICE or a user's external workflow while preserving data integrity and context. ICE data curation provides the structure, reliability, and accessibility needed for data to support chemical assessments.

FDA Emergency Use Authorization-Approved Novel Coronavirus Disease 2019, Pressure-Regulated, Mechanical Ventilator Splitter That Enables Differential Compliance Multiplexing.

Infection with the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may cause viral pneumonia and acute respiratory distress syndrome (ARDS). Treatment of ARDS often requires mechanical ventilation and may take weeks for resolution. In areas with a large outbreaks, there may be shortages of ventilators available. While rudimentary methods for ventilator splitting have been described, given the range of independent ventilatory settings required for each patient, this solution is suboptimal. Here, we describe a device that can split a ventilator among up to four patients while allowing for individualized settings. The device has been validated in vitro and in vivo .

Application of an Accessible Interface for Pharmacokinetic Modeling and In Vitro to In Vivo Extrapolation.

Regulatory toxicology testing has traditionally relied on in vivo methods to inform decision-making. However, scientific, practical, and ethical considerations have led to an increased interest in the use of in vitro and in silico methods to fill data gaps. While in vitro experiments have the advantage of rapid application across large chemical sets, interpretation of data coming from these non-animal methods can be challenging due to the mechanistic nature of many assays. In vitro to in vivo extrapolation (IVIVE) has emerged as a computational tool to help facilitate this task. Specifically, IVIVE uses physiologically based pharmacokinetic (PBPK) models to estimate tissue-level chemical concentrations based on various dosing parameters. This approach is used to estimate the administered dose needed to achieve in vitro bioactivity concentrations within the body. IVIVE results can be useful to inform on metrics such as margin of exposure or to prioritize potential chemicals of concern, but the PBPK models used in this approach have extensive data requirements. Thus, access to input parameters, as well as the technical requirements of applying and interpreting models, has limited the use of IVIVE as a routine part of in vitro testing. As interest in using non-animal methods for regulatory and research contexts continues to grow, our perspective is that access to computational support tools for PBPK modeling and IVIVE will be essential for facilitating broader application and acceptance of these techniques, as well as for encouraging the most scientifically sound interpretation of in vitro results. We highlight recent developments in two open-access computational support tools for PBPK modeling and IVIVE accessible via the Integrated Chemical Environment (https://ice.ntp.niehs.nih.gov/), demonstrate the types of insights these tools can provide, and discuss how these analyses may inform in vitro-based decision making.

Quantitative in vitro to in vivo extrapolation for developmental toxicity potency of valproic acid analogues.

BACKGROUND: The developmental toxicity potential (dTP) concentration from the devTOX quickPredict (devTOXqP ) assay, a metabolomics-based human induced pluripotent stem cell assay, predicts a chemical's developmental toxicity potency. Here, in vitro to in vivo extrapolation (IVIVE) approaches were applied to address whether the devTOXqP assay could quantitatively predict in vivo developmental toxicity lowest effect levels (LELs) for the prototypical teratogen valproic acid (VPA) and a group of structural analogues. METHODS: VPA and a series of structural analogues were tested with the devTOXqP assay to determine dTP concentration and we estimated the equivalent administered doses (EADs) that would lead to plasma concentrations equivalent to the in vitro dTP concentrations. The EADs were compared to the LELs in rat developmental toxicity studies, human clinical doses, and EADs reported using other in vitro assays. To evaluate the impact of different pharmacokinetic (PK) models on IVIVE outcomes, we compared EADs predicted using various open-source and commercially available PK and physiologically based PK (PBPK) models. To evaluate the effect of in vitro kinetics, an equilibrium distribution model was applied to translate dTP concentrations to free medium concentrations before subsequent IVIVE analyses. RESULTS: The EAD estimates for the VPA analogues based on different PK/PBPK models were quantitatively similar to in vivo data from both rats and humans, where available, and the derived rank order of the chemicals was consistent with observed in vivo developmental toxicity. Different models were identified that provided accurate predictions for rat prenatal LELs and conservative estimates of human safe exposure. The impact of in vitro kinetics on EAD estimates is chemical-dependent. EADs from this study were within range of predicted doses from other in vitro and model organism data. CONCLUSIONS: This study highlights the importance of pharmacokinetic considerations when using in vitro assays and demonstrates the utility of the devTOXqP human stem cell-based platform to quantitatively assess a chemical's developmental toxicity potency.

Drug-facilitated sexual assault, impaired trauma memory, and implications for mental health treatment.

