Exposure Assessment Study on Lithium-Ion Battery Fire in Explosion Test Room in Battery Testing Facility.

A lithium-ion battery is a rechargeable battery that uses the reversible reduction of lithium ions to store energy and is the predominant battery type in many industrial and consumer electronics. The lithium-ion batteries are essential to ensure they operate safely. We conducted an exposure assessment five days after a fire in a battery-testing facility. We assessed some of the potentially hazardous materials after a lithium-ion battery fire. We sampled total suspended particles, hydrogen fluoride, and lithium with real-time monitoring of particulate matter (PM) 1, 2.5, and 10 micrometers (µm). The area sampling results indicated that primary potential hazardous materials such as dust, hydrogen fluoride, and lithium were below the recommended limits suggested by the Korean Ministry of Labor and the American Conference of Governmental Industrial Hygienists Threshold Limit Values. Based on our assessment, workers were allowed to return to work.

A dynamic in vitro developing testis model reflects structures and functions of testicular development in vivo.

To better define appropriate applications of our 3-dimensional testicular co-culture as a model for reproductive toxicology, we evaluated the ability of the model to capture structural and functional elements that can be targeted by reproductive toxicants. Testicular co-cultures were prepared from postnatal day 5 male rats and cultured with a Matrigel overlay. Following a 2-day acclimation period, we characterized functional pathway dynamics by evaluating morphology, protein expression, testosterone concentrations, and global gene expression at a range of timepoints from experimental days 0-21. Western blotting confirmed expression of Sertoli cell, Leydig cell, and spermatogonial cell-specific protein markers. Testosterone detected in cell culture media indicates active testosterone production. Quantitative pathway analysis identified Gene Ontology biological processes enriched among genes significantly changing over the course of 21 days. Processes enriched among genes significantly increasing through time include general developmental processes (morphogenesis, tissue remodeling, etc.), steroid regulation, Sertoli cell development, immune response, and stress and apoptosis. Processes enriched among genes significantly decreasing over time include several related to male reproductive development (seminiferous tubule development, male gonad development, Leydig cell differentiation, Sertoli cell differentiation), all of which appear to peak in expression between days 1 and 5 before decreasing at later timepoints. This analysis provides a temporal roadmap for specific biological process of interest for reproductive toxicology in the model and anchors the model to sensitive phases of in vivo development, helping to define the relevance of the model for in vivo processes.

Alteration of oral microbiome composition in children living with pesticide-exposed farm workers.

Our prior work shows that azinphos-methyl pesticide exposure is associated with altered oral microbiomes in exposed farmworkers. Here we extend this analysis to show the same association pattern is also evident in their children. Oral buccal swab samples were analyzed at two time points, the apple thinning season in spring-summer 2005 for 78 children and 101 adults and the non-spray season in winter 2006 for 62 children and 82 adults. The pesticide exposure for the children were defined by the farmworker occupation of the cohabitating household adult and the blood azinphos-methyl detection of the cohabitating adult. Oral buccal swab 16S rRNA sequencing determined taxonomic microbiota proportional composition from concurrent samples from both adults and children. Analysis of the identified bacteria showed significant proportional changes for 12 of 23 common oral microbiome genera in association with azinphos-methyl detection and farmworker occupation. The most common significantly altered genera had reductions in the abundance of Streptococcus, suggesting an anti-microbial effect of the pesticide. Principal component analysis of the microbiome identified two primary clusters, with association of principal component 1 to azinphos-methyl blood detection and farmworker occupational status of the household. The children's buccal microbiota composition clustered with their household adult in ∼95% of the households. Household adult farmworker occupation and household pesticide exposure is associated with significant alterations in their children's oral microbiome composition. This suggests that parental occupational exposure and pesticide take-home exposure pathways elicit alteration of their children's microbiomes.

Associations between extreme precipitation, drinking water, and protozoan acute gastrointestinal illnesses in four North American Great Lakes cities (2009-2014).

