Application of Signaling Pathway-Based Adverse Outcome Pathways and High Throughput Toxicokinetic-PBPK for Developmental Cardiac Malformations

EPA Science Inventory

Associating putative molecular initiating events (MIE) with downstream cell signaling pathways and modeling fetal exposure kinetics is an important challenge for integration in developmental systems toxicology. Here, we describe an integrative systems toxicology model for develop...

A review of models for near-field exposure pathways of chemicals in consumer products.

PubMed

Huang, Lei; Ernstoff, Alexi; Fantke, Peter; Csiszar, Susan A; Jolliet, Olivier

2017-01-01

Exposure to chemicals in consumer products has been gaining increasing attention, with multiple studies showing that near-field exposures from products is high compared to far-field exposures. Regarding the numerous chemical-product combinations, there is a need for an overarching review of models able to quantify the multiple transfers of chemicals from products used near-field to humans. The present review therefore aims at an in-depth overview of modeling approaches for near-field chemical release and human exposure pathways associated with consumer products. It focuses on lower-tier, mechanistic models suitable for life cycle assessments (LCA), chemical alternative assessment (CAA) and high-throughput screening risk assessment (HTS). Chemicals in a product enter the near-field via a defined "compartment of entry", are transformed or transferred to adjacent compartments, and eventually end in a "human receptor compartment". We first focus on models of physical mass transfers from the product to 'near-field' compartments. For transfers of chemicals from article interior, adequate modeling of in-article diffusion and of partitioning between article surface and air/skin/food is key. Modeling volatilization and subsequent transfer to the outdoor is crucial for transfers of chemicals used in the inner space of appliances, on object surfaces or directly emitted to indoor air. For transfers from skin surface, models need to reflect the competition between dermal permeation, volatilization and fraction washed-off. We then focus on transfers from the 'near-field' to 'human' compartments, defined as respiratory tract, gastrointestinal tract and epidermis, for which good estimates of air concentrations, non-dietary ingestion parameters and skin permeation are essential, respectively. We critically characterize for each exposure pathway the ability of models to estimate near-field transfers and to best inform LCA, CAA and HTS, summarizing the main characteristics of the potentially best-suited models. This review identifies large knowledge gaps for several near-field pathways and suggests research needs and future directions. Copyright © 2016 Elsevier B.V. All rights reserved.

The Global Food System as a Transport Pathway for Hazardous Chemicals: The Missing Link between Emissions and Exposure.

PubMed

Ng, Carla A; von Goetz, Natalie

2017-01-01

Food is a major pathway for human exposure to hazardous chemicals. The modern food system is becoming increasingly complex and globalized, but models for food-borne exposure typically assume locally derived diets or use concentrations directly measured in foods without accounting for food origin. Such approaches may not reflect actual chemical intakes because concentrations depend on food origin, and representative analysis is seldom available. Processing, packaging, storage, and transportation also impart different chemicals to food and are not yet adequately addressed. Thus, the link between environmental emissions and realistic human exposure is effectively broken. We discuss the need for a fully integrated treatment of the modern industrialized food system, and we propose strategies for using existing models and relevant supporting data sources to track chemicals during production, processing, packaging, storage, and transport. Fate and bioaccumulation models describe how chemicals distribute in the environment and accumulate through local food webs. Human exposure models can use concentrations in food to determine body burdens based on individual or population characteristics. New models now include the impacts of processing and packaging but are far from comprehensive. We propose to close the gap between emissions and exposure by utilizing a wider variety of models and data sources, including global food trade data, processing, and packaging models. A comprehensive approach that takes into account the complexity of the modern global food system is essential to enable better prediction of human exposure to chemicals in food, sound risk assessments, and more focused risk abatement strategies. Citation: Ng CA, von Goetz N. 2017. The global food system as a transport pathway for hazardous chemicals: the missing link between emissions and exposure. Environ Health Perspect 125:1-7; http://dx.doi.org/10.1289/EHP168.

The relationship between inadvertent ingestion and dermal exposure pathways: a new integrated conceptual model and a database of dermal and oral transfer efficiencies.

PubMed

Gorman Ng, Melanie; Semple, Sean; Cherrie, John W; Christopher, Yvette; Northage, Christine; Tielemans, Erik; Veroughstraete, Violaine; Van Tongeren, Martie

2012-11-01

Occupational inadvertent ingestion exposure is ingestion exposure due to contact between the mouth and contaminated hands or objects. Although individuals are typically oblivious to their exposure by this route, it is a potentially significant source of occupational exposure for some substances. Due to the continual flux of saliva through the oral cavity and the non-specificity of biological monitoring to routes of exposure, direct measurement of exposure by the inadvertent ingestion route is challenging; predictive models may be required to assess exposure. The work described in this manuscript has been carried out as part of a project to develop a predictive model for estimating inadvertent ingestion exposure in the workplace. As inadvertent ingestion exposure mainly arises from hand-to-mouth contact, it is closely linked to dermal exposure. We present a new integrated conceptual model for dermal and inadvertent ingestion exposure that should help to increase our understanding of ingestion exposure and our ability to simultaneously estimate exposure by the dermal and ingestion routes. The conceptual model consists of eight compartments (source, air, surface contaminant layer, outer clothing contaminant layer, inner clothing contaminant layer, hands and arms layer, perioral layer, and oral cavity) and nine mass transport processes (emission, deposition, resuspension or evaporation, transfer, removal, redistribution, decontamination, penetration and/or permeation, and swallowing) that describe event-based movement of substances between compartments (e.g. emission, deposition, etc.). This conceptual model is intended to guide the development of predictive exposure models that estimate exposure from both the dermal and the inadvertent ingestion pathways. For exposure by these pathways the efficiency of transfer of materials between compartments (for example from surfaces to hands, or from hands to the mouth) are important determinants of exposure. A database of transfer efficiency data relevant for dermal and inadvertent ingestion exposure was developed, containing 534 empirically measured transfer efficiencies measured between 1980 and 2010 and reported in the peer-reviewed and grey literature. The majority of the reported transfer efficiencies (84%) relate to transfer between surfaces and hands, but the database also includes efficiencies for other transfer scenarios, including surface-to-glove, hand-to-mouth, and skin-to-skin. While the conceptual model can provide a framework for a predictive exposure assessment model, the database provides detailed information on transfer efficiencies between the various compartments. Together, the conceptual model and the database provide a basis for the development of a quantitative tool to estimate inadvertent ingestion exposure in the workplace.

Inhalation toxicity of indoor air pollutants in Drosophila melanogaster using integrated transcriptomics and computational behavior analyses

NASA Astrophysics Data System (ADS)

Eom, Hyun-Jeong; Liu, Yuedan; Kwak, Gyu-Suk; Heo, Muyoung; Song, Kyung Seuk; Chung, Yun Doo; Chon, Tae-Soo; Choi, Jinhee

2017-06-01

We conducted an inhalation toxicity test on the alternative animal model, Drosophila melanogaster, to investigate potential hazards of indoor air pollution. The inhalation toxicity of toluene and formaldehyde was investigated using comprehensive transcriptomics and computational behavior analyses. The ingenuity pathway analysis (IPA) based on microarray data suggests the involvement of pathways related to immune response, stress response, and metabolism in formaldehyde and toluene exposure based on hub molecules. We conducted a toxicity test using mutants of the representative genes in these pathways to explore the toxicological consequences of alterations of these pathways. Furthermore, extensive computational behavior analysis showed that exposure to either toluene or formaldehyde reduced most of the behavioral parameters of both wild-type and mutants. Interestingly, behavioral alteration caused by toluene or formaldehyde exposure was most severe in the p38b mutant, suggesting that the defects in the p38 pathway underlie behavioral alteration. Overall, the results indicate that exposure to toluene and formaldehyde via inhalation causes severe toxicity in Drosophila, by inducing significant alterations in gene expression and behavior, suggesting that Drosophila can be used as a potential alternative model in inhalation toxicity screening.

Inhalation toxicity of indoor air pollutants in Drosophila melanogaster using integrated transcriptomics and computational behavior analyses

PubMed Central

Eom, Hyun-Jeong; Liu, Yuedan; Kwak, Gyu-Suk; Heo, Muyoung; Song, Kyung Seuk; Chung, Yun Doo; Chon, Tae-Soo; Choi, Jinhee

2017-01-01

We conducted an inhalation toxicity test on the alternative animal model, Drosophila melanogaster, to investigate potential hazards of indoor air pollution. The inhalation toxicity of toluene and formaldehyde was investigated using comprehensive transcriptomics and computational behavior analyses. The ingenuity pathway analysis (IPA) based on microarray data suggests the involvement of pathways related to immune response, stress response, and metabolism in formaldehyde and toluene exposure based on hub molecules. We conducted a toxicity test using mutants of the representative genes in these pathways to explore the toxicological consequences of alterations of these pathways. Furthermore, extensive computational behavior analysis showed that exposure to either toluene or formaldehyde reduced most of the behavioral parameters of both wild-type and mutants. Interestingly, behavioral alteration caused by toluene or formaldehyde exposure was most severe in the p38b mutant, suggesting that the defects in the p38 pathway underlie behavioral alteration. Overall, the results indicate that exposure to toluene and formaldehyde via inhalation causes severe toxicity in Drosophila, by inducing significant alterations in gene expression and behavior, suggesting that Drosophila can be used as a potential alternative model in inhalation toxicity screening. PMID:28621308

EPA's SHEDS-multimedia model: children's cumulative pyrethroid exposure estimates and evaluation against NHANES biomarker data

EPA Science Inventory

The U.S. EPA's SHEDS-Multimedia model was applied to enhance the understanding of children's exposures and doses to multiple pyrethroid pesticides, including major contributing chemicals and pathways. This paper presents combined dietary and residential exposure estimates and cum...

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data.

PubMed

Deziel, Nicole C; Freeman, Laura E Beane; Graubard, Barry I; Jones, Rena R; Hoppin, Jane A; Thomas, Kent; Hines, Cynthia J; Blair, Aaron; Sandler, Dale P; Chen, Honglei; Lubin, Jay H; Andreotti, Gabriella; Alavanja, Michael C R; Friesen, Melissa C

2017-03-01

Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and ≥ 20%, respectively (88 statistics, five studies). Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296-305; http://dx.doi.org/10.1289/EHP426.

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data

PubMed Central

Deziel, Nicole C.; Freeman, Laura E. Beane; Graubard, Barry I.; Jones, Rena R.; Hoppin, Jane A.; Thomas, Kent; Hines, Cynthia J.; Blair, Aaron; Sandler, Dale P.; Chen, Honglei; Lubin, Jay H.; Andreotti, Gabriella; Alavanja, Michael C. R.; Friesen, Melissa C.

2016-01-01

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. Methods: From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). Results: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1–19% and ≥ 20%, respectively (88 statistics, five studies). Conclusion: Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296–305; http://dx.doi.org/10.1289/EHP426 PMID:27458779

APPLICATION OF A MICROSCALE EMISSION FACTOR MODEL FOR PARTICULATE MATTER (MICROFACPM) TO CALCULATE VEHICLE GENERATED CONTRIBUTION PM 2.5 EMISSIONS

EPA Science Inventory

The United States Environmental Protection Agency's (EPA) National Exposure Research Laboratory is developing improved methods for modeling the source through the air pathway to human exposure in significant microenvironments of exposure. As a part of this project, we develope...

Dermal permeation data and models for the prioritization and screening-level exposure assessment of organic chemicals

EPA Science Inventory

High throughput screening (HTS) models are being developed and applied to prioritize chemicals for more comprehensive exposure and risk assessment. Dermal pathways are possible exposure routes to humans for thousands of chemicals found in personal care products and the indoor env...

Integrating human health and ecological data into cumulative risk assessment through the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks

EPA Science Inventory

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from relevant stressors across different species. Integration is important to provide a more complete assessment of risk, but evaluating endpoints a...

Evaluating environmental modeling and sampling data with biomarker data to identify sources and routes of exposure

NASA Astrophysics Data System (ADS)

Shin, Hyeong-Moo; McKone, Thomas E.; Bennett, Deborah H.

2013-04-01

Exposure to environmental chemicals results from multiple sources, environmental media, and exposure routes. Ideally, modeled exposures should be compared to biomonitoring data. This study compares the magnitude and variation of modeled polycyclic aromatic hydrocarbons (PAHs) exposures resulting from emissions to outdoor and indoor air and estimated exposure inferred from biomarker levels. Outdoor emissions result in both inhalation and food-based exposures. We modeled PAH intake doses using U.S. EPA's 2002 National Air Toxics Assessment (NATA) county-level emissions data for outdoor inhalation, the CalTOX model for food ingestion (based on NATA emissions), and indoor air concentrations from field studies for indoor inhalation. We then compared the modeled intake with the measured urine levels of hydroxy-PAH metabolites from the 2001-2002 National Health and Nutrition Examination Survey (NHANES) survey as quantifiable human intake of PAH parent-compounds. Lognormal probability plots of modeled intakes and estimated intakes inferred from biomarkers suggest that a primary route of exposure to naphthalene, fluorene, and phenanthrene for the U.S. population is likely inhalation from indoor sources. For benzo(a)pyrene, the predominant exposure route is likely from food ingestion resulting from multi-pathway transport and bioaccumulation due to outdoor emissions. Multiple routes of exposure are important for pyrene. We also considered the sensitivity of the predicted exposure to the proportion of the total naphthalene production volume emitted to the indoor environment. The comparison of PAH biomarkers with exposure variability estimated from models and sample data for various exposure pathways supports that both indoor and outdoor models are needed to capture the sources and routes of exposure to environmental contaminants.

Problems in evaluating radiation dose via terrestrial and aquatic pathways.

PubMed Central

Vaughan, B E; Soldat, J K; Schreckhise, R G; Watson, E C; McKenzie, D H

1981-01-01

This review is concerned with exposure risk and the environmental pathways models used for predictive assessment of radiation dose. Exposure factors, the adequacy of available data, and the model subcomponents are critically reviewed from the standpoint of absolute error propagation. Although the models are inherently capable of better absolute accuracy, a calculated dose is usually overestimated by from two to six orders of magnitude, in practice. The principal reason for so large an error lies in using "generic" concentration ratios in situations where site specific data are needed. Major opinion of the model makers suggests a number midway between these extremes, with only a small likelihood of ever underestimating the radiation dose. Detailed evaluations are made of source considerations influencing dose (i.e., physical and chemical status of released material); dispersal mechanisms (atmospheric, hydrologic and biotic vector transport); mobilization and uptake mechanisms (i.e., chemical and other factors affecting the biological availability of radioelements); and critical pathways. Examples are shown of confounding in food-chain pathways, due to uncritical application of concentration ratios. Current thoughts of replacing the critical pathways approach to calculating dose with comprehensive model calculations are also shown to be ill-advised, given present limitations in the comprehensive data base. The pathways models may also require improved parametrization, as they are not at present structured adequately to lend themselves to validation. The extremely wide errors associated with predicting exposure stand in striking contrast to the error range associated with the extrapolation of animal effects data to the human being. PMID:7037381

Transcriptional Pathways Altered in Response to Vibration in a Model of Hand-Arm Vibration Syndrome.