Background: Sexual assault (SA) is a highly prevalent global public health problem and a robust predictor of posttraumatic stress disorder (PTSD), substance use disorder (SUD), and suicidality. A large percentage are drug or alcohol facilitated (DFSA), impairing trauma memory and affecting the application of evidence-based treatments. Despite these problems, few have investigated DFSA-specific mental health (MH) needs. Objective: Goals of this study were (1) to identify psychological sequelae characterizing DFSA towards explaining why symptoms have been treatment-refractory, comparing survivors with involuntary substance ingestion (forced, covert: DFSA-I), voluntary ingestion (DFSA-V), and non-DFSA; and (2) to determine how impaired trauma memory relates to the development of PTSD and depression symptoms. Method: Data from a retrospective chart review of 74 adults receiving SA MH services at an outpatient trauma center are presented. The sample includes a 2-year cohort seen acutely at an urban rape treatment center. The study is one of the first to examine therapy records beyond case studies for DFSA. Logistic, Poisson, and negative binomial regression analyses of quantitative data and qualitative thematic analysis of trauma cognitions and treatment foci were conducted. Results: DFSA-V had five times greater odds of SUD, and notable substance-related self-blame compared to DFSA-I. DFSA-I had prominent relationship distress and self-blame for missing danger of perpetrator drugging. Survivors with impaired trauma memory had significantly fewer hyper-arousal and overall PTSD symptoms, and specifically less hypervigilance. No differences were found in re-experiencing symptoms. Conclusion: Impaired trauma memory is common in DFSA and is associated with fewer baseline hyper-arousal and overall PTS. Despite this, DFSA issues including re-experiencing symptoms that are particularly distressing without the ability to cognitively connect the intrusions contribute to increased treatment needs. Impaired memory limits the application of evidence-based treatments, and collectively these findings call for the development of trauma-specific treatment protocols to enhance recovery for DFSA survivors. HIGHLIGHTS: Survivors of drug-facilitated sexual assault have prominent PTSD including reexperiencing, though trauma memory may not be encoded. • Those absent trauma memory have less hyperarousal, but DFSA complications explain why it is treatment refractory and inform treatment development.

Antecedentes: La agresión sexual (AS) es un problema de salud pública mundial de alta prevalencia y es un sólido predictor del trastorno de estrés postraumático (TEPT), del trastorno por uso de sustancias (TUS) y de suicidalidad. Un gran porcentaje de AS son facilitadas por drogas o alcohol (ASFDA), deteriorando la memoria del trauma y afectando la aplicación de tratamientos basados en la evidencia. A pesar de estos problemas, pocos han investigado las necesidades de salud mental (SM) específicas de los ASFDA.Objetivo: Los objetivos de este estudio fueron; primero, identificar las secuelas psicológicas que caracterizan a las ASFDA para explicar por qué los síntomas han sido refractarios al tratamiento. Para ello, se comparó a sobrevivientes a una ingestión involuntaria de sustancias (forzada, encubierta: ASFDA-I), a una ingestión voluntaria (ASFDA-V), y a una AS no-ASFDA; y, segundo; determinar cómo el deterioro de la memoria del trauma se relaciona con el desarrollo de síntomas del TEPT y depresión.Método: Se presentan los datos de una revisión retrospectiva de las historias clínicas de 74 adultos que recibieron servicios de SM por AS en un centro de trauma para pacientes ambulatorios. La muestra incluye a una cohorte de 2 años en donde los casos de AS fueron vistos de forma aguda en un centro urbano de tratamiento para violación. El estudio es uno de los primeros, más allá de los estudios de casos, en examinar los registros de terapia por ASFDA. Se realizaron análisis de regresión logística, Poisson y binomial negativa de datos cuantitativos y un análisis temático cualitativo de las cogniciones del trauma y los puntos clave del tratamiento.Resultados: Los ASFDA-V tuvieron cinco veces más probabilidades de TUS y de un notable sentimiento de culpa relacionado con las sustancias comparado con los ASFDA-I. Las ASFDA tenían problemas de relación importantes y sentimientos de culpa por haber pasado por alto el peligro de que el agresor se drogara. Los sobrevivientes con deterioro de la memoria traumática tuvieron significativamente menos síntomas de hiperactivación y del TEPT en general y, específicamente, menos hipervigilancia. No se encontraron diferencias en los síntomas de reexperimentación.Conclusión: El deterioro de la memoria traumática es común en las ASFDA y se asocia con menos hiperactivación de base y síntomas postraumáticos en general. A pesar de esto, los problemas de los ASFDA incluyen a los síntomas de reexperimentación que son particularmente angustiantes y que restan la capacidad de conectar cognitivamente las intrusiones, por lo que contribuyen a aumentar las necesidades de tratamiento. El deterioro de la memoria limita la aplicación de tratamientos basados en la evidencia y, en conjunto, estos hallazgos exigen el desarrollo de protocolos de tratamiento específicos para trauma para mejorar la recuperación de los sobrevivientes a las ASFDA.