Climate change is already impacting the North American Great Lakes ecosystem and understanding the relationship between climate events and public health, such as waterborne acute gastrointestinal illnesses (AGIs), can help inform needed adaptive capacity for drinking water systems (DWSs). In this study, we assessed a harmonized binational dataset for the effects of extreme precipitation events (≥90th percentile) and preceding dry periods, source water turbidity, total coliforms, and protozoan AGIs - cryptosporidiosis and giardiasis - in the populations served by four DWSs that source surface water from Lake Ontario (Hamilton and Toronto, Ontario, Canada) and Lake Michigan (Green Bay and Milwaukee, Wisconsin, USA) from January 2009 through August 2014. We used distributed lag non-linear Poisson regression models adjusted for seasonality and found extreme precipitation weeks preceded by dry periods increased the relative risk of protozoan AGI after 1 and 3-5 weeks in three of the four cities, although only statistically significant in two. Our results suggest that the risk of protozoan AGI increases with extreme precipitation preceded by a dry period. As extreme precipitation patterns become more frequent with climate change, the ability to detect changes in water quality and effectively treat source water of varying quality is increasingly important for adaptive capacity and protection of public health.

Perfluorinated Carboxylic Acids with Increasing Carbon Chain Lengths Upregulate Amino Acid Transporters and Modulate Compensatory Response of Xenobiotic Transporters in HepaRG Cells.

Perfluorinated carboxylic acids (PFCAs) are widespread environmental pollutants for which human exposure has been documented. PFCAs at high doses are known to regulate xenobiotic transporters partly through peroxisome proliferator-activated receptor alpha (PPARα) and constitutive androstane receptor (CAR) in rodent models. Less is known regarding how various PFCAs at a lower concentration modulate transporters for endogenous substrates, such as amino acids in human hepatocytes. Such studies are of particular importance because amino acids are involved in chemical detoxification, and their transport system may serve as a promising therapeutic target for structurally similar xenobiotics. The focus of this study was to further elucidate how PFCAs modulate transporters involved in intermediary metabolism and xenobiotic biotransformation. We tested the hepatic transcriptomic response of HepaRG cells exposed to 45 µM of perfluorooctanoic acid, perfluorononanoic acid, or perfluorodecanoic acid in triplicates for 24 hours (vehicle: 0.1% DMSO), as well as the prototypical ligands for PPARα (WY-14643, 45 µM) and CAR (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime [CITCO], 2 µM). PFCAs with increasing carbon chain lengths (C8-C10) regulated more liver genes, with amino acid metabolism and transport ranked among the top enriched pathways and PFDA ranked as the most potent PFCA tested. Genes encoding amino acid transporters, which are essential for protein synthesis, were novel inducible targets by all three PFCAs, suggesting a potentially protective mechanism to reduce further toxic insults. None of the transporter regulations appeared to be through PPARα or CAR but potential involvement of nuclear factor erythroid 2-related factor 2 is noted for all 3 PFCAs. In conclusion, PFCAs with increasing carbon chain lengths up-regulate amino acid transporters and modulate xenobiotic transporters to limit further toxic exposures in HepaRG cells. SIGNIFICANCE STATEMENT: Little is known regarding how various perfluorinated carboxylic acids modulate the transporters for endogenous substrates in human liver cells. Using HepaRG cells, this study is among the first to show that perfluorinated carboxylic acids with increasing carbon chain lengths upregulate amino acid transporters, which are essential for protein synthesis, and modulate xenobiotic transporters to limit further toxic exposures at concentrations lower than what was used in the literature.

Health Measurement Model-Bringing a Life Course Perspective to Health Measurement: The PRISM Model.

Health is a multidimensional concept that is challenging to measure, and in the rapidly evolving developmental changes that occur during the first 21 years of human life, requires a dynamic approach to accurately capture the transitions, and overall arc of a complex process of internal and external interactions. We propose an approach that integrates a lifecourse framework with a layered series of assessments, each layer using a many to many mapping, to converge on four fundamental dimensions of health measurement-Potential, Adaptability, Performance, and Experience. The four dimensions can conceptually be mapped onto a plane with each edge of the resulting quadrilateral corresponding to one dimension and each dimensions assessment calibrated against a theoretical ideal. As the plane evolves over time, the sequential measurements will form a volume. We term such a model the Prism Model, and describe conceptually how single domain assessments can be built up to generate the holistic description through the vehicle of a layer of Exemplar Cases. The model is theoretical but future work can use the framework and principles to generate scalable and adaptable applications that can unify and improve the precision of serial measurements that integrate environmental and physiologic influences to improve the science of child health measurement.

Recommendations for Assessment of Environmental Exposures in Longitudinal Life Course Studies Such as the National Children's Study.