PubMed

Waugh, Stacey; Kashon, Michael L; Li, Shengqiao; Miller, Gerome R; Johnson, Claud; Krajnak, Kristine

2016-04-01

The aim of this study was to use an established model of vibration-induced injury to assess frequency-dependent changes in transcript expression in skin, artery, and nerve tissues. Transcript expression in tissues from control and vibration-exposed rats (4 h/day for 10 days at 62.5, 125, or 250 Hz; 49 m/s, rms) was measured. Transcripts affected by vibration were used in bioinformatics analyses to identify molecular- and disease-related pathways associated with exposure to vibration. Analyses revealed that cancer-related pathways showed frequency-dependent changes in activation or inhibition. Most notably, the breast-related cancer-1 pathway was affected. Other pathways associated with breast cancer type 1 susceptibility protein related signaling, or associated with cancer and cell cycle/cell survivability were also affected. Occupational exposure to vibration may result in DNA damage and alterations in cell signaling pathways that have significant effects on cellular division.

Exposure matrix development for the Libby cohort.

PubMed

Noonan, C W

2006-11-01

The Libby, MT, cohort includes current and former residents with potential historical exposure to asbestos-contaminated vermiculite. This cohort includes individuals with a broad range of exposure experiences and work histories. While both occupational and nonoccupational exposure pathways were found to be relevant in recent investigations of health effects among this cohort, there has not been a comprehensive approach to characterizing these varied exposure pathways. Any approach toward assessing historical exposures among this population must account for three general categories: (1) occupational exposures, (2) residential exposures, and (3) exposures related to a variety of nonoccupational activities thought to be associated with vermiculite/asbestos exposure in this community. First, a job exposure matrix is commonly used in occupational epidemiology to assess historical worker exposures, allowing for the incorporation of numerous occupational categories and weighting factors applied to specific jobs for different time periods. Second, residential exposures can best be quantified by integrating individuals' residential histories with data on environmental asbestos contamination in the community. Previous soil or sediment sampling as well as air modeling could inform estimates of time- and spatial-dependent exposure concentrations for a residential exposure matrix. Finally, exposure opportunities due to nonoccupational activities could be weighted by factors such as time, geography, environmental sampling, and an assessment of the relative importance for each pathway. These three matrices for occupational, residential, and activity exposure pathways could be combined or used separately to provide a more comprehensive and quantitative, or semiquantitative, assessment of individual exposure in future epidemiological studies of this cohort.

Pathways of inhalation exposure to manganese in children living near a ferromanganese refinery: A structural equation modeling approach

EPA Science Inventory

Manganese (Mn) is both essential element and neurotoxicant. Exposure to Mn can occur from various sources and routes. Structural equation modeling was used to examine routes of exposure to Mn among children residing near a ferromanganese refinery in Marietta, Ohio. An inhalation ...

Refining the aggregate exposure pathway

EPA Science Inventory

Advancements in measurement technologies and modeling capabilities continue to result in an abundance of exposure information, adding to that currently in existence. However, fragmentation within the exposure science community acts as an obstacle for realizing the vision set fort...

A fugacity-based indoor residential pesticide fate model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bennett, Deborah H.; Furtaw, Edward J.; McKone, Thomas E.

Dermal and non-dietary pathways are potentially significant exposure pathways to pesticides used in residences. Exposure pathways include dermal contact with residues on surfaces, ingestion from hand- and object-to-mouth activities, and absorption of pesticides into food. A limited amount of data has been collected on pesticide concentrations in various residential compartments following an application. But models are needed to interpret this data and make predictions about other pesticides based on chemical properties. In this paper, we propose a mass-balance compartment model based on fugacity principles. We include air (both gas phase and aerosols), carpet, smooth flooring, and walls as model compartments.more » Pesticide concentrations on furniture and toys, and in food, are being added to the model as data becomes available. We determine the compartmental fugacity capacity and mass transfer-rate coefficient for wallboard as an example. We also present the framework and equations needed for a dynamic mass-balance model.« less

The Global Food System as a Transport Pathway for Hazardous Chemicals: The Missing Link between Emissions and Exposure

PubMed Central

Ng, Carla A.; von Goetz, Natalie

2016-01-01

Background: Food is a major pathway for human exposure to hazardous chemicals. The modern food system is becoming increasingly complex and globalized, but models for food-borne exposure typically assume locally derived diets or use concentrations directly measured in foods without accounting for food origin. Such approaches may not reflect actual chemical intakes because concentrations depend on food origin, and representative analysis is seldom available. Processing, packaging, storage, and transportation also impart different chemicals to food and are not yet adequately addressed. Thus, the link between environmental emissions and realistic human exposure is effectively broken. Objectives: We discuss the need for a fully integrated treatment of the modern industrialized food system, and we propose strategies for using existing models and relevant supporting data sources to track chemicals during production, processing, packaging, storage, and transport. Discussion: Fate and bioaccumulation models describe how chemicals distribute in the environment and accumulate through local food webs. Human exposure models can use concentrations in food to determine body burdens based on individual or population characteristics. New models now include the impacts of processing and packaging but are far from comprehensive. We propose to close the gap between emissions and exposure by utilizing a wider variety of models and data sources, including global food trade data, processing, and packaging models. Conclusions: A comprehensive approach that takes into account the complexity of the modern global food system is essential to enable better prediction of human exposure to chemicals in food, sound risk assessments, and more focused risk abatement strategies. Citation: Ng CA, von Goetz N. 2017. The global food system as a transport pathway for hazardous chemicals: the missing link between emissions and exposure. Environ Health Perspect 125:1–7; http://dx.doi.org/10.1289/EHP168 PMID:27384039

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats.

PubMed

Qin, Liyan; Dai, Xufang; Yin, Yunhou

2016-09-01

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, limited verbal communication and repetitive behaviors. Recent studies have demonstrated that Wnt signaling and mTOR signaling play important roles in the pathogenesis of ASD. However, the relationship of these two signaling pathways in ASD remains unclear. We assessed this question using the valproic acid (VPA) rat model of autism. Our results demonstrated that VPA exposure activated mTOR signaling and suppressed autophagy in the prefrontal cortex, hippocampus and cerebellum of autistic model rats, characterized by enhanced phospho-mTOR and phospho-S6 and decreased Beclin1, Atg5, Atg10, LC3-II and autophagosome formation. Rapamycin treatment suppressed the effect of VPA on mTOR signaling and ameliorated the autistic-like behaviors of rats in our autism model. The administration of VPA also activated Wnt signaling through up-regulating beta-catenin and phospho-GSK3beta. Suppression of the Wnt pathway by sulindac relieved autistic-like behaviors and attenuated VPA-induced mTOR signaling activation in autistic model rats. Our results demonstrate that VPA exposure sequentially activates Wnt signaling and mTOR signaling in rats. Suppression of the Wnt signaling pathway relieves autistic-like behaviors partially by deactivating the mTOR signaling pathway in VPA-exposed rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Complementary proteomic approaches reveal mitochondrial dysfunction, immune and inflammatory dysregulation in a mouse model of Gulf War Illness.

PubMed

Zakirova, Zuchra; Reed, Jon; Crynen, Gogce; Horne, Lauren; Hassan, Samira; Mathura, Venkatarajan; Mullan, Michael; Crawford, Fiona; Ait-Ghezala, Ghania

2017-09-01

Long-term consequences of combined pyridostigmine bromide (PB) and permethrin (PER) exposure in C57BL6/J mice using a well-characterized mouse model of exposure to these Gulf War (GW) agents were explored at the protein level. We used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches-stable isotope dimethyl labeling and iTRAQ. The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation. Collectively, our work identified key pathways which were chronically impacted in the mouse CNS following acute GW agent exposure, this may lead to the identification of potential targets for therapeutic intervention in the future. Long-term consequences of combined PB and PER exposure in C57BL6/J mice using a well-characterized mouse model of exposure to these GW agents were explored at the protein level. Expanding on earlier work, we used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches-stable isotope dimethyl labeling and iTRAQ. The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation at 5 months postexposure to PB + PER. © 2017 The Authors. PROTEOMICS - Clinical Applications published by WILEY-VCH Verlag GmbH & Co. KGaA.

Complementary proteomic approaches reveal mitochondrial dysfunction, immune and inflammatory dysregulation in a mouse model of Gulf War Illness

PubMed Central

Zakirova, Zuchra; Reed, Jon; Crynen, Gogce; Horne, Lauren; Hassan, Samira; Mathura, Venkatarajan; Mullan, Michael; Crawford, Fiona

2017-01-01

Purpose Long‐term consequences of combined pyridostigmine bromide (PB) and permethrin (PER) exposure in C57BL6/J mice using a well‐characterized mouse model of exposure to these Gulf War (GW) agents were explored at the protein level. Experimental design We used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane‐bound protein fractions from brain samples using two orthogonal isotopic labeling LC‐MS/MS proteomic approaches—stable isotope dimethyl labeling and iTRAQ. Results The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. Conclusions and clinical relevance The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation. Collectively, our work identified key pathways which were chronically impacted in the mouse CNS following acute GW agent exposure, this may lead to the identification of potential targets for therapeutic intervention in the future. Long‐term consequences of combined PB and PER exposure in C57BL6/J mice using a well‐characterized mouse model of exposure to these GW agents were explored at the protein level. Expanding on earlier work, we used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane‐bound protein fractions from brain samples using two orthogonal isotopic labeling LC‐MS/MS proteomic approaches—stable isotope dimethyl labeling and iTRAQ. The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation at 5 months postexposure to PB + PER. PMID:28371386

Estimating human exposure to PFOS isomers and PFCA homologues: the relative importance of direct and indirect (precursor) exposure.

PubMed

Gebbink, Wouter A; Berger, Urs; Cousins, Ian T

2015-01-01

Contributions of direct and indirect (via precursors) pathways of human exposure to perfluorooctane sulfonic acid (PFOS) isomers and perfluoroalkyl carboxylic acids (PFCAs) are estimated using a Scenario-Based Risk Assessment (SceBRA) modelling approach. Monitoring data published since 2008 (including samples from 2007) are used. The estimated daily exposures (resulting from both direct and precursor intake) for the general adult population are highest for PFOS and perfluorooctanoic acid (PFOA), followed by perfluorohexanoic acid (PFHxA) and perfluorodecanoic acid (PFDA), while lower daily exposures are estimated for perfluorobutanoic acid (PFBA) and perfluorododecanoic acid (PFDoDA). The precursor contributions to the individual perfluoroalkyl acid (PFAA) daily exposures are estimated to be 11-33% for PFOS, 0.1-2.5% for PFBA, 3.7-34% for PFHxA, 13-64% for PFOA, 5.2-66% for PFDA, and 0.7-25% for PFDoDA (ranges represent estimated precursor contributions in a low- and high-exposure scenario). For PFOS, direct intake via diet is the major exposure pathway regardless of exposure scenario. For PFCAs, the dominant exposure pathway is dependent on perfluoroalkyl chain length and exposure scenario. Modelled PFOS and PFOA concentrations in human serum using the estimated intakes from an intermediate-exposure scenario are in agreement with measured concentrations in different populations. The isomer pattern of PFOS resulting from total intakes (direct and via precursors) is estimated to be enriched with linear PFOS (84%) relative to technical PFOS (70% linear). This finding appears to be contradictory to the observed enrichment of branched PFOS isomers in recent human serum monitoring studies and suggests that either external exposure is not fully understood (e.g. there are unknown precursors, missing or poorly quantified exposure pathways) and/or that there is an incomplete understanding of the isomer-specific human pharmacokinetic processes of PFOS, its precursors and intermediates. Copyright © 2014. Published by Elsevier Ltd.

Parsing the Effects Violence Exposure in Early Childhood: Modeling Developmental Pathways

PubMed Central

Carter, Alice S.; Ford, Julian D.

2012-01-01

Objective To prospectively examine pathways from early childhood violence exposure and trauma-related symptoms to school-age emotional health. Methods A longitudinal, birth cohort (N = 437) was assessed with parent reports of lifetime violence exposure and trauma-related symptoms at 3 years of age and later, internalizing and externalizing symptoms, and social competence at school age. Results Early family and neighborhood violence correlated significantly with early trauma-related symptoms and also significantly predicted school-age internalizing and externalizing symptoms and poorer competence, independent of sociodemographic risk and past-year violence exposure. Longitudinal pathways were significantly mediated by arousal and avoidance symptoms at 3 years of age, which increased risk for clinically significant emotional problems and lower competence at school age (adjusted odds ratios = 3.1–6.1, p < 0.01). Conclusions Trauma-related symptoms may mediate developmental pathways from early violence exposure to later emotional health. Interventions that prevent or reduce early trauma-related symptoms may ameliorate the long-term deleterious impact of violence exposure. PMID:21903730

SHEDS-Multimedia Model Version 3 (a) Technical Manual; (b) User Guide; and (c) Executable File to Launch SAS Program and Install Model

EPA Science Inventory

Reliable models for assessing human exposures are important for understanding health risks from chemicals. The Stochastic Human Exposure and Dose Simulation model for multimedia, multi-route/pathway chemicals (SHEDS-Multimedia), developed by EPA’s Office of Research and Developm...

The evaluation of stack metal emissions from hazardous waste incinerators: assessing human exposure through noninhalation pathways.

PubMed Central

Sedman, R M; Polisini, J M; Esparza, J R

1994-01-01

Potential public health effects associated with exposure to metal emissions from hazardous waste incinerators through noninhalation pathways were evaluated. Instead of relying on modeling the movement of toxicants through various environmental media, an approach based on estimating changes from baseline levels of exposure was employed. Changes in soil and water As, Cd, Hg, Pb, Cr, and Be concentrations that result from incinerator emissions were first determined. Estimates of changes in human exposure due to direct contact with shallow soil or the ingestion of surface water were then ascertained. Projected changes in dietary intakes of metals due to incinerator emissions were estimated based on changes from baseline dietary intakes that are monitored in U.S. Food and Drug Administration total diet studies. Changes from baseline intake were deemed to be proportional to the projected changes in soil or surface water metal concentrations. Human exposure to metals emitted from nine hazardous waste incinerators were then evaluated. Metal emissions from certain facilities resulted in tangible human exposure through noninhalation pathways. However, the analysis indicated that the deposition of metals from ambient air would result in substantially greater human exposure through noninhalation pathways than the emissions from most of the facilities. PMID:7925180

MODELING EXPOSURES TO PESTICIDES APPROACHES AND MODELING NEEDS

EPA Science Inventory

Estimation of exposures of children to pesticides requires careful consideration of sources and concentrations of pesticides that may be present in different environmental media and in foods and beverages consumed by children, as well as the different routes and pathways of exp...