IVIVE: Facilitating the Use of In Vitro Toxicity Data in Risk Assessment and Decision Making.

During the past few decades, the science of toxicology has been undergoing a transformation from observational to predictive science. New approach methodologies (NAMs), including in vitro assays, in silico models, read-across, and in vitro to in vivo extrapolation (IVIVE), are being developed to reduce, refine, or replace whole animal testing, encouraging the judicious use of time and resources. Some of these methods have advanced past the exploratory research stage and are beginning to gain acceptance for the risk assessment of chemicals. A review of the recent literature reveals a burst of IVIVE publications over the past decade. In this review, we propose operational definitions for IVIVE, present literature examples for several common toxicity endpoints, and highlight their implications in decision-making processes across various federal agencies, as well as international organizations, including those in the European Union (EU). The current challenges and future needs are also summarized for IVIVE. In addition to refining and reducing the number of animals in traditional toxicity testing protocols and being used for prioritizing chemical testing, the goal to use IVIVE to facilitate the replacement of animal models can be achieved through their continued evolution and development, including a strategic plan to qualify IVIVE methods for regulatory acceptance.

CATMoS: Collaborative Acute Toxicity Modeling Suite.

BACKGROUND: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [LD50 (LD50≤50mg/kg)], and nontoxic chemicals (LD50>2,000mg/kg). METHODS: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495.

Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder.

Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ∼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.

Exploring in vitro to in vivo extrapolation for exposure and health impacts of e-cigarette flavor mixtures.

In vitro to in vivo extrapolation (IVIVE) leverages in vitro biological activities to predict corresponding in vivo exposures, therefore potentially reducing the need for animal safety testing that are traditionally performed to support the hazard and risk assessment. Interpretation of IVIVE predictions are affected by various factors including the model type, exposure route and kinetic assumptions for the test article, and choice of in vitro assay(s) that are relevant to clinical outcomes. Exposure scenarios are further complicated for mixtures where the in vitro activity may stem from one or more components in the mixture. In this study, we used electronic cigarette (EC) aerosols, a complex mixture, to explore impacts of these factors on the use of IVIVE in hazard identification, using open-source pharmacokinetic models of varying complexity and publicly available data. Results suggest in vitro assay selection has a greater impact on exposure estimates than modeling approaches. Using cytotoxicity assays, high exposure estimates (>1000 EC cartridges (pods) or > 700 mL EC liquid per day) would be needed to obtain the in vivo plasma levels that are corresponding to in vitro assay data, suggesting acute toxicity would be unlikely in typical usage scenarios. When mechanistic (Tox21) assays were used, the exposure estimates were much lower for the low end, but the range of exposure estimate became wider across modeling approaches. These proof-of-concept results highlight challenges and complexities in IVIVE for mixtures.

Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation.

In vitro methods offer opportunities to provide mechanistic insight into bioactivity as well as human-relevant toxicological assessments compared to animal testing. One of the challenges for this task is putting in vitro bioactivity data in an in vivo exposure context, for which in vitro to in vivo extrapolation (IVIVE) translates in vitro bioactivity to clinically relevant exposure metrics using reverse dosimetry. This study applies an IVIVE approach to the toxicity assessment of ingredients and their mixtures in e-cigarette (EC) aerosols as a case study. Reported in vitro cytotoxicity data of EC aerosols, as well as in vitro high-throughput screening (HTS) data for individual ingredients in EC liquids (e-liquids) are used. Open-source physiologically based pharmacokinetic (PBPK) models are used to calculate the plasma concentrations of individual ingredients, followed by reverse dosimetry to estimate the human equivalent administered doses (EADs) needed to obtain these plasma concentrations for the total e-liquids. Three approaches (single actor approach, additive effect approach, and outcome-oriented ingredient integration approach) are used to predict EADs of e-liquids considering differential contributions to the bioactivity from the ingredients (humectant carriers [propylene glycol and glycerol], flavors, benzoic acid, and nicotine). The results identified critical factors for the EAD estimation, including the ingredients of the mixture considered to be bioactive, in vitro assay selection, and the data integration approach for mixtures. Further, we introduced the outcome-oriented ingredient integration approach to consider e-liquid ingredients that may lead to a common toxicity outcome (e.g., cytotoxicity), facilitating a quantitative evaluation of in vitro toxicity data in support of human risk assessment.

First-Trimester Abortion Complications: Simulation Cases for OB/GYN Residents in Sepsis and Hemorrhage.