An important step toward understanding the relationship between the environment and child health and development is the comprehensive cataloging of external environmental factors that may modify health and development over the life course. Our understanding of the environmental influences on health is growing increasingly complex. Significant key questions exist as to what genes, environment, and life stage mean to defining normal variations and altered developmental trajectories throughout the life course and also across generations. With the rapid advances in genetic technology came large-scale genomic studies to search for the genetic etiology of complex diseases. While genome-wide association studies (GWAS) have revealed genetic factors and networks that advance our understanding to some extent, it is increasingly recognized that disease causation is largely non-genetic and reflects interactions between an individual's genetic susceptibility and his or her environment. Thus, the full promise of the human genome project to prevent or treat disease and promote good health arguably depends on a commitment to understanding the interactions between our environment and our genetic makeup and requires a design with prospective environmental data collection that considers critical windows of susceptibility that likely correspond to the expression of specific genes and gene pathways. Unlike the genome, which is static, relevant exposures as well as our response to exposures, change over time. This has fostered the complementary concept of the exposome ideally defined as the measure of all exposures of an individual over a lifetime and how those exposures relate to health. The exposome framework considers multiple external exposures (e.g., chemical, social) and behaviors that may modify exposures (e.g., diet), as well as consequences of environmental exposures indexed via biomarkers of physiological response or measures of behavioral response throughout the lifespan. The exposome concept can be applied in prospective developmental studies such as the National Children's Study (NCS) with the practical understanding that even a partial characterization will bring major advances to health. Lessons learned from the NCS provide an important opportunity to inform future studies that can leverage these evolving paradigms in elucidating the role of environment on health across the life course.

Human Health Exposure Analysis Resource (HHEAR): A model for incorporating the exposome into health studies.

BACKGROUND: Characterizing the complexity of environmental exposures in relation to human health is critical to advancing our understanding of health and disease throughout the life span. Extant cohort studies open the door for such investigations more rapidly and inexpensively than launching new cohort studies and the Human Health Exposure Analysis Resource (HHEAR) provides a resource for implementing life-stage exposure studies within existing study populations. Primary challenges to incorporation of environmental exposure assessment in health studies include: (1) lack of widespread knowledge of biospecimen and environmental sampling and storage requirements for environmental exposure assessment among investigators; (2) lack of availability of and access to laboratories capable of analyzing multiple environmental exposures throughout the life-course; and (3) studies lacking sufficient power to assess associations across life-stages. HHEAR includes a consortium of researchers with expertise in laboratory analyses, statistics and logistics to overcome these limitations and enable inclusion of exposomics in human health studies. OBJECTIVE: This manuscript describes the structure and strengths of implementing the harmonized HHEAR resource model, and our approaches to addressing challenges. We describe how HHEAR incorporates analyses of biospecimens and environmental samples and human health studies across the life span - serving as a model for incorporating environmental exposures into national and international research. We also present program successes to date. DISCUSSION: HHEAR provides a full-service laboratory and data analysis exposure assessment resource, linking scientific, life span, and toxicological consultation with both laboratory and data analysis expertise. HHEAR services are provided without cost but require NIH, NCI, NHLBI, or ECHO funding of the original cohort; internal HHEAR scientific review and approval of a brief application; and adherence to data sharing and publication policies. We describe the benefits of HHEAR's structure, collaborative framework and coordination across project investigators, analytical laboratories, biostatisticians and bioinformatics specialists; quality assurance/quality control (QA/QC) including integrated sample management; and tools that have been developed to support the research (exposure information pages, ontology, new analytical methods, common QA/QC approach across laboratories, etc.). This foundation supports HHEAR's inclusion of new laboratory and statistical analysis methods and studies that are enhanced by including targeted analysis of specific exposures and untargeted analysis of chemicals associated with phenotypic endpoints in biological and environmental samples. CONCLUSION: HHEAR is an interdisciplinary team of toxicologists, epidemiologists, laboratory scientists, and data scientists across multiple institutions to address broad and complex questions that benefit from integrated laboratory and data analyses. HHEAR's processes, features, and tools include all life stages and analysis of biospecimens and environmental samples. They are available to the wider scientific community to augment studies by adding state of the art environmental analyses to be linked to human health outcomes.

The effects of gene × environment interactions on silver nanoparticle toxicity in the respiratory system: An adverse outcome pathway.