Leaching of plastic additives to marine organisms.

PubMed

Koelmans, Albert A; Besseling, Ellen; Foekema, Edwin M

2014-04-01

It is often assumed that ingestion of microplastics by aquatic species leads to increased exposure to plastic additives. However, experimental data or model based evidence is lacking. Here we assess the potential of leaching of nonylphenol (NP) and bisphenol A (BPA) in the intestinal tracts of Arenicola marina (lugworm) and Gadus morhua (North Sea cod). We use a biodynamic model that allows calculations of the relative contribution of plastic ingestion to total exposure of aquatic species to chemicals residing in the ingested plastic. Uncertainty in the most crucial parameters is accounted for by probabilistic modeling. Our conservative analysis shows that plastic ingestion by the lugworm yields NP and BPA concentrations that stay below the lower ends of global NP and BPA concentration ranges, and therefore are not likely to constitute a relevant exposure pathway. For cod, plastic ingestion appears to be a negligible pathway for exposure to NP and BPA. Copyright © 2013 Elsevier Ltd. All rights reserved.

Prioritization of pesticides based on daily dietary exposure potential as determined from the SHEDS model

EPA Science Inventory

A major pathway for exposure to many pesticides is through diet. The objectives were to rank pesticides by comparing their calculated daily dietary exposure as determined by EPA's Stochastic Human Exposure and Dose Simulation (SHEDS) to single pesticides for different age groups ...

INTEGRATED HUMAN EXPOSURE SOURCE-TO-DOSE MODELING

EPA Science Inventory

The NERL human exposure research program is designed to provide a sound, scientifically-based approach to understanding how people are actually exposed to pollutants and the factors and pathways influencing exposure and dose. This research project serves to integrate and incorpo...

Chains of risk for alcohol use disorder: Mediators of exposure to neighborhood deprivation in early and middle childhood.

PubMed

Karriker-Jaffe, Katherine J; Lönn, Sara L; Cook, Won K; Kendler, Kenneth S; Sundquist, Kristina

2018-03-01

Our goal was to test a cascade model to identify developmental pathways, or chains of risk, from neighborhood deprivation in childhood to alcohol use disorder (AUD) in young adulthood. Using Swedish general population data, we examined whether exposure to neighborhood deprivation during early and middle childhood was associated with indicators of social functioning in adolescence and emerging adulthood, and whether these were predictive of AUD. Structural equation models showed exposure to neighborhood deprivation was associated with lower school achievement during adolescence, poor social functioning during emerging adulthood, and the development of AUD for both males and females. Understanding longitudinal pathways from early exposure to adverse environments to later AUD can inform prevention and intervention efforts. Copyright © 2018 Elsevier Ltd. All rights reserved.

Use of a simple pharmacokinetic model to study the impact of breast-feeding on infant and toddler body burdens of PCB 153, BDE 47, and DDE.

PubMed

Lorber, Matthew; Toms, Leisa-Maree L

2017-10-01

Several studies have examined the role of breast milk consumption in the buildup of environmental chemicals in infants, and have concluded that this pathway elevates infant body burdens above what would occur in a formula-only diet. Unique data from Australia provide an opportunity to study this finding using simple pharmacokinetic (PK) models. Pooled serum samples from infants in the general population provided data on PCB 153, BDE 47, and DDE at 6-month increments from birth until 4 years of age. General population breast-feeding scenarios for Australian conditions were crafted and input into a simple PK model which predicted infant serum concentrations over time. Comparison scenarios of background exposures to characterize formula-feeding were also crafted. It was found that the models were able to replicate the rise in measured infant body burdens for PCB 153 and DDE in the breast-feeding scenarios, while the background scenarios resulted in infant body burdens substantially below the measurements. The same was not true for BDE 47, however. Both the breast-feeding and background scenarios substantially underpredicted body burden measurements. Two possible explanations were offered: that exposure to higher BDE congeners would debrominate and form BDE 47 in the body, and/or, a second overlooked exposure pathway for PBDEs might be the cause of high infant and toddler body burdens. This pathway was inhalation due to the use of PBDEs as flame retardants in bedding materials. More research to better understand and quantify this pathway, or other unknown pathways, to describe infant and toddler exposures to PBDEs is needed. Published by Elsevier Ltd.

Transcriptional Pathways Altered in Response to Vibration in a Model of Hand-Arm Vibration Syndrome

PubMed Central

Waugh, Stacey; Kashon, Michael L.; Li, Shengqiao; Miller, Gerome R.; Johnson, Claud; Krajnak, Kristine

2016-01-01

Objective The aim of this study was to use an established model of vibration-induced injury to assess frequency-dependent changes in transcript expression in skin, artery, and nerve tissues. Methods Transcript expression in tissues from control and vibration-exposed rats (4 h/day for 10 days at 62.5, 125, or 250 Hz; 49 m/s2, rms) was measured. Transcripts affected by vibration were used in bioinformatics analyses to identify molecular- and disease-related pathways associated with exposure to vibration. Results Analyses revealed that cancer-related pathways showed frequency-dependent changes in activation or inhibition. Most notably, the breast-related cancer-1 pathway was affected. Other pathways associated with breast cancer type 1 susceptibility protein related signaling, or associated with cancer and cell cycle/cell survivability were also affected. Conclusion Occupational exposure to vibration may result in DNA damage and alterations in cell signaling pathways that have significant effects on cellular division. PMID:27058473

Health assessment of future PM2.5 exposures from indoor, outdoor, and secondhand tobacco smoke concentrations under alternative policy pathways in Ulaanbaatar, Mongolia

PubMed Central

Edwards, Rufus; Turner, Jay R.; Argo, Yuma D.; Olkhanud, Purevdorj B.; Odsuren, Munkhtuul; Guttikunda, Sarath; Ochir, Chimedsuren; Smith, Kirk R.

2017-01-01

Introduction Winter air pollution in Ulaanbaatar, Mongolia is among the worst in the world. The health impacts of policy decisions affecting air pollution exposures in Ulaanbaatar were modeled and evaluated under business as usual and two more-strict alternative emissions pathways through 2024. Previous studies have relied on either outdoor or indoor concentrations to assesses the health risks of air pollution, but the burden is really a function of total exposure. This study combined projections of indoor and outdoor concentrations of PM2.5 with population time-activity estimates to develop trajectories of total age-specific PM2.5 exposure for the Ulaanbaatar population. Indoor PM2.5 contributions from secondhand tobacco smoke (SHS) were estimated in order to fill out total exposures, and changes in population and background disease were modeled. The health impacts were derived using integrated exposure-response curves from the Global Burden of Disease Study. Results Annual average population-weighted PM2.5 exposures at baseline (2014) were estimated at 59 μg/m3. These were dominated by exposures occurring indoors, influenced considerably by infiltrated outdoor pollution. Under current control policies, exposures increased slightly to 60 μg/m3 by 2024; under moderate emissions reductions and under a switch to clean technologies, exposures were reduced from baseline levels by 45% and 80%, respectively. The moderate improvement pathway decreased per capita annual disability-adjusted life year (DALY) and death burdens by approximately 40%. A switch to clean fuels decreased per capita annual DALY and death burdens by about 85% by 2024 with the relative SHS contribution increasing substantially. Conclusion This study demonstrates a way to combine estimated changes in total exposure, background disease and population levels, and exposure-response functions to project the health impacts of alternative policy pathways. The resulting burden analysis highlights the need for aggressive action, including the elimination of residential coal burning and the reduction of current smoking rates. PMID:29088256

Effect of occupational exposures on lung cancer susceptibility: a study of gene-environment interaction analysis.

PubMed

Malhotra, Jyoti; Sartori, Samantha; Brennan, Paul; Zaridze, David; Szeszenia-Dabrowska, Neonila; Świątkowska, Beata; Rudnai, Peter; Lissowska, Jolanta; Fabianova, Eleonora; Mates, Dana; Bencko, Vladimir; Gaborieau, Valerie; Stücker, Isabelle; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo

2015-03-01

Occupational exposures are known risk factors for lung cancer. Role of genetically determined host factors in occupational exposure-related lung cancer is unclear. We used genome-wide association (GWA) data from a case-control study conducted in 6 European countries from 1998 to 2002 to identify gene-occupation interactions and related pathways for lung cancer risk. GWA analysis was performed for each exposure using logistic regression and interaction term for genotypes, and exposure was included in this model. Both SNP-based and gene-based interaction P values were calculated. Pathway analysis was performed using three complementary methods, and analyses were adjusted for multiple comparisons. We analyzed 312,605 SNPs and occupational exposure to 70 agents from 1,802 lung cancer cases and 1,725 cancer-free controls. Mean age of study participants was 60.1 ± 9.1 years and 75% were male. Largest number of significant associations (P ≤ 1 × 10(-5)) at SNP level was demonstrated for nickel, brick dust, concrete dust, and cement dust, and for brick dust and cement dust at the gene-level (P ≤ 1 × 10(-4)). Approximately 14 occupational exposures showed significant gene-occupation interactions with pathways related to response to environmental information processing via signal transduction (P < 0.001 and FDR < 0.05). Other pathways that showed significant enrichment were related to immune processes and xenobiotic metabolism. Our findings suggest that pathways related to signal transduction, immune process, and xenobiotic metabolism may be involved in occupational exposure-related lung carcinogenesis. Our study exemplifies an integrative approach using pathway-based analysis to demonstrate the role of genetic variants in occupational exposure-related lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 24(3); 570-9. ©2015 AACR. ©2015 American Association for Cancer Research.

REFINED PBPK MODEL OF AGGREGATE EXPOSURE TO METHYL TERTIARY-BUTYL ETHER

EPA Science Inventory

Aggregate (multiple pathway) exposures to methyl tertiary-butyl ether (MTBE) in air and water occur via dermal, inhalation, and oral routes. Previously, physiologically-based pharmacokinetic (PBPK) models have been used to quantify the kinetic behavior of MTBE and its primary met...

QUANTIFYING AGGREGATE CHLORPYRIFOS EXPOSURE AND DOSE TO CHILDREN USING A PHYSICALLY-BASED TWO-STAGE MONTE CARLO PROBABILISTIC MODEL

EPA Science Inventory

To help address the Food Quality Protection Act of 1996, a physically-based, two-stage Monte Carlo probabilistic model has been developed to quantify and analyze aggregate exposure and dose to pesticides via multiple routes and pathways. To illustrate model capabilities and ide...

A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA)

EPA Science Inventory

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from multiple stressors. While CSMs may encompass multiple species, evaluating end points across taxa can be challenging due to data availability an...

The Role of Influenza in the Delay between Low Temperature and Ischemic Heart Disease: Evidence from Simulation and Mortality Data from Japan

PubMed Central

Imai, Chisato; Barnett, Adrian G.; Hashizume, Masahiro; Honda, Yasushi

2016-01-01

Many studies have found that cardiovascular deaths mostly occur within a few days of exposure to heat, whereas cold-related deaths can occur up to 30 days after exposure. We investigated whether influenza infection could explain the delayed cold effects on ischemic heart diseases (IHD) as they can trigger IHD. We hypothesized two pathways between cold exposure and IHD: a direct pathway and an indirect pathway through influenza infection. We created a multi-state model of the pathways and simulated incidence data to examine the observed delayed patterns in cases. We conducted cross-correlation and time series analysis with Japanese daily pneumonia and influenza (P&I) mortality data to help validate our model. Simulations showed the IHD incidence through the direct pathway occurred mostly within 10 days, while IHD through influenza infection peaked at 4–6 days, followed by delayed incidences of up to 20–30 days. In the mortality data from Japan, P&I lagged IHD in cross-correlations. Time series analysis showed strong delayed cold effects in the older population. There was also a strong delay on intense days of influenza which was more noticeable in the older population. Influenza can therefore be a plausible explanation for the delayed association between cold exposure and cardiovascular mortality. PMID:27136571

A Physiologically-Based Pharmacokinetic (PBPK) Model With Metabolic Interactions of Chloroform (CHCL3) and Trichloroethylene

EPA Science Inventory

Exposure to mixtures is frequent, but biologic pathways such as metabolic inhibition, are poorly understood. CHCl3 and TCE are model volatiles frequently co-occurring; combined exposure results in less than additive hepatotoxicity. Here, we explore the underlying metabolic inte...

MODELING INHALATION AND MULTIMEDIA MULTIPATHWAY HUMAN EXPOSURES TO ENVIRONMENTAL POLLUTANTS

EPA Science Inventory

Estimation of exposures of children and adults to air toxics or multimedia pollutants require careful consideration of sources and concentrations of pollutants that may be present in different media, as well as various routes and pathways of exposures associated with age-specif...

MODELED RESIDENTIAL CHLORPYRIFOS EXPOSURE AND DOSE TO CHILDREN VIA DERMAL SURFACE RESIDUE CONTACT AND NON-DIETARY INGESTION

EPA Science Inventory

A physically-based stochastic model has been applied to estimate residential chlorpyrifos exposure and dace to children via the non-dietary ingestion and dermal residue contact pathways. Time-location-activity data for 2825 children were sampled from national surveys to generat...

Comparison of Four Probabilistic Models (CARES, Calendex, ConsEspo, SHEDS) to Estimate Aggregate Residential Exposures to Pesticides

EPA Science Inventory

Two deterministic models (US EPA’s Office of Pesticide Programs Residential Standard Operating Procedures (OPP Residential SOPs) and Draft Protocol for Measuring Children’s Non-Occupational Exposure to Pesticides by all Relevant Pathways (Draft Protocol)) and four probabilistic mo...

Exploration of potential biomarkers and related biological pathways for PCB exposure in maternal and cord serum: A pilot birth cohort study in Chiba, Japan.