Introduction: Serious complications associated with first-trimester abortions are rare. The US mortality rate for these procedures is 0.7 per 100,000, primarily due to infection and hemorrhage. While complications are unlikely to arise during training, residents must be prepared to manage them in practice. To address this, we developed a 2-hour simulation-based abortion complication curriculum for OB/GYN resident learners. Methods: OB/GYN residents participated in three sessions: a case-based didactic reviewing institutional aspiration abortion practice and preop preparation; an in-vivo aspiration abortion hemorrhage simulation; and an interdepartmental postabortal sepsis simulation. Participants completed surveys before and after their participation that evaluated clinical knowledge, and self-rated competence in, and preparedness for, managing first-trimester abortion complications. Results: Resident learners (N = 26) represented all four classes of OB/GYN residents. Residents initially showed stronger clinical knowledge in managing postabortal hemorrhage than sepsis (90% vs. 62%, p < .001). Clinical knowledge improved following the sepsis simulation (62% to 91%, p < .001), and remained strong but unchanged after the hemorrhage simulation (90% to 87%, p = .3). Resident self-assessments of competence and preparedness were significantly improved after both the hemorrhage (p = .006) and sepsis (p = .002) simulations. Learners reported that the simulation increased their level of comfort in managing these complications in their future practice. Discussion: Postabortal hemorrhage and sepsis simulations increased OB/GYN residents' knowledge, comfort, and preparedness for managing rare complications of first-trimester abortions. In-vivo simulation and interdepartmental collaboration were novel aspects of these simulations that may facilitate increased preparedness and management skills.

An integrated chemical environment with tools for chemical safety testing.

Moving toward species-relevant chemical safety assessments and away from animal testing requires access to reliable data to develop and build confidence in new approaches. The Integrated Chemical Environment (ICE) provides tools and curated data centered around chemical safety assessment. This article describes updates to ICE, including improved accessibility and interpretability of in vitro data via mechanistic target mapping and enhanced interactive tools for in vitro to in vivo extrapolation (IVIVE). Mapping of in vitro assay targets to toxicity endpoints of regulatory importance uses literature-based mode-of-action information and controlled terminology from existing knowledge organization systems to support data interoperability with external resources. The most recent ICE update includes Tox21 high-throughput screening data curated using analytical chemistry data and assay-specific parameters to eliminate potential artifacts or unreliable activity. Also included are physicochemical/ADME parameters for over 800,000 chemicals predicted by quantitative structure-activity relationship models. These parameters are used by the new ICE IVIVE tool in combination with the U.S. Environmental Protection Agency's httk R package to estimate in vivo exposures corresponding to in vitro bioactivity concentrations from stored or user-defined assay data. These new ICE features allow users to explore the applications of an expanded data space and facilitate building confidence in non-animal approaches.

Building Interdisciplinary Partnerships for Community-Engaged Environmental Health Research in Appalachian Virginia.

This article describes a collaboration among a group of university faculty, undergraduate students, local governments, local residents, and U.S. Army staff to address long-standing concerns about the environmental health effects of an Army ammunition plant. The authors describe community-responsive scientific pilot studies that examined potential environmental contamination and a related undergraduate research course that documented residents' concerns, contextualized those concerns, and developed recommendations. We make a case for the value of resource-intensive university-community partnerships that promote the production of knowledge through collaborations across disciplinary paradigms (natural/physical sciences, social sciences, health sciences, and humanities) in response to questions raised by local residents. Our experience also suggests that enacting this type of research through a university class may help promote researchers' adoption of "epistemological pluralism", and thereby facilitate the movement of a study from being "multidisciplinary" to "transdisciplinary".

The labor and birth experience of women with opioid use disorder: A qualitative study.

OBJECTIVE: This study describes the experience of pregnancy and childbirth from the perspective of women with opioid use disorder. METHODS: This qualitative study analyzed semi-structured interviews about the prenatal care and birth experience of nine women with opioid use disorder as a sub-analysis of a qualitative study of women with a history of sexual trauma. Transcripts were analyzed using inductive content analysis. RESULTS: Analysis revealed unique interactions with the healthcare system specific to pregnant women with opioid use disorder. Participants identified pregnancy as a reason to enter and maintain recovery and an increased availability of resources when pregnant. Yet during labor and birth, concerns regarding pain control, child protective services involvement and provider stigma led to negative interactions with the healthcare system. CONCLUSION: Pregnant woman with opioid use disorder face unique challenges when seeking care. The perspectives of women with a history of opioid use disorder can inform creation of a harm reduction, non-stigmatizing model of prenatal, labor and birth, and postpartum care.