The Adverse Outcome Pathway (AOP) framework is serving as a basis to integrate new data streams in order to enhance the power of predictive toxicology. AOP development for engineered nanomaterials (ENM), including silver nanoparticles (AgNP), is currently lagging behind other chemicals of regulatory interest due to our limited understanding of the mechanism by which underlying genetics or diseases directly modify host response to AgNP exposures. This also highlights the importance of considering the Aggregate Exposure Pathway (AEP) framework, which precedes the AOP framework and outlines source to target site exposure. The AEP and AOP frameworks interface at the target site, where a molecular initiating event (MIE) occurs and is followed by key events (KE) for adverse cellular and organ responses along a biological pathway and ends with the adverse organism response. The primary goal of this study is to use AgNP to interrogate the AEP-AOP framework by organizing and integrating in vitro dose-response data and in vivo exposure-response data from previous studies to evaluate the effects of interactions between host genetic and acquired factors, or gene × environment interactions (G × E), on AgNP toxicity in the respiratory system. Using this framework will help us to identify plausible key event relationships (KER) between MIE and adverse organism responses when KE are not measured using the same assay in order to derive future predictive models, guide research, and support development of tools for making risk-based, regulatory decisions on ENM. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine.

FutureTox IV Workshop Summary: Predictive Toxicology for Healthy Children.

FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high-throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals. Coupling this vast amount of mechanistic data with a deeper understanding of molecular embryology and post-natal development lays the groundwork for using new approach methodologies (NAMs) to evaluate chemical toxicity, drug efficacy, and safety assessment for embryo-fetal development. NAM is a term recently adopted in reference to any technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment to avoid the use of intact animals (U.S. Environmental Protection Agency [EPA], Strategic plan to promote the development and implementation of alternative test methods within the tsca program, 2018, https://www.epa.gov/sites/production/files/2018-06/documents/epa_alt_strat_plan_6-20-18_clean_final.pdf). There are challenges to implementing NAMs to evaluate chemicals for developmental toxicity compared with adult toxicity. This forum article reviews the 2018 workshop activities, highlighting challenges and opportunities for applying NAMs for adverse pregnancy outcomes (eg, preterm labor, malformations, low birth weight) as well as disorders manifesting postnatally (eg, neurodevelopmental impairment, breast cancer, cardiovascular disease, fertility). DART is an important concern for different regulatory statutes and test guidelines. Leveraging advancements in such approaches and the accompanying efficiencies to detecting potential hazards to human development are the unifying concepts toward implementing NAMs in DART testing. Although use of NAMs for higher level regulatory decision making is still on the horizon, the conference highlighted novel testing platforms and computational models that cover multiple levels of biological organization, with the unique temporal dynamics of embryonic development, and novel approaches for estimating toxicokinetic parameters essential in supporting in vitro to in vivo extrapolation.

Single-cell profiling for advancing birth defects research and prevention.

Cellular analysis of developmental processes and toxicities has traditionally entailed bulk methods (e.g., transcriptomics) that lack single cell resolution or tissue localization methods (e.g., immunostaining) that allow only a few genes to be monitored in each experiment. Recent technological advances have enabled interrogation of genomic function at the single-cell level, providing new opportunities to unravel developmental pathways and processes with unprecedented resolution. Here, we review emerging technologies of single-cell RNA-sequencing (scRNA-seq) to globally characterize the gene expression sets of different cell types and how different cell types emerge from earlier cell states in development. Cell atlases of experimental embryology and human embryogenesis at single-cell resolution will provide an encyclopedia of genes that define key stages from gastrulation to organogenesis. This technology, combined with computational models to discover key organizational principles, was recognized by Science magazine as the "Breakthrough of the year" for 2018 due to transformative potential on the way we study how human cells mature over a lifetime, how tissues regenerate, and how cells change in diseases (e.g., patient-derived organoids to screen disease-specific targets and design precision therapy). Profiling transcriptomes at the single-cell level can fulfill the need for greater detail in the molecular progression of all cell lineages, from pluripotency to adulthood and how cell-cell signaling pathways control progression at every step. Translational opportunities emerge for elucidating pathogenesis of genetic birth defects with cellular precision and improvements for predictive toxicology of chemical teratogenesis.

The use of dried blood spots for characterizing children's exposure to organic environmental chemicals.

Biomonitoring is a commonly used tool for exposure assessment of organic environmental chemicals with urine and blood samples being the most commonly used matrices. However, for children's studies, blood samples are often difficult to obtain. Dried blood spots (DBS) represent a potential matrix for blood collection in children that may be used for biomonitoring. DBS are typically collected at birth to screen for several congenital disorders and diseases; many of the states that are required to collect DBS archive these spots for years. If the archived DBS can be accessed by environmental health researchers, they potentially could be analyzed to retrospectively assess exposure in these children. Furthermore, DBS can be collected prospectively in the field from children ranging in age from newborn to school-aged with little concern from parents and minimal risk to the child. Here, we review studies that have evaluated the measurement of organic environmental toxicants in both archived and prospectively collected DBS, and where available, the validation procedures that have been performed to ensure these measurements are comparable to traditional biomonitoring measurements. Among studies thus far, the amount of validation has varied considerably with no studies systematically evaluating all parameters from field collection, shipping and storage contamination and stability to laboratory analysis feasibility. These validation studies are requisite to ensure reliability of the measurement and comparability to more traditional matrices. Thus, we offer some recommendations for validation studies and other considerations before DBS should be adopted as a routine matrix for biomonitoring.