PubMed

Eguchi, Akifumi; Sakurai, Kenichi; Watanabe, Masahiro; Mori, Chisato

2017-05-01

Polychlorinated biphenyls (PCBs) have been associated with adverse human reproductive and fetal developmental measures or outcomes because of their endocrine-disrupting effects; however, the biological mechanisms of adverse effects of PCB exposure in humans are not currently well established. In this study, we aimed to identify the biological pathways and potential biomarkers of PCB exposure in maternal and umbilical cord serum using a hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) metabolomics platform. The median concentration of total PCBs in maternal (n=93) and cord serum (n=93) were 350 and 70pgg -1 wet wt, respectively. PCB levels in maternal and fetal serum from the Chiba Study of Mother and Children's Health (C-MACH) cohort are comparable to those of earlier cohort studies conducted in Japan, the USA, and European countries. We used the random forest model with the metabolome profile to predict exposure levels of PCB (first quartile [Q1] and fourth quartile [Q4]) for pregnant women and fetuses. In the prediction model for classification of Q1 versus Q4 (area-under-curve [AUC]: pregnant women=0.812 and fetuses=0.919), citraconic acid level in maternal serum and ethanolamine, p-hydroxybenzoate, and purine levels in cord serum had >0.70 AUC values. These candidate biomarkers and metabolite included in composited models were related to glutathione and amino acid metabolism in maternal serum and the amino acid metabolism and ubiquinone and other terpenoid-quinone biosynthesis in cord serum (FDR <0.10), indicating disruption of metabolic pathways by PCB exposure in pregnant women and fetuses. These results showed that metabolome analysis might be useful to explore potential biomarkers and related biological pathways for PCB exposure. Thus, more detailed studies are needed to verify sensitivity of the biomarkers and clarify the biochemical changes resulting from PCB exposure. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

SIP Version 1.0 User's Guide for Pesticide Exposure of Birds and Mammals through Drinking Water

EPA Pesticide Factsheets

Model provides an upper bound estimate of exposure of birds and mammals to pesticides through drinking water alone. Intended for use in problem formulation to determine whether or not drinking water exposure alone is a potential pathway of concern.

EVALUATION OF VADOSE ZONE AND SOURCE MODELS FOR MULTI-MEDIA, MULTI-PATHWAY, MULTI-RECEPTOR RISK ASSESSMENT USING LARGE SOIL COLUMN EXPERIMENT DATA

EPA Science Inventory

The U.S. Environmental Protection Agency (EPA) is developing a comprehensive environmental exposure and risk analysis software system for agency-wide application using the methodology of a Multi-media, Multi-pathway, Multi-receptor Risk Assessment (3MRA) model. This software sys...

Multipathway Quantitative Assessment of Exposure to Fecal Contamination for Young Children in Low-Income Urban Environments in Accra, Ghana: The SaniPath Analytical Approach

PubMed Central

Wang, Yuke; Moe, Christine L.; Null, Clair; Raj, Suraja J.; Baker, Kelly K.; Robb, Katharine A.; Yakubu, Habib; Ampofo, Joseph A.; Wellington, Nii; Freeman, Matthew C.; Armah, George; Reese, Heather E.; Peprah, Dorothy; Teunis, Peter F. M.

2017-01-01

Abstract. Lack of adequate sanitation results in fecal contamination of the environment and poses a risk of disease transmission via multiple exposure pathways. To better understand how eight different sources contribute to overall exposure to fecal contamination, we quantified exposure through multiple pathways for children under 5 years old in four high-density, low-income, urban neighborhoods in Accra, Ghana. We collected more than 500 hours of structured observation of behaviors of 156 children, 800 household surveys, and 1,855 environmental samples. Data were analyzed using Bayesian models, estimating the environmental and behavioral factors associated with exposure to fecal contamination. These estimates were applied in exposure models simulating sequences of behaviors and transfers of fecal indicators. This approach allows us to identify the contribution of any sources of fecal contamination in the environment to child exposure and use dynamic fecal microbe transfer networks to track fecal indicators from the environment to oral ingestion. The contributions of different sources to exposure were categorized into four types (high/low by dose and frequency), as a basis for ranking pathways by the potential to reduce exposure. Although we observed variation in estimated exposure (108–1016 CFU/day for Escherichia coli) between different age groups and neighborhoods, the greatest contribution was consistently from food (contributing > 99.9% to total exposure). Hands played a pivotal role in fecal microbe transfer, linking environmental sources to oral ingestion. The fecal microbe transfer network constructed here provides a systematic approach to study the complex interaction between contaminated environment and human behavior on exposure to fecal contamination. PMID:29031283

Potential pathways by which maternal second-hand smoke exposure during pregnancy causes full-term low birth weight.

PubMed

Niu, Zhongzheng; Xie, Chuanbo; Wen, Xiaozhong; Tian, Fuying; Yuan, Shixin; Jia, Deqin; Chen, Wei-Qing

2016-04-29

It is well documented that maternal exposure to second-hand smoke (SHS) during pregnancy causes low birth weight (LBW), but its mechanism remains unknown. This study explored the potential pathways. We enrolled 195 pregnant women who delivered full-term LBW newborns, and 195 who delivered full-term normal birth weight newborns as the controls. After controlling for maternal age, education level, family income, pre-pregnant body mass index, newborn gender and gestational age, logistic regression analysis revealed that LBW was significantly and positively associated with maternal exposure to SHS during pregnancy, lower placental weight, TNF-α and IL-1β, and that SHS exposure was significantly associated with lower placental weight, TNF-α and IL-1β. Structural equation modelling identified two plausible pathways by which maternal exposure to SHS during pregnancy might cause LBW. First, SHS exposure induced the elevation of TNF-α, which might directly increase the risk of LBW by transmission across the placenta. Second, SHS exposure first increased maternal secretion of IL-1β and TNF-α, which then triggered the secretion of VCAM-1; both TNF-α and VCAM-1 were significantly associated with lower placental weight, thus increasing the risk of LBW. In conclusion, maternal exposure to SHS during pregnancy may lead to LBW through the potential pathways of maternal inflammation and lower placental weight.

Metabolomics and In-Silico Analysis Reveal Critical Energy Deregulations in Animal Models of Parkinson’s Disease

PubMed Central

Poliquin, Pierre O.; Chen, Jingkui; Cloutier, Mathieu; Trudeau, Louis-Éric; Jolicoeur, Mario

2013-01-01

Parkinson’s disease (PD) is a multifactorial disease known to result from a variety of factors. Although age is the principal risk factor, other etiological mechanisms have been identified, including gene mutations and exposure to toxins. Deregulation of energy metabolism, mostly through the loss of complex I efficiency, is involved in disease progression in both the genetic and sporadic forms of the disease. In this study, we investigated energy deregulation in the cerebral tissue of animal models (genetic and toxin induced) of PD using an approach that combines metabolomics and mathematical modelling. In a first step, quantitative measurements of energy-related metabolites in mouse brain slices revealed most affected pathways. A genetic model of PD, the Park2 knockout, was compared to the effect of CCCP, a complex I blocker. Model simulated and experimental results revealed a significant and sustained decrease in ATP after CCCP exposure, but not in the genetic mice model. In support to data analysis, a mathematical model of the relevant metabolic pathways was developed and calibrated onto experimental data. In this work, we show that a short-term stress response in nucleotide scavenging is most probably induced by the toxin exposure. In turn, the robustness of energy-related pathways in the model explains how genetic perturbations, at least in young animals, are not sufficient to induce significant changes at the metabolite level. PMID:23935941

Biologically based modeling of multimedia, multipathway, multiroute population exposures to arsenic

PubMed Central

Georgopoulos, Panos G.; Wang, Sheng-Wei; Yang, Yu-Ching; Xue, Jianping; Zartarian, Valerie G.; Mccurdy, Thomas; Özkaynak, Halûk

2011-01-01

This article presents an integrated, biologically based, source-to-dose assessment framework for modeling multimedia/multipathway/multiroute exposures to arsenic. Case studies demonstrating this framework are presented for three US counties (Hunderton County, NJ; Pima County, AZ; and Franklin County, OH), representing substantially different conditions of exposure. The approach taken utilizes the Modeling ENvironment for TOtal Risk studies (MENTOR) in an implementation that incorporates and extends the approach pioneered by Stochastic Human Exposure and Dose Simulation (SHEDS), in conjunction with a number of available databases, including NATA, NHEXAS, CSFII, and CHAD, and extends modeling techniques that have been developed in recent years. Model results indicate that, in most cases, the food intake pathway is the dominant contributor to total exposure and dose to arsenic. Model predictions are evaluated qualitatively by comparing distributions of predicted total arsenic amounts in urine with those derived using biomarker measurements from the NHEXAS — Region V study: the population distributions of urinary total arsenic levels calculated through MENTOR and from the NHEXAS measurements are in general qualitative agreement. Observed differences are due to various factors, such as interindividual variation in arsenic metabolism in humans, that are not fully accounted for in the current model implementation but can be incorporated in the future, in the open framework of MENTOR. The present study demonstrates that integrated source-to-dose modeling for arsenic can not only provide estimates of the relative contributions of multipathway exposure routes to the total exposure estimates, but can also estimate internal target tissue doses for speciated organic and inorganic arsenic, which can eventually be used to improve evaluation of health risks associated with exposures to arsenic from multiple sources, routes, and pathways. PMID:18073786

High-throughput dietary exposure predictions for chemical migrants from food contact substances for use in chemical prioritization.

PubMed

Biryol, Derya; Nicolas, Chantel I; Wambaugh, John; Phillips, Katherine; Isaacs, Kristin

2017-11-01

Under the ExpoCast program, United States Environmental Protection Agency (EPA) researchers have developed a high-throughput (HT) framework for estimating aggregate exposures to chemicals from multiple pathways to support rapid prioritization of chemicals. Here, we present methods to estimate HT exposures to chemicals migrating into food from food contact substances (FCS). These methods consisted of combining an empirical model of chemical migration with estimates of daily population food intakes derived from food diaries from the National Health and Nutrition Examination Survey (NHANES). A linear regression model for migration at equilibrium was developed by fitting available migration measurements as a function of temperature, food type (i.e., fatty, aqueous, acidic, alcoholic), initial chemical concentration in the FCS (C 0 ) and chemical properties. The most predictive variables in the resulting model were C 0 , molecular weight, log K ow , and food type (R 2 =0.71, p<0.0001). Migration-based concentrations for 1009 chemicals identified via publicly-available data sources as being present in polymer FCSs were predicted for 12 food groups (combinations of 3 storage temperatures and food type). The model was parameterized with screening-level estimates of C 0 based on the functional role of chemicals in FCS. By combining these concentrations with daily intakes for food groups derived from NHANES, population ingestion exposures of chemical in mg/kg-bodyweight/day (mg/kg-BW/day) were estimated. Calibrated aggregate exposures were estimated for 1931 chemicals by fitting HT FCS and consumer product exposures to exposures inferred from NHANES biomonitoring (R 2 =0.61, p<0.001); both FCS and consumer product pathway exposures were significantly predictive of inferred exposures. Including the FCS pathway significantly impacted the ratio of predicted exposures to those estimated to produce steady-state blood concentrations equal to in-vitro bioactive concentrations. While these HT methods have large uncertainties (and thus may not be appropriate for assessments of single chemicals), they can provide critical refinement to aggregate exposure predictions used in risk-based chemical priority-setting. Published by Elsevier Ltd.

In vitro short-term exposure to air pollution PM{sub 2.5-0.3} induced cell cycle alterations and genetic instability in a human lung cell coculture model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abbas, Imane; EA4492-UCEIV, Université du Littoral-Côte d’Opale, Dunkerque; Lebanese Atomic Energy Commission – CNRS, Beirut

Although its adverse health effects of air pollution particulate matter (PM2.5) are well-documented and often related to oxidative stress and pro-inflammatory response, recent evidence support the role of the remodeling of the airway epithelium involving the regulation of cell death processes. Hence, the overarching goals of the present study were to use an in vitro coculture model, based on human AM and L132 cells to study the possible alteration of TP53-RB gene signaling pathways (i.e. cell cycle phases, gene expression of TP53, BCL2, BAX, P21, CCND1, and RB, and protein concentrations of their active forms), and genetic instability (i.e. LOHmore » and/or MSI) in the PM{sub 2.5-0.3}-exposed coculture model. PM{sub 2.5-0.3} exposure of human AM from the coculture model induced marked cell cycle alterations after 24 h, as shown by increased numbers of L132 cells in subG1 and S+G2 cell cycle phases, indicating apoptosis and proliferation. Accordingly, activation of the TP53-RB gene signaling pathways after the coculture model exposure to PM{sub 2.5-0.3} was reported in the L132 cells. Exposure of human AM from the coculture model to PM{sub 2.5-0.3} resulted in MS alterations in 3p chromosome multiple critical regions in L132 cell population. Hence, in vitro short-term exposure of the coculture model to PM{sub 2.5-0.3} induced cell cycle alterations relying on the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation and genetic instability. - Highlights: • Better knowledge on health adverse effects of air pollution PM{sub 2.5}. • Human alveolar macrophage and normal human epithelial lung cell coculture. • Molecular abnormalities from TP53-RB gene signaling pathway. • Loss of heterozygosity and microsatellite instability. • Pathologic changes in morphology and number of cells in relation to airway remodeling.« less

Relative contributions of four exposure pathways to influenza infection risk.

PubMed

Nicas, Mark; Jones, Rachael M

2009-09-01

The relative contribution of four influenza virus exposure pathways-(1) virus-contaminated hand contact with facial membranes, (2) inhalation of respirable cough particles, (3) inhalation of inspirable cough particles, and (4) spray of cough droplets onto facial membranes-must be quantified to determine the potential efficacy of nonpharmaceutical interventions of transmission. We used a mathematical model to estimate the relative contributions of the four pathways to infection risk in the context of a person attending a bed-ridden family member ill with influenza. Considering the uncertainties in the sparse human subject influenza dose-response data, we assumed alternative ratios of 3,200:1 and 1:1 for the infectivity of inhaled respirable virus to intranasally instilled virus. For the 3,200:1 ratio, pathways (1), (2), and (4) contribute substantially to influenza risk: at a virus saliva concentration of 10(6) mL(-1), pathways (1), (2), (3), and (4) contribute, respectively, 31%, 17%, 0.52%, and 52% of the infection risk. With increasing virus concentrations, pathway (2) increases in importance, while pathway (4) decreases in importance. In contrast, for the 1:1 infectivity ratio, pathway (1) is the most important overall: at a virus saliva concentration of 10(6) mL(-1), pathways (1), (2), (3), and (4) contribute, respectively, 93%, 0.037%, 3.3%, and 3.7% of the infection risk. With increasing virus concentrations, pathway (3) increases in importance, while pathway (4) decreases in importance. Given the sparse knowledge concerning influenza dose and infectivity via different exposure pathways, nonpharmaceutical interventions for influenza should simultaneously address potential exposure via hand contact to the face, inhalation, and droplet spray.