The effects of genotype × phenotype interactions on silver nanoparticle toxicity in organotypic cultures of murine tracheal epithelial cells.

Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. Previous studies have identified AgNP toxicity in airway epithelial cells, but no in vitro studies to date have used organotypic cultures as a high-content in vitro model of the conducting airway to characterize the effects of interactions between host genetic and acquired factors, or gene × phenotype interactions (G × P), on AgNP toxicity. In the present study, we derived organotypic cultures from primary murine tracheal epithelial cells (MTEC) to characterize nominal and dosimetric dose-response relationships for AgNPs with a gold core on barrier dysfunction, glutathione (GSH) depletion, reactive oxygen species (ROS) production, lipid peroxidation, and cytotoxicity across two genotypes (A/J and C57BL/6J mice), two phenotypes ('Normal' and 'Type 2 [T2]-Skewed'), and two exposures (an acute exposure of 24 h and a subacute exposure of 4 h, every other day, over 5 days [5 × 4 h]). We characterized the 'T2-Skewed' phenotype as an in vitro model of chronic respiratory diseases, which was marked by increased sensitivity to AgNP-induced barrier dysfunction, GSH depletion, ROS production, lipid peroxidation, and cytotoxicity, suggesting that asthmatics are a sensitive population to AgNP exposures in occupational settings. This also suggests that exposure limits, which should be based upon the most sensitive population, should be derived using in vitro and in vivo models of chronic respiratory diseases. This study highlights the importance of considering dosimetry as well as G × P effects when screening and prioritizing potential respiratory toxicants. Such in vitro studies can be used to inform regulatory policy aimed at special protections for all populations.

Mode of silver clearance following 28-day inhalation exposure to silver nanoparticles determined from lung burden assessment including post-exposure observation periods.

Recently revised OECD inhalation toxicity testing guidelines require measurements of lung burden immediately after and for periods following exposure for nanomaterials. Lung burden is a function of pulmonary deposition and retention of nanoparticles. Using lung burden studies as per OECD guidelines, it may be possible to assess clearance mechanisms of nanoparticles. In this study, male rats were exposed to silver nanoparticle (AgNP) aerosols (18.1-19.6 nm) generated from a spark generator. Exposure groups consisted of (1) control (fresh air), (2) low (31.2 ± 8.5 µg/m3), (3) moderate (81.8 ± 11.4 µg/m3), and (4) high concentrations (115.6 ± 30.5 µg/m3). Rats were exposed for 6-h/day, 5-days/week for 4 weeks (28-days) based on the revised OECD test guideline 412. Bronchoalveolar lavage (BAL) fluids were collected on post-exposure observation (PEO)-1 and PEO-7 days and analyzed for inflammatory cells and inflammatory biomarkers. The lung burdens of Ag from AgNPs were measured on PEO-1, PEO-7, and PEO-28 days to obtain quantitative mass concentrations per lung. Differential counting of blood cells and inflammatory biomarkers in BAL fluid and histopathological evaluation of lung tissue indicated that exposure to the high concentrations of AgNP aerosol induced inflammation at PEO-1, slowly resolved at PEO-7 and completely resolved at PEO-28 days. Lung burden measurement suggested that Ag from AgNPs was cleared through two different modes; fast and slow clearance. The fast clearance component was concentration-dependent with half-times ranging from two to four days and clearance rates of 0.35-0.17/day-1 from low to high concentrations. The slow clearance had half-times of 100, 57, and 76 days and clearance rates of 0.009, 0.012, and 0.007/day-1 for the high, moderate and low concentration exposure. The exact mechanism of clearance is not known currently. The fast clearance component which was concentration-dependent could be dependent on the dissolution of AgNPs and the slow clearance would be due to slow clearance of the low dissolution AgNPs secondary particles originating from silver ions reacting with biogenic anions. These secondary AgNPs might be cleared by mechanisms other than dissolution such as mucociliary escalation, translocation to the lymphatic system or other organs.