A biosphere modeling methodology for dose assessments of the potential Yucca Mountain deep geological high level radioactive waste repository.

PubMed

Watkins, B M; Smith, G M; Little, R H; Kessler, J

1999-04-01

Recent developments in performance standards for proposed high level radioactive waste disposal at Yucca Mountain suggest that health risk or dose rate limits will likely be part of future standards. Approaches to the development of biosphere modeling and dose assessments for Yucca Mountain have been relatively lacking in previous performance assessments due to the absence of such a requirement. This paper describes a practical methodology used to develop a biosphere model appropriate for calculating doses from use of well water by hypothetical individuals due to discharges of contaminated groundwater into a deep well. The biosphere model methodology, developed in parallel with the BIOMOVS II international study, allows a transparent recording of the decisions at each step, from the specification of the biosphere assessment context through to model development and analysis of results. A list of features, events, and processes relevant to Yucca Mountain was recorded and an interaction matrix developed to help identify relationships between them. Special consideration was given to critical/potential exposure group issues and approaches. The conceptual model of the biosphere system was then developed, based on the interaction matrix, to show how radionuclides migrate and accumulate in the biosphere media and result in potential exposure pathways. A mathematical dose assessment model was specified using the flexible AMBER software application, which allows users to construct their own compartment models. The starting point for the biosphere calculations was a unit flux of each radionuclide from the groundwater in the geosphere into the drinking water in the well. For each of the 26 radionuclides considered, the most significant exposure pathways for hypothetical individuals were identified. For 14 of the radionuclides, the primary exposure pathways were identified as consumption of various crops and animal products following assumed agricultural use of the contaminated water derived from the deep well. Inhalation of dust (11 radionuclides) and external irradiation (1 radionuclide) were also identified as significant exposure modes. Contribution to the total flux to dose conversion factor from the drinking water pathway for each radionuclide was also assessed and for most radionuclides was found to be less than 10% of the total flux to dose conversion factor summed across all pathways. Some of the uncertainties related to the results were considered. The biosphere modeling results have been applied within an EPRI Total Systems Performance Assessment of Yucca Mountain. Conclusions and recommendations for future performance assessments are provided.

Predicting SVOC Emissions into Air and Foods in Support of ...

EPA Pesticide Factsheets

The release of semi-volatile organic compounds (SVOCs) from consumer articles may be a critical human exposure pathway. In addition, the migration of SVOCs from food packaging materials into foods may also be a dominant source of exposure for some chemicals. Here we describe recent efforts to characterize emission-related parameters for these exposure pathways to support prediction of aggregate exposures for thousands of chemicals For chemicals in consumer articles, Little et al. (2012) developed a screening-level indoor exposure prediction model which, for a given SVOC, principally depends on steady-state gas-phase concentrations (y0). We have developed a model that predicts y0 for SVOCs in consumer articles, allowing exposure predictions for 274 ToxCast chemicals. Published emissions data for 31 SVOCs found in flooring materials, provided a training set where both chemical-specific physicochemical properties, article specific formulation properties, and experimental design aspects were available as modeling descriptors. A linear regression yielded R2- and p- values of approximately 0.62 and 3.9E-05, respectively. A similar model was developed based upon physicochemical properties alone, since article information is often not available for a given SVOC or product. This latter model yielded R2 - and p- values of approximately 0.47 and 1.2E-10, respectively. Many SVOCs are also used as additives (e.g. plasticizers, antioxidants, lubricants) in plastic food pac

From betrayal to the bottle: investigating possible pathways from trauma to problematic substance use.

PubMed

Delker, Brianna C; Freyd, Jennifer J

2014-10-01

Research in both community and clinical settings has found that exposure to cumulative interpersonal trauma predicts substance use problems. Less is known about betrayal as a dimension of trauma exposure that predicts substance use, and about the behavioral and psychological pathways that explain the relation between trauma and substance use. In a sample of 362 young adults, this study evaluated three intervening pathways between betrayal trauma exposure prior to age 18 years and problematic substance use: (a) substance use to cope with negative affect, (b) difficulty discerning and/or heeding risk, and (c) self-destructiveness. In addition, exposure to trauma low in betrayal (e.g., earthquake) was included in the model. Bootstrap tests of indirect effects revealed that betrayal trauma prior to age 18 years was associated with problematic substance use via posttraumatic stress and two intervening pathways: difficulty discerning/heeding risk (β = .07, p < .001), and self-destructiveness (β = .12, p < .001). Exposure to lower betrayal trauma was not associated with posttraumatic stress or problematic substance use. Results contribute to a trauma-informed understanding of substance use that persists despite potentially harmful consequences. Copyright © 2014 International Society for Traumatic Stress Studies.

Short and Long-Term Sunlight Radiation and Stroke Incidence

PubMed Central

McClure, Leslie A.; Judd, Suzanne E.; Howard, Virginia J.; Crosson, William L.; Al-Hamdan, Mohammad Z.; Wadley, Virginia G.; Peace, Fredrick; Kabagambe, Edmond K.

2012-01-01

OBJECTIVE Examine whether long and short-term sunlight radiation is related to stroke incidence. METHODS Fifteen-year residential histories merged with satellite, ground monitor, and model reanalysis data were used to determine sunlight radiation (insolation) and temperature exposure for a cohort of 16,606 stroke and coronary artery disease free black and white participants aged 45+ from the 48 contiguous United States. Fifteen, ten, five, two and one-year exposures were used to predict stroke incidence during follow-up in Cox proportional hazard models. Potential confounders and mediators were included during model-building. RESULTS Shorter exposure periods exhibited similar, but slightly stronger relationships than longer exposure periods. After adjustment for other covariates, the previous year’s monthly average insolation exposure below the median gave an HR=1.61 (95% CI: 1.15, 2.26) and the previous year’s highest compared to the second highest quartile of monthly average maximum temperature exposure gave an HR=1.92 (1.27, 2.92). INTERPRETATION These results indicate a relationship between lower levels of sunlight radiation and higher stroke incidence. The biological pathway of this relationship is not clear. Future research will show whether this finding stands, the pathway for this relationship, and if it is due to short or long-term exposures. PMID:23225379

Merging Models and Biomonitoring Data to Characterize Sources andPathways of Human Exposure to Organophosphorous Pesticides in the SalinasValley of California

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKone, Thomas E.; Castorina, Rosemary; Kuwabara, Yu

2006-06-01

By drawing on human biomonitoring data and limited environmental samples together with outputs from the CalTOX multimedia, multipathway source-to-dose model, we characterize cumulative intake of organophosphorous (OP) pesticides in an agricultural region of California. We assemble regional OP pesticide use, environmental sampling, and biological tissue monitoring data for a large and geographically dispersed population cohort of 592 pregnant Latina women in California (the CHAMACOS cohort). We then use CalTOX with regional pesticide usage data to estimate the magnitude and uncertainty of exposure and intake from local sources. We combine model estimates of intake from local sources with food intake basedmore » on national residue data to estimate for the CHAMACOS cohort cumulative median OP intake, which corresponds to expected levels of urinary dialkylphosphate (DAP) metabolite excretion for this cohort. From these results we develop premises about relative contributions from different sources and pathways of exposure. We evaluate these premises by comparing the magnitude and variation of DAPs in the CHAMACOS cohort with the whole U.S. population using data from the National Health and Nutrition Evaluation Survey (NHANES). This comparison supports the premise that in both populations diet is the common and dominant exposure pathway. Both the model results and biomarker comparison supports the observation that the CHAMACOS population has a statistically significant higher intake of OP pesticides that appears as an almost constant additional dose among all participants. We attribute the magnitude and small variance of this intake to non-dietary exposure in residences from local sources.« less

Children's Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making.

PubMed

Zartarian, Valerie; Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-09-12

Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)'s National Drinking Water Advisory Council (NDWAC) recommended establishment of a "health-based, household action level" for lead in drinking water based on children's exposure. The primary objective was to develop a coupled exposure-dose modeling approach that can be used to determine what drinking water lead concentrations keep children's blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. A modeling approach using the EPA's Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Modeled BLLs compared well with nationally representative BLLs (0-23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605.

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

Evidence Theory Based Uncertainty Quantification in Radiological Risk due to Accidental Release of Radioactivity from a Nuclear Power Plant

NASA Astrophysics Data System (ADS)

Ingale, S. V.; Datta, D.

2010-10-01

Consequence of the accidental release of radioactivity from a nuclear power plant is assessed in terms of exposure or dose to the members of the public. Assessment of risk is routed through this dose computation. Dose computation basically depends on the basic dose assessment model and exposure pathways. One of the exposure pathways is the ingestion of contaminated food. The aim of the present paper is to compute the uncertainty associated with the risk to the members of the public due to the ingestion of contaminated food. The governing parameters of the ingestion dose assessment model being imprecise, we have approached evidence theory to compute the bound of the risk. The uncertainty is addressed by the belief and plausibility fuzzy measures.

Sun exposure and skin cancer, and the puzzle of cutaneous melanoma: A perspective on Fears et al. Mathematical models of age and ultraviolet effects on the incidence of skin cancer among whites in the United States. American Journal of Epidemiology 1977; 105: 420-427.

PubMed

Armstrong, Bruce K; Cust, Anne E

2017-06-01

Sunlight has been known as an important cause of skin cancer since around the turn of the 20th Century. A 1977 landmark paper of US scientists Fears, Scotto, and Schneiderman advanced a novel hypothesis whereby cutaneous melanoma was primarily caused by intermittent sun exposure (i.e. periodic, brief episodes of exposure to high-intensity ultraviolet radiation) while the keratinocyte cancers, squamous cell carcinoma and basal cell carcinoma, were primarily caused by progressive accumulation of sun exposure. With respect to cutaneous melanoma, this became known as the intermittent exposure hypothesis. The hypothesis stemmed from analysis of measured ambient ultraviolet radiation and age-specific incidence rates of melanoma and keratinocyte cancers collected as an extension to the US Third National Cancer Survey in several US States. In this perspective paper, we put this novel hypothesis into the context of knowledge at the time, and describe subsequent epidemiological and molecular research into melanoma that elaborated the intermittent exposure hypothesis and ultimately replaced it with a dual pathway hypothesis. Our present understanding is of two distinct biological pathways by which cutaneous melanoma might develop; a nevus prone pathway initiated by early sun exposure and promoted by intermittent sun exposure or possibly host factors; and a chronic sun exposure pathway in sun sensitive people who progressively accumulate sun exposure to the sites of future melanomas. Copyright © 2017 Elsevier Ltd. All rights reserved.

Aggregate Exposure Pathways in Support of Risk Assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Yu-Mei; Leonard, Jeremy A.; Edwards, Stephen

Over time, risk assessment has shifted from establishing relationships between exposure to a single chemical and a resulting adverse health outcome, to evaluation of multiple chemicals and disease outcomes simultaneously. As a result, there is an increasing need to better understand the complex mechanisms that influence risk of chemical and non-chemical stressors, beginning at their source and ending at a biological endpoint relevant to human or ecosystem health risk assessment. Just as the Adverse Outcome Pathway (AOP) framework has emerged as a means of providing insight into mechanism-based toxicity, the exposure science community has seen the recent introduction of themore » Aggregate Exposure Pathway (AEP) framework. AEPs aid in making exposure data applicable to the FAIR (i.e., findable, accessible, interoperable, and reusable) principle, especially by (1) organizing continuous flow of disjointed exposure information;(2) identifying data gaps, to focus resources on acquiring the most relevant data; (3) optimizing use and repurposing of existing exposure data; and (4) facilitating interoperability among predictive models. Herein, we discuss integration of the AOP and AEP frameworks and how such integration can improve confidence in both traditional and cumulative risk assessment approaches.« less

Aggregate Exposure Pathways in Support of Risk Assessment

DOE PAGES

Tan, Yu-Mei; Leonard, Jeremy A.; Edwards, Stephen; ...

2018-03-29

Over time, risk assessment has shifted from establishing relationships between exposure to a single chemical and a resulting adverse health outcome, to evaluation of multiple chemicals and disease outcomes simultaneously. As a result, there is an increasing need to better understand the complex mechanisms that influence risk of chemical and non-chemical stressors, beginning at their source and ending at a biological endpoint relevant to human or ecosystem health risk assessment. Just as the Adverse Outcome Pathway (AOP) framework has emerged as a means of providing insight into mechanism-based toxicity, the exposure science community has seen the recent introduction of themore » Aggregate Exposure Pathway (AEP) framework. AEPs aid in making exposure data applicable to the FAIR (i.e., findable, accessible, interoperable, and reusable) principle, especially by (1) organizing continuous flow of disjointed exposure information;(2) identifying data gaps, to focus resources on acquiring the most relevant data; (3) optimizing use and repurposing of existing exposure data; and (4) facilitating interoperability among predictive models. Herein, we discuss integration of the AOP and AEP frameworks and how such integration can improve confidence in both traditional and cumulative risk assessment approaches.« less

Using meta-regression models to systematically evaluate data in the published literature: relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations

EPA Science Inventory

Background: Data reported in the published literature have been used qualitatively to aid exposure assessment activities in epidemiologic studies. Analyzing these data in computational models presents statistical challenges because these data are often reported as summary statist...

Exposure to Community Violence: Processes That Increase the Risk for Inner-City Middle School Children

ERIC Educational Resources Information Center

Salzinger, Suzanne; Ng-Mak, Daisy S.; Feldman, Richard S.; Kam, Chi-Ming; Rosario, Margaret

2006-01-01

An ecologically framed model is presented describing processes accounting for early adolescents' exposure to community violence in high-risk neighborhoods as a function of risk factors in four ecological domains assessed in the prior year. The model was tested for hypothesized pathways along which the combined domains of risk might operate. The…

In vivo Assessment and Potential Diagnosis of Xenobiotics that Perturb the Thyroid Pathway: Proteomic Analysis of Xenopus laevis Brain Tissue following Exposure to Model T4 Inhibitors

EPA Science Inventory

As part of a multi-endpoint systems approach to develop comprehensive methods for assessing endocrine stressors in vertebrates, differential protein profiling was used to investigate expression profiles in the brain of an amphibian model (Xenopus laevis) following in vivo exposur...

Assessing the public health risk of microbial intrusion events in distribution systems: conceptual model, available data, and challenges.