Potential frameworks to support evaluation of mechanistic data for developmental neurotoxicity outcomes: A symposium report.

A key challenge in systematically incorporating mechanistic data into human health assessments is that, compared to studies of apical health endpoints, these data are both more abundant (mechanistic studies routinely outnumber other studies by several orders of magnitude) and more heterogeneous (e.g. different species, test system, tissue, cell type, exposure paradigm, or specific assays performed). A structured decision-making process for organizing, integrating, and weighing mechanistic DNT data for use in human health risk assessments will improve the consistency and efficiency of such evaluations. At the Developmental Neurotoxicology Society (DNTS) 2016 annual meeting, a symposium was held to address the application of existing organizing principles and frameworks for evaluation of mechanistic data relevant to interpreting neurotoxicology data. Speakers identified considerations with potential to advance the use of mechanistic DNT data in risk assessment, including considering the context of each exposure, since epigenetics, tissue type, sex, stress, nutrition and other factors can modify toxicity responses in organisms. It was also suggested that, because behavior is a manifestation of complex nervous system function, the presence and absence of behavioral change itself could be used to organize the interpretation of multiple complex simultaneous mechanistic changes. Several challenges were identified with frameworks and their implementation, and ongoing research to develop these approaches represents an early step toward full evaluation of mechanistic DNT data for assessments.

Characterizing the Neurodevelopmental Pesticide Exposome in a Children's Agricultural Cohort.

The exposome provides a conceptual model for identifying and characterizing lifetime environmental exposures and resultant health effects. In this study, we applied key exposome concepts to look specifically at the neurodevelopmental pesticide exposome, which focuses on exposures to pesticides that have the potential to cause an adverse neurodevelopmental impact. Using household dust samples from a children's agricultural cohort located in the Yakima Valley of Washington state, we identified 87 individual pesticides using liquid chromatography-tandem mass spectrometry. A total of 47 of these have evidence of neurotoxicity included in the Environmental Protection Agency (EPA) (re)registration materials. We used a mixed effects model to model trends in pesticide exposure. Over the two study years (2005 and 2011), we demonstrate a significant decrease in the neurodevelopmental pesticide exposome across the cohort, but particularly among farmworker households. Additional analysis with a non-parametric binomial analysis that weighted the levels of potentially neurotoxic pesticides detected in household dust by their reference doses revealed that the decrease in potentially neurotoxic pesticides was largely a result of decreases in some of the most potent neurotoxicants. Overall, this study provides evidence that the neurodevelopmental pesticide exposome framework is a useful tool in assessing the effectiveness of specific interventions in reducing exposure as well as setting priorities for future targeted actions.

The Effects of Genotype × Phenotype Interactions on Transcriptional Response to Silver Nanoparticle Toxicity in Organotypic Cultures of Murine Tracheal Epithelial Cells.

The airway epithelium is critical for maintaining innate and adaptive immune responses, and occupational exposures that disrupt its immune homeostasis may initiate and amplify airway inflammation. In our previous study, we demonstrated that silver nanoparticles (AgNP), which are engineered nanomaterials used in multiple applications but primarily in the manufacturing of many antimicrobial products, induce toxicity in organotypic cultures derived from murine tracheal epithelial cells (MTEC), and those differentiated toward a "Type 2 [T2]-Skewed" phenotype experienced an increased sensitivity to AgNP toxicity, suggesting that asthmatics could be a sensitive population to AgNP exposures in occupational settings. However, the mechanistic basis for this genotype × phenotype (G × P) interaction has yet to be defined. In this study, we conducted transcriptional profiling using RNA-sequencing to predict the enrichment of specific canonical pathways and upstream transcriptional regulators to assist in defining a mechanistic basis for G × P effects on AgNP toxicity. Organotypic cultures were derived from MTEC across 2 genetically inbred mouse strains (A/J and C57BL/6J mice), 2 phenotypes ("Normal" and "T2-Skewed"), and 1 AgNP exposure (an acute 24 h exposure) to characterize G × P effects on transcriptional response to AgNP toxicity. The "T2-Skewed" phenotype was marked by increased pro-inflammatory T17 responses to AgNP toxicity, which are significant predictors of neutrophilic/difficult-to-control asthma and suggests that asthmatics could be a sensitive population to AgNP exposures in occupational settings. This study highlights the importance of considering G × P effects when identifying these sensitive populations, whose underlying genetics or diseases could directly modify their response to AgNP exposures.