PubMed

Besner, Marie-Claude; Prévost, Michèle; Regli, Stig

2011-01-01

Low and negative pressure events in drinking water distribution systems have the potential to result in intrusion of pathogenic microorganisms if an external source of contamination is present (e.g., nearby leaking sewer main) and there is a pathway for contaminant entry (e.g., leaks in drinking water main). While the public health risk associated with such events is not well understood, quantitative microbial risk assessment can be used to estimate such risk. A conceptual model is provided and the state of knowledge, current assumptions, and challenges associated with the conceptual model parameters are presented. This review provides a characterization of the causes, magnitudes, durations and frequencies of low/negative pressure events; pathways for pathogen entry; pathogen occurrence in external sources of contamination; volumes of water that may enter through the different pathways; fate and transport of pathogens from the pathways of entry to customer taps; pathogen exposure to populations consuming the drinking water; and risk associated with pathogen exposure. Copyright © 2010 Elsevier Ltd. All rights reserved.

PARTITION COEFFICIENTS FOR METALS IN SURFACE WATER, SOIL, AND WASTE

EPA Science Inventory

This report presents metal partition coefficients for the surface water pathway and for the source model used in the Multimedia, Multi-pathway, Multi-receptor Exposure and Risk Assessment (3MRA) technology under development by the U.S. Environmental Protection Agency. Partition ...

PHARMACOKINETIC MODELS IN THE DESIGN OF BIOMONITORING PROGRAMS

EPA Science Inventory

Measurements of chemicals in tissues, blood, or urine can be related to health effects because they are an integrated measure of absorbed dose following exposure. However, the direct relationship between biomonitoring data and pathway-specific exposures is more tenuous. In chem...

Triazole induced concentration-related gene signatures in rat whole embryo culture.

PubMed

Robinson, Joshua F; Tonk, Elisa C M; Verhoef, Aart; Piersma, Aldert H

2012-09-01

Commonly used as antifungal agents in agriculture and medicine, triazoles have been shown to cause teratogenicity in a diverse set of animal models. Here, we evaluated the dose-dependent impacts of flusilazole, cyproconazole and triadimefon, on global gene expression in relation to effects on embryonic development using the rat whole embryo culture (WEC) model. After 4 h exposure, we identified changes in gene expression due to triazole exposure which preceded morphological alterations observed at 48 h. In general, across the three triazoles, we observed similar directionality of regulation in gene expression and the magnitude of effects on gene expression correlated with the degree of induced developmental toxicity. Significantly regulated genes included key members of steroid/cholesterol and retinoic acid metabolism and hindbrain developmental pathways. Direct comparisons with previous studies suggest that triazole-gene signatures identified in the WEC overlap with zebrafish and mouse, and furthermore, triazoles impact gene expression in a similar manner as retinoic acid exposures in rat embryos. In summary, we further differentiate pathways underlying triazole-developmental toxicity using WEC and demonstrate the conservation of these response-pathways across model systems. Copyright © 2012 Elsevier Inc. All rights reserved.

IRE1α pathway of endoplasmic reticulum stress induces neuronal apoptosis in the locus coeruleus of rats under single prolonged stress.

PubMed

Zhao, Wei; Han, Fang; Shi, Yuxiu

2016-08-01

Our previous studies have shown evidence of endoplasmic reticulum (ER) stress-induced apoptosis in the hippocampus and mPFC in an animal model of post- traumatic stress disorder (PTSD). Inositol-requiring enzyme 1α (IRE1α) and its downstream molecule X-box binding protein 1 (XBP1) play key roles in the ER-related apoptosis pathway. Dysregulation of the locus coeruleus (LC) has been reported to contribute to cognitive and/or arousal impairments associated with PTSD. The aim of the present study was to explore the role of IRE1α pathway in neuronal apoptosis in the LC of rat models of PTSD. We used an acute exposure to prolonged stress (single prolonged stress, SPS) to model PTSD in rats and examined the effects related to the IRE1α pathway. Neuronal apoptosis in LC was detected by transmission electron microscopy and TUNEL staining. The results showed that the level of LC neuronal apoptosis was markedly increased after SPS. SPS exposure triggered IRE1α pathway, as evidenced by the increased activity of IRE1α, specific splicing of XBP1, and up-regulated expression of binding immunoglobulin protein/78kDa glucose-regulated protein (BiP/GRP78), and C/EBP-homologous protein (CHOP). Treatment with STF-083010, an IRE1α RNase-specific inhibitor, successfully attenuated the above changes. These results indicate that excessive activation of the ER stress-associated IRE1α pathway is involved in LC neuronal apoptosis induced by SPS exposure; this may be a crucial mechanism of the pathogenesis of PTSD. Copyright © 2016 Elsevier Inc. All rights reserved.

Incorporation of additional radionuclides and the external exposure pathway into the BECAMP (Basic Environmental Compliance and Monitoring Program) radiological assessment model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ng, Yook C.; Rodean, H.C.; Anspaugh, L.R.

The Nevada Applied Ecology Group (NAEG) Model of transport and dose for transuranic radionuclides was modified and expanded for the analysis of radionuclides other than pure alpha-emitters. Doses from internal and external exposures were estimated for the inventories and soil distributions of the individual radionuclides quantified in Areas 2 and 4 of the Nevada Test Site (NTS). We found that the dose equivalents via inhalation to liver, lungs, bone marrow, and bone surface from the plutonium isotopes and /sup 241/Am, those via ingestion to bone marrow and bone surfaces from /sup 90/Sr, and those via ingestion to all the targetmore » organs from /sup 137/Cs were the highest from internal exposures. The effective dose equivalents from /sup 137/Cs, /sup 152/Eu, and /sup 154/Eu were the highest from the external exposures. The /sup 60/Co, /sup 152/Eu, /sup 154/Eu, and /sup 155/Eu dose estimates for external exposures greatly exceeded those for internal exposures. The /sup 60/Co, /sup 90/Sr, and /sup 137/Cs dose equivalents from internal exposures were underestimated due to the adoption of some of the foodchain parameter values originally selected for /sup 239/Pu. Nonetheless, the ingestion pathway contributed significantly to the dose estimates for /sup 90/Sr and /sup 137/Cs, but contributed very much less than external exposures to the dose estimates for /sup 60/Co. Therefore, the use of more appropriate values would not alter the identification of important radionuclides, pathways, target organs, and exposure modes in this analysis. 19 refs., 13 figs., 12 tabs.« less

Prenatal alcohol and other early childhood adverse exposures: Direct and indirect pathways to adolescent drinking

PubMed Central

Cornelius, Marie D.; De Genna, Natacha M.; Goldschmidt, Lidush; Larkby, Cynthia; Day, Nancy L.

2016-01-01

We examined direct and indirect pathways between adverse environmental exposures during gestation and childhood and drinking in mid-adolescence. Mothers and their offspring (n = 917 mother/child dyads) were followed prospectively from second trimester to a 16-year follow-up assessment. Interim assessments occurred at delivery, 6, 10, and 14 years. Adverse environmental factors included gestational exposures to alcohol, tobacco, and marijuana, exposures to childhood maltreatment and violence, maternal psychological symptoms, parenting practices, economic and home environments, and demographic characteristics of the mother and child. Indirect effects of early child behavioral characteristics including externalizing, internalizing activity, attention, and impulsivity were also examined. Polytomous logistic regression analyses were used to evaluate direct effects of adverse environmental exposures with level of adolescent drinking. Structural equation modeling (SEM) was applied to simultaneously estimate the relation between early adversity variables, childhood characteristics, and drinking level at age 16 while controlling for significant covariates. Level of drinking among the adolescent offspring was directly predicted by prenatal exposure to alcohol, less parental strictness, and exposures to maltreatment and violence during childhood. Whites and offspring with older mothers were more likely to drink at higher levels. There was a significant indirect effect between childhood exposure to violence and adolescent drinking via childhood externalizing behavior problems. All other hypothesized indirect pathways were not significant. Thus most of the early adversity measures directly predicted adolescent drinking and did not operate via childhood behavioral dysregulation characteristics. These results highlight the importance of adverse environmental exposures on pathways to adolescent drinking. PMID:26994529

Children’s Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making

PubMed Central

Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-01-01

Background: Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)’s National Drinking Water Advisory Council (NDWAC) recommended establishment of a “health-based, household action level” for lead in drinking water based on children’s exposure. Objectives: The primary objective was to develop a coupled exposure–dose modeling approach that can be used to determine what drinking water lead concentrations keep children’s blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. Methods: A modeling approach using the EPA’s Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Results: Modeled BLLs compared well with nationally representative BLLs (0–23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. Conclusions: This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605 PMID:28934096

Pathways of Change Explaining the Effect of Smoke-Free Legislation on Smoking Cessation in the Netherlands. An Application of the International Tobacco Control Conceptual Model

PubMed Central

de Vries, Hein; Fong, Geoffrey T.; Candel, Math J. J. M.; Thrasher, James F.; van den Putte, Bas; Thompson, Mary E.; Cummings, K. Michael; Willemsen, Marc C.

2012-01-01

Introduction: This study aims to test the pathways of change from individual exposure to smoke-free legislation on smoking cessation, as hypothesized in the International Tobacco Control (ITC) Conceptual Model. Methods: A nationally representative sample of Dutch smokers aged 15 years and older was surveyed during 4 consecutive annual surveys. Of the 1,820 baseline smokers, 1,012 participated in the fourth survey. Structural Equation Modeling was employed to test a model of the effects of individual exposure to smoke-free legislation through policy-specific variables (support for smoke-free legislation and awareness of the harm of [secondhand] smoking) and psychosocial mediators (attitudes, subjective norm, self-efficacy, and intention to quit) on quit attempts and quit success. Results: The effect of individual exposure to smoke-free legislation on smoking cessation was mediated by 1 pathway via support for smoke-free legislation, attitudes about quitting, and intention to quit smoking. Exposure to smoke-free legislation also influenced awareness of the harm of (secondhand) smoking, which in turn influenced the subjective norm about quitting. However, only attitudes about quitting were significantly associated with intention to quit smoking, whereas subjective norm and self-efficacy for quitting were not. Intention to quit predicted quit attempts and quit success, and self-efficacy for quitting predicted quit success. Conclusions: Our findings support the ITC Conceptual Model, which hypothesized that policies influence smoking cessation through policy-specific variables and psychosocial mediators. Smoke-free legislation may increase smoking cessation, provided that it succeeds in influencing support for the legislation. PMID:22491892

Pathways of change explaining the effect of smoke-free legislation on smoking cessation in The Netherlands. An application of the international tobacco control conceptual model.

PubMed

Nagelhout, Gera E; de Vries, Hein; Fong, Geoffrey T; Candel, Math J J M; Thrasher, James F; van den Putte, Bas; Thompson, Mary E; Cummings, K Michael; Willemsen, Marc C

2012-12-01

This study aims to test the pathways of change from individual exposure to smoke-free legislation on smoking cessation, as hypothesized in the International Tobacco Control (ITC) Conceptual Model. A nationally representative sample of Dutch smokers aged 15 years and older was surveyed during 4 consecutive annual surveys. Of the 1,820 baseline smokers, 1,012 participated in the fourth survey. Structural Equation Modeling was employed to test a model of the effects of individual exposure to smoke-free legislation through policy-specific variables (support for smoke-free legislation and awareness of the harm of [secondhand] smoking) and psychosocial mediators (attitudes, subjective norm, self-efficacy, and intention to quit) on quit attempts and quit success. The effect of individual exposure to smoke-free legislation on smoking cessation was mediated by 1 pathway via support for smoke-free legislation, attitudes about quitting, and intention to quit smoking. Exposure to smoke-free legislation also influenced awareness of the harm of (secondhand) smoking, which in turn influenced the subjective norm about quitting. However, only attitudes about quitting were significantly associated with intention to quit smoking, whereas subjective norm and self-efficacy for quitting were not. Intention to quit predicted quit attempts and quit success, and self-efficacy for quitting predicted quit success. Our findings support the ITC Conceptual Model, which hypothesized that policies influence smoking cessation through policy-specific variables and psychosocial mediators. Smoke-free legislation may increase smoking cessation, provided that it succeeds in influencing support for the legislation.

A case study to illustrate the utility of the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks for integrating human health and ecological data into cumulative risk assessment

EPA Science Inventory

Cumulative risk assessment (CRA) methods, which evaluate the risk of multiple adverse outcomes (AOs) from multiple chemicals, promote the use of a conceptual site model (CSM) to integrate risk from relevant stressors. The Adverse Outcome Pathway (AOP) framework can inform these r...

Children, computer exposure and musculoskeletal outcomes: the development of pathway models for school and home computer-related musculoskeletal outcomes.

PubMed

Harris, Courtenay; Straker, Leon; Pollock, Clare; Smith, Anne

2015-01-01

Children's computer use is rapidly growing, together with reports of related musculoskeletal outcomes. Models and theories of adult-related risk factors demonstrate multivariate risk factors associated with computer use. Children's use of computers is different from adult's computer use at work. This study developed and tested a child-specific model demonstrating multivariate relationships between musculoskeletal outcomes, computer exposure and child factors. Using pathway modelling, factors such as gender, age, television exposure, computer anxiety, sustained attention (flow), socio-economic status and somatic complaints (headache and stomach pain) were found to have effects on children's reports of musculoskeletal symptoms. The potential for children's computer exposure to follow a dose-response relationship was also evident. Developing a child-related model can assist in understanding risk factors for children's computer use and support the development of recommendations to encourage children to use this valuable resource in educational, recreational and communication environments in a safe and productive manner. Computer use is an important part of children's school and home life. Application of this developed model, that encapsulates related risk factors, enables practitioners, researchers, teachers and parents to develop strategies that assist young people to use information technology for school, home and leisure in a safe and productive manner.

Modeling Tribal Exposures to PCBs from Fish Consumption

EPA Science Inventory

Studies have shown that U.S. population continues to be exposed to polychlorinated biphenyls (PCBs), despite the ban ~40 years ago. Fish intake is a major pathway, especially, for high fish-consumption groups. Exposure assessment and risk management considerations for tribal fish...

Potential impact of clinical use of noninvasive FFRCT on radiation dose exposure and downstream clinical event rate.

PubMed

Bilbey, Nicolas; Blanke, Philipp; Naoum, Christopher; Arepalli, Chesnel Dey; Norgaard, Bjarne Linde; Leipsic, Jonathon

2016-01-01

This study aims to determine the potential impact of introducing noninvasive fractional flow reserve based on coronary computed tomography angiography (CTA) into clinical practice, with respect to radiation dose exposure and downstream event rate. We modeled a population of 1000 stable, symptomatic patients with suspected coronary artery disease, using the disease prevalence from the CONFIRM registry to estimate the pretest likelihood. Four potential clinical pathways were modeled based on the first noninvasive diagnostic test performed: (1) dobutamine echo; (2) single-photon emission computerized tomography (SPECT); (3) coronary CTA; and (4) CTA+FFRCT and leading to possible invasive coronary angiography. The posttest likelihood of testing positive/negative by each test was based on the presenting disease burden and diagnostic accuracy of each test. The dobutamine echo pathway resulted in the lowest radiation dose of 5.4 mSv, with 4.0 mSv from angiography and 1.4 mSv from percutaneous coronary intervention (PCI). The highest dose was with SPECT, with 26.5 mSv. The coronary computed tomography angiography (cCTA) pathway demonstrated a dose of 14.2 mSv, 3.7 mSv from cCTA, 7.7 mSv from angiography, and 2.8 mSv from PCI. The CTA+FFRCT pathway exhibited a radiation dose of 9.7 mSv, 3.7 mSv for cCTA, 4.2 mSv for angiography, and 1.8 mSv for PCI. Radiation dose exposure for CTA+FFRCT was lower than for SPECT (P<.001). The CTA+FFRCT pathway resulted in the lowest projected death/myocardial infarction rate at 1 year (2.44%) while the dobutamine stress pathway had the highest 1-year event rate (2.84%). Our analysis suggests that integrating FFRCT into the CTA clinical pathway may result in reduced cumulative radiation exposure, while promoting favorable clinical outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Addressing bystander exposure to agricultural pesticides in life cycle impact assessment.

PubMed

Ryberg, Morten Walbech; Rosenbaum, Ralph K; Mosqueron, Luc; Fantke, Peter

2018-04-01

Residents living near agricultural fields may be exposed to pesticides drifting from the fields after application to different field crops. To address this currently missing exposure pathway in life cycle assessment (LCA), we developed a modeling framework for quantifying exposure of bystanders to pesticide spray drift from agricultural fields. Our framework consists of three parts addressing: (1) loss of pesticides from an agricultural field via spray drift; (2) environmental fate of pesticide in air outside of the treated field; and (3) exposure of bystanders to pesticides via inhalation. A comparison with measured data in a case study on pesticides applied to potato fields shows that our model gives good predictions of pesticide air concentrations. We compared our bystander exposure estimates with pathways currently included in LCA, namely aggregated inhalation and ingestion exposure mediated via the environment for the general population, and general population exposure via ingestion of pesticide residues in consumed food crops. The results show that exposure of bystanders is limited relative to total population exposure from ingestion of pesticide residues in crops, but that the exposure magnitude of individual bystanders can be substantially larger than the exposure of populations not living in the proximity to agricultural fields. Our framework for assessing bystander exposure to pesticide applications closes a relevant gap in the exposure assessment included in LCA for agricultural pesticides. This inclusion aids decision-making based on LCA as previously restricted knowledge about exposure of bystanders can now be taken into account. Copyright © 2018 Elsevier Ltd. All rights reserved.

The effect of misunderstanding the chemical properties of environmental contaminants on exposure beliefs: A case involving dioxins

PubMed Central

Zikmund-Fisher, Brian J.; Turkelson, Angela; Franzblau, Alfred; Diebol, Julia K.; Allerton, Lindsay A.; Parker, Edith A.

2013-01-01

Chemical properties of contaminants lead them to behave in particular ways in the environment and hence have specific pathways to human exposure. If residents of affected communities lack awareness of these properties, however, they could make incorrect assumptions about where and how exposure occurs. We conducted a mailed survey of 904 residents of Midland and Saginaw counties in Michigan, USA to assess to what degree residents of a community with known dioxin contamination appear to understand the hydrophobic nature of dioxins and the implications of that fact on different potential exposure pathways. Participants assessed whether various statements about dioxins were true, including multiple statements assessing beliefs about dioxins in different types of water. Participants also stated whether they believed different exposure pathways were currently significant sources of dioxin exposure in this community. A majority of residents believed that dioxins can be found in river water that has been filtered to completely remove all particulates, well water, and even city tap water, beliefs which are incongruous with the hydrophobic nature of dioxins. Mistrust of government and personal concern about dioxins predicted greater beliefs about dioxins in water. In turn, holding more beliefs about dioxins in water predicted beliefs that drinking and touching water are currently significant exposure pathways for dioxins. Ensuring that community residents’ mental models accurately reflect the chemical properties of different contaminants can be important to helping them to adjust their risk perceptions and potentially their risk mitigation behaviors accordingly. PMID:23391895

Multiple metal exposures and their correlation with monoamine neurotransmitter metabolism in Chinese electroplating workers.

PubMed

Wu, Lin-Lin; Gong, Wei; Shen, Si-Peng; Wang, Zhong-He; Yao, Jia-Xi; Wang, Jun; Yu, Jing; Gao, Rong; Wu, Gang

2017-09-01

Excessive metal exposure has been recognized as one of the detrimental factors for brain damage. However, the potential adverse effects induced by heavy metals on monoamine neurotransmitter pathways remains poorly understood. Our study aimed to investigate the possible association between metal exposure and neurotransmitter metabolism. By a cross-sectional investigation, 224 electroplating workers and 213 non-electroplating exposure workers were recruited in the exposure and control groups. Metal exposure levels were analyzed using inductively-coupled plasma mass spectrometry and monoamine neurotransmitter pathway metabolites were measured by ultra-performance liquid chromatography tandem mass spectrometry in human urine samples. Multivariate linear regression model was used to assess the dose-response relationships of urinary metals and neurotransmitter pathway metabolites. Significant dose-dependent trends of urinary vanadium quartiles with all metabolites were observed, and the trends demonstrated significance after multiple testing correction. It also showed that urinary chromium levels were significantly associated with decreased serotonin level and cadmium was positively associated with norepinephrine and epinephrine. In addition, arsenic was positively associated with tryptophan, serotonin, dopamine and norepinephrine. Iron was positively associated with increased homovanillic acid (HVA) and epinephrine while nickel was negatively associated with increased epinephrine levels. Zinc was positively related to tryptophan, kynurenin (KYN), 5-hydroxyindole acetic acid (5-HIAA), dopamine, HVA and norepinephrine. There was no significant association between urinary copper with any other metabolites after adjusting of multiple metal models. Metal exposure may be associated with neurotransmitter metabolism disturbances. The present work is expected to provide some support in the prevention and management of metal-associated neurological diseases. Copyright © 2017. Published by Elsevier Ltd.

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Consideration of exposure pathways... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Consideration of exposure pathways... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Consideration of exposure pathways... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 26 2012-07-01 2011-07-01 true Consideration of exposure pathways. 194... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Consideration of exposure pathways... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

Gene expression profiles following exposure to a developmental neurotoxicant, Aroclor 1254: Pathway analysis for possible mode(s) of action.

EPA Science Inventory

Epidemiological studies indicate that low levels of polychlorinated biphenyl (PCB) exposure can adversely affect neurocognitive development. In animal models, perturbations in calcium signaling, neurotransmitters, and thyroid hormones have been postulated as potential mechanisms...

Human health risk assessment of lead from mining activities at semi-arid locations in the context of total lead exposure.

PubMed

Zheng, Jiajia; Huynh, Trang; Gasparon, Massimo; Ng, Jack; Noller, Barry

2013-12-01

Lead from historical mining and mineral processing activities may pose potential human health risks if materials with high concentrations of bioavailable lead minerals are released to the environment. Since the Joint Expert Committee on Food Additives of Food and Agriculture Organization/World Health Organization withdrew the Provisional Tolerable Weekly Intake of lead in 2011, an alternative method was required for lead exposure assessment. This study evaluated the potential lead hazard to young children (0-7 years) from a historical mining location at a semi-arid area using the U.S. EPA Integrated Exposure Uptake Biokinetic (IEUBK) Model, with selected site-specific input data. This study assessed lead exposure via the inhalation pathway for children living in a location affected by lead mining activities and with specific reference to semi-arid conditions and made comparison with the ingestion pathway by using the physiologically based extraction test for gastro-intestinal simulation. Sensitivity analysis for major IEUBK input parameters was conducted. Three groups of input parameters were classified according to the results of predicted blood concentrations. The modelled lead absorption attributed to the inhalation route was lower than 2 % (mean ± SE, 0.9 % ± 0.1 %) of all lead intake routes and was demonstrated as a less significant exposure pathway to children's blood, compared with ingestion. Whilst dermal exposure was negligible, diet and ingestion of soil and dust were the dominant parameters in terms of children's blood lead prediction. The exposure assessment identified the changing role of dietary intake when house lead loadings varied. Recommendations were also made to conduct comprehensive site-specific human health risk assessment in future studies of lead exposure under a semi-arid climate.

Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework

PubMed Central

Teeguarden, Justin. G.; Tan, Yu-Mei; Edwards, Stephen W.; Leonard, Jeremy A.; Anderson, Kim A.; Corley, Richard A.; Harding, Anna K; Kile, Molly L.; Simonich, Staci M; Stone, David; Tanguay, Robert L.; Waters, Katrina M.; Harper, Stacey L.; Williams, David E.

2016-01-01

Synopsis Driven by major scientific advances in analytical methods, biomonitoring, computational tools, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the Aggregate Exposure Pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the Adverse Outcome Pathway (AOP) concept in the toxicological sciences. Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more efficient integration of exposure assessment and hazard identification. Together, the two pathways form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making. PMID:26759916

The Cardiopulmonary Effects of Ambient Air Pollution and Mechanistic Pathways: A Comparative Hierarchical Pathway Analysis

PubMed Central

Thomas, Duncan C.; Zhang, Junfeng; Kipen, Howard M.; Rich, David Q.; Zhu, Tong; Huang, Wei; Hu, Min; Wang, Guangfa; Wang, Yuedan; Zhu, Ping; Lu, Shou-En; Ohman-Strickland, Pamela; Diehl, Scott R.; Eckel, Sandrah P.

2014-01-01

Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2–3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system. PMID:25502951

Nrf2 protects against oxidative stress induced by SiO2 nanoparticles.

PubMed

Liu, Wei; Hu, Tao; Zhou, Li; Wu, Desheng; Huang, Xinfeng; Ren, Xiaohu; Lv, Yuan; Hong, Wenxu; Huang, Guanqin; Lin, Zequn; Liu, Jianjun

2017-10-01

The aim of our study was to explore the role of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) on the exposure of SiO 2 nanoparticles (NPs) and its influence. To understand the mechanism of NP-induced oxidative stress, the involvement of oxidative-stress-responding transcription factors and the Nrf2/antioxidant reactive element (ARE) signaling pathway in the toxicity of SiO 2 NPs' exposure was investigated via in vivo and in vitro models. A549 cells showed a significant cytotoxic effect while A549-shNrf2 cells showed decreased cell viability after nm-SiO 2 exposure. SiO 2 NPs' exposure activated the Nrf2/ARE signaling pathway. Nrf2 -/- exposed mice showed increased reactive oxygen species, 8-hydroxyl deoxyguanosine level and decreased total antioxidant capacity. Nrf2/ARE signaling pathway activation disrupted, leading inhibition of heme oxygenase-1 and upregulation of PKR-like endoplasmic-reticulum-regulated kinase. Our findings suggested that Nrf2 could protect against oxidative stress induced by SiO 2 NPs, and the Nrf2/ARE pathway might be involved in mild-to-moderate SiO 2 NP-induced oxidative stress that was evident from dampened activity of Nrf2.

Applying Aggregate Exposure Pathway and Adverse Outcome ...

EPA Pesticide Factsheets

Hazard assessment for nanomaterials often involves applying in vitro dose-response data to estimate potential health risks that arise from exposure to products that contain nanomaterials. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the perturbations of biological mechanisms that lead to apical adverse health outcomes in living organisms. The Adverse Outcome Pathway (AOP) framework addresses this uncertainty by acting as a scaffold onto which in vitro toxicity testing and other data can be arranged to aid in the interpretation of these results in terms of biologically-relevant responses, as an AOP connects an upstream molecular initiating event (MIE) to a downstream adverse outcome. In addition to hazard assessment, risk estimation also requires reconciling in vitro concentrations sufficient to produce bioactivity with in vivo concentrations that can trigger a MIE at the relevant biological target. Such target site exposures (TSEs) can be estimated by integrating pharmacokinetic considerations with environmental and exposure factors. Environmental and exposure data have been historically scattered in various resources, such as monitoring data for air pollutants or exposure models for specific chemicals. The Aggregate Exposure Pathway (AEP) framework is introduced to organize existing knowledge concerning biologically, chemically, and physically plausible, as well as empirically supported, links between the i

Explicit Pharmacokinetic Modeling: Tools for Documentation, Verification, and Portability

EPA Science Inventory

Quantitative estimates of tissue dosimetry of environmental chemicals due to multiple exposure pathways require the use of complex mathematical models, such as physiologically-based pharmacokinetic (PBPK) models. The process of translating the abstract mathematics of a PBPK mode...

Conceptual site models as a tool in evaluating ecological health: the case of the Department of Energy's Amchitka Island nuclear test site.

PubMed

Burger, Joanna; Mayer, Henry J; Greenberg, Michael; Powers, Charles W; Volz, Conrad D; Gochfeld, Michael

2006-07-01

Managers of contaminated sites are faced with options ranging from monitoring natural attenuation to complete removal of contaminants to meet residential health standards. Conceptual site models (CSMs) are one tool used by the U.S. Department of Energy (DOE) and other environmental managers to understand, track, help with decisions, and communicate with the public about the risk from contamination. CSMs are simplified graphical representations of the sources, releases, transport and exposure pathways, and receptors, along with possible barriers to interdict pathways and reduce exposure. In this article, three CSMs are created using Amchitka Island, where the remaining contamination is from underground nuclear test shot cavities containing large quantities of numerous radionuclides in various physical and chemical forms: (1) a typical underground nuclear test shot CSM (modeled after other sites), (2) an expanded CSM with more complex receptors, and (3) a regional CSM that takes into account contaminant pathways from sources other than Amchitka. The objective was to expand the CSM used by DOE to be more responsive to different types of receptors. Amchitka Island differs from other DOE test shot sites because it is surrounded by a marine environment that is highly productive and has a high biodiversity, and the source of contamination is underground, not on the surface. The surrounding waters of the Bering Sea and North Pacific Ocean are heavily exploited by commercial fisheries and provide the United States and other countries with a significant proportion of its seafood. It is proposed that the CSMs on Amchitka Island should focus more on the pathways of exposure and critical receptors, rather than sources and blocks. Further, CSMs should be incorporated within a larger regional model because of the potentially rapid transport within ocean ecosystems. The large number of migratory or highly mobile species that pass by Amchitka provide the potential for a direct pathway to the local human population, known as Aleut, and commercial fisheries, which are remote from the island itself. The exposure matrix for receptors requires expansion for the Amchitka Island ecosystem because of the valuable marine and seafood resources in the region. CSMs with an expanded exposure/receptor matrix can be used effectively to clarify the conceptualization of the problem for scientists, regulators, and the general public.

Studying Biology to Understand Risk: Dosimetry Models and Quantitative Adverse Outcome Pathways

EPA Science Inventory

Confidence in the quantitative prediction of risk is increased when the prediction is based to as great an extent as possible on the relevant biological factors that constitute the pathway from exposure to adverse outcome. With the first examples now over 40 years old, physiologi...

Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework.

PubMed

Teeguarden, Justin G; Tan, Yu-Mei; Edwards, Stephen W; Leonard, Jeremy A; Anderson, Kim A; Corley, Richard A; Kile, Molly L; Simonich, Staci M; Stone, David; Tanguay, Robert L; Waters, Katrina M; Harper, Stacey L; Williams, David E

2016-05-03

Driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the "systems approaches" used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.

Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells

PubMed Central

Chudasama, Vaishali L.; Ovacik, Meric A.; Abernethy, Darrell R.

2015-01-01

Systems models of biological networks show promise for informing drug target selection/qualification, identifying lead compounds and factors regulating disease progression, rationalizing combinatorial regimens, and explaining sources of intersubject variability and adverse drug reactions. However, most models of biological systems are qualitative and are not easily coupled with dynamical models of drug exposure-response relationships. In this proof-of-concept study, logic-based modeling of signal transduction pathways in U266 multiple myeloma (MM) cells is used to guide the development of a simple dynamical model linking bortezomib exposure to cellular outcomes. Bortezomib is a commonly used first-line agent in MM treatment; however, knowledge of the signal transduction pathways regulating bortezomib-mediated cell cytotoxicity is incomplete. A Boolean network model of 66 nodes was constructed that includes major survival and apoptotic pathways and was updated using responses to several chemical probes. Simulated responses to bortezomib were in good agreement with experimental data, and a reduction algorithm was used to identify key signaling proteins. Bortezomib-mediated apoptosis was not associated with suppression of nuclear factor κB (NFκB) protein inhibition in this cell line, which contradicts a major hypothesis of bortezomib pharmacodynamics. A pharmacodynamic model was developed that included three critical proteins (phospho-NFκB, BclxL, and cleaved poly (ADP ribose) polymerase). Model-fitted protein dynamics and cell proliferation profiles agreed with experimental data, and the model-predicted IC50 (3.5 nM) is comparable to the experimental value (1.5 nM). The cell-based pharmacodynamic model successfully links bortezomib exposure to MM cellular proliferation via protein dynamics, and this model may show utility in exploring bortezomib-based combination regimens. PMID:26163548

Refining the aggregate exposure pathway.

PubMed

Tan, Yu-Mei; Leonard, Jeremy A; Edwards, Stephen; Teeguarden, Justin; Egeghy, Peter

2018-03-01

Advancements in measurement technologies and modeling capabilities continue to result in an abundance of exposure information, adding to that currently in existence. However, fragmentation within the exposure science community acts as an obstacle for realizing the vision set forth in the National Research Council's report on Exposure Science in the 21 st century to consider exposures from source to dose, on multiple levels of integration, and to multiple stressors. The concept of an Aggregate Exposure Pathway (AEP) was proposed as a framework for organizing and integrating diverse exposure information that exists across numerous repositories and among multiple scientific fields. A workshop held in May 2016 followed introduction of the AEP concept, allowing members of the exposure science community to provide extensive evaluation and feedback regarding the framework's structure, key components, and applications. The current work briefly introduces topics discussed at the workshop and attempts to address key challenges involved in refining this framework. The resulting evolution in the AEP framework's features allows for facilitating acquisition, integration, organization, and transparent application and communication of exposure knowledge in a manner that is independent of its ultimate use, thereby enabling reuse of such information in many applications.

Evaluation of depleted uranium in the environment at Aberdeen Proving Grounds, Maryland and Yuma Proving Grounds, Arizona. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kennedy, P.L.; Clements, W.H.; Myers, O.B.

1995-01-01

This report represents an evaluation of depleted uranium (DU) introduced into the environment at the Aberdeen Proving Grounds (APG), Maryland and Yuma Proving Grounds (YPG) Arizona. This was a cooperative project between the Environmental Sciences and Statistical Analyses Groups at LANL and with the Department of Fishery and Wildlife Biology at Colorado State University. The project represents a unique approach to assessing the environmental impact of DU in two dissimilar ecosystems. Ecological exposure models were created for each ecosystem and sensitivity/uncertainty analyses were conducted to identify exposure pathways which were most influential in the fate and transport of DU inmore » the environment. Research included field sampling, field exposure experiment, and laboratory experiments. The first section addresses DU at the APG site. Chapter topics include bioenergetics-based food web model; field exposure experiments; bioconcentration by phytoplankton and the toxicity of U to zooplankton; physical processes governing the desorption of uranium from sediment to water; transfer of uranium from sediment to benthic invertebrates; spead of adsorpion by benthic invertebrates; uptake of uranium by fish. The final section of the report addresses DU at the YPG site. Chapters include the following information: Du transport processes and pathway model; field studies of performance of exposure model; uptake and elimination rates for kangaroo rates; chemical toxicity in kangaroo rat kidneys.« less

Predictive models of poly(ethylene-terephthalate) film degradation under multi-factor accelerated weathering exposures

PubMed Central

Ngendahimana, David K.; Fagerholm, Cara L.; Sun, Jiayang; Bruckman, Laura S.

2017-01-01

Accelerated weathering exposures were performed on poly(ethylene-terephthalate) (PET) films. Longitudinal multi-level predictive models as a function of PET grades and exposure types were developed for the change in yellowness index (YI) and haze (%). Exposures with similar change in YI were modeled using a linear fixed-effects modeling approach. Due to the complex nature of haze formation, measurement uncertainty, and the differences in the samples’ responses, the change in haze (%) depended on individual samples’ responses and a linear mixed-effects modeling approach was used. When compared to fixed-effects models, the addition of random effects in the haze formation models significantly increased the variance explained. For both modeling approaches, diagnostic plots confirmed independence and homogeneity with normally distributed residual errors. Predictive R2 values for true prediction error and predictive power of the models demonstrated that the models were not subject to over-fitting. These models enable prediction under pre-defined exposure conditions for a given exposure time (or photo-dosage in case of UV light exposure). PET degradation under cyclic exposures combining UV light and condensing humidity is caused by photolytic and hydrolytic mechanisms causing yellowing and haze formation. Quantitative knowledge of these degradation pathways enable cross-correlation of these lab-based exposures with real-world conditions for service life prediction. PMID:28498875

Assessing natural direct and indirect effects through multiple pathways.

PubMed

Lange, Theis; Rasmussen, Mette; Thygesen, Lau Caspar

2014-02-15

Within the fields of epidemiology, interventions research and social sciences researchers are often faced with the challenge of decomposing the effect of an exposure into different causal pathways working through defined mediator variables. The goal of such analyses is often to understand the mechanisms of the system or to suggest possible interventions. The case of a single mediator, thus implying only 2 causal pathways (direct and indirect) from exposure to outcome, has been extensively studied. By using the framework of counterfactual variables, researchers have established theoretical properties and developed powerful tools. However, in practical problems, it is not uncommon to have several distinct causal pathways from exposure to outcome operating through different mediators. In this article, we suggest a widely applicable approach to quantifying and ranking different causal pathways. The approach is an extension of the natural effect models proposed by Lange et al. (Am J Epidemiol. 2012;176(3):190-195). By allowing the analysis of distinct multiple pathways, the suggested approach adds to the capabilities of modern mediation techniques. Furthermore, the approach can be implemented using standard software, and we have included with this article implementation examples using R (R Foundation for Statistical Computing, Vienna, Austria) and Stata software (StataCorp LP, College Station, Texas).

Radiation doses to critical groups since the early 1950s due to discharges of liquid radioactive waste from Sellafield.

PubMed

Hunt, G J

1997-04-01

First, some of the early work is reviewed on exposure pathways in connection with proposed and early liquid radioactive waste discharges from Sellafield. The main historical features of these discharges, affected by relevant plant operations, are then briefly described. The important radiological exposure pathways resulting from the discharges and people's consumption and occupancy habits are considered. To place the changing scenario onto a consistent basis using present-day methodology, a reconstruction of exposures has been carried out using environmental monitoring data and models. The three major pathways are examined of Porphyra/laverbread consumption in South Wales, fish and shellfish consumption near Sellafield, and external exposure over local and more distant sediments. The results show that over the period 1952 to about 1970 the laverbread pathway was probably critical, taking a cautious approach. Effective dose rates fluctuated at around 1 mSv y(-1) from about 1956 to 1971. From about 1970 to 1985, the fish and shellfish pathway was likely to have been critical, with effective dose rates peaking at about 2 mSv y(-1) in 1975-1976. External exposure was likely to have been of lesser importance than the other two pathways until about 1985, when with the retention of previously-released radiocesium on sediments it has become dominant. This phenomenon applies particularly further afield where radiocesium concentrations have been slower to decline; in the Ribble estuary, houseboat dwellers have been the critical group from about 1985. Effective doses have been at about 0.3 mSv y(-1) and declining; they are due to the effects of radiocesium discharges in earlier years. Dose rates have remained within contemporary ICRP dose limits.

CKow -- A More Transparent and Reliable Model for Chemical Transfer to Meat and Milk

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosenbaum, Ralph K.; McKone, Thomas E.; Jolliet, Olivier

The objective of this study is to increase the understanding and transparency of chemical biotransfer modeling into meat and milk and explicitly confront the uncertainties in exposure assessments of chemicals that require such estimates. In cumulative exposure assessments that include food pathways, much of the overall uncertainty is attributable to the estimation of transfer into biota and through food webs. Currently, the most commonly used meat and milk-biotransfer models date back two decades and, in spite of their widespread use in multimedia exposure models few attempts have been made to advance or improve the outdated and highly uncertain Kow regressionsmore » used in these models. Furthermore, in the range of Kow where meat and milk become the dominant human exposure pathways, these models often provide unrealistic rates and do not reflect properly the transfer dynamics. To address these issues, we developed a dynamic three-compartment cow model (called CKow), distinguishing lactating and non-lactating cows. For chemicals without available overall removal rates in the cow, a correlation is derived from measured values reported in the literature to predict this parameter from Kow. Results on carry over rates (COR) and biotransfer factors (BTF) demonstrate that a steady-state ratio between animal intake and meat concentrations is almost never reached. For meat, empirical data collected on short term experiments need to be adjusted to provide estimates of average longer term behaviors. The performance of the new model in matching measurements is improved relative to existing models--thus reducing uncertainty. The CKow model is straight forward to apply at steady state for milk and dynamically for realistic exposure durations for meat COR.« less

Multi-pathway exposure modeling of chemicals in cosmetics with application to shampoo.

PubMed

Ernstoff, Alexi S; Fantke, Peter; Csiszar, Susan A; Henderson, Andrew D; Chung, Susie; Jolliet, Olivier

2016-01-01

We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based on the chemical mass originally applied via a product, multiplied by the product intake fractions (PiF, the fraction of a chemical in a product that is taken in by exposed persons) to yield intake rates. The average PiFs for the evaluated chemicals in shampoo ranged from 3×10(-4) up to 0.3 for rapidly absorbed ingredients. Average intake rates ranged between nano- and micrograms per kilogram bodyweight per day; the order of chemical prioritization was strongly affected by the ingredient concentration in shampoo. Dermal intake and inhalation (for 20% of the evaluated chemicals) during use dominated exposure, while the skin permeation coefficient dominated the estimated uncertainties. The fraction of chemical taken in by a shampoo user often exceeded, by orders of magnitude, the aggregated fraction taken in by the population through post-use environmental emissions. Chemicals with relatively high octanol-water partitioning and/or volatility, and low molecular weight tended to have higher use stage exposure. Chemicals with low intakes during use (<1%) and subsequent high post-use emissions, however, may yield comparable intake for a member of the general population. The presented PiF based framework offers a novel and critical advancement for life cycle assessments and high-throughput exposure screening of chemicals in cosmetic products demonstrating the importance of consistent consideration of near- and far-field multi-pathway exposures. Copyright © 2016 Elsevier Ltd. All rights reserved.

Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway

PubMed Central

Lim, Sanghee; Kwak, Minhye; Gray, Christy D.; Xu, Michael; Choi, Jun H.; Junn, Sue; Kim, Jieun; Xu, Jing; Schaefer, Michele; Johns, Roger A.; Song, Hongjun; Ming, Guo-Li; Mintz, C. David

2017-01-01

Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition. PMID:28683067

Completing the link between exposure science and toxicology for improved environmental health decision making: The aggregate exposure pathway framework

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teeguarden, Justin G.; Tan, Yu -Mei; Edwards, Stephen W.

Here, driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences.more » Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.« less

Completing the link between exposure science and toxicology for improved environmental health decision making: The aggregate exposure pathway framework

DOE PAGES

Teeguarden, Justin G.; Tan, Yu -Mei; Edwards, Stephen W.; ...

2016-01-13

Here, driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences.more » Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.« less

EVALUATION OF VADOSE ZONE AND SORUCE MODULES FOR MULTI-MEDIA, MULTI-PATHWAY, AND MULTI-RECEPTOR RISK ASSESSMENT USING LARGE-SOIL-COLUMN EXPERIMENTAL DATA

EPA Science Inventory

The United States Environmental Protection Agency (EPA) is developing a comprehensive environmental exposure and risk analysis software system for agency-wide application using the methodology of a Multi-media, Multi-pathway, Multi-receptor Risk Assessment (3MRA) model. This sof...

Life-Stage Physiologically-Based Pharmacokinetic (PBPK) ...

EPA Pesticide Factsheets

This presentation discusses methods used to extrapolate from in vitro high-throughput screening (HTS) toxicity data for an endocrine pathway to in vivo for early life stages in humans, and the use of a life stage PBPK model to address rapidly changing physiological parameters. Adverse outcome pathways (AOPs), in this case endocrine disruption during development, provide a biologically-based framework for linking molecular initiating events triggered by chemical exposures to key events leading to adverse outcomes. The application of AOPs to human health risk assessment requires extrapolation of in vitro HTS toxicity data to in vivo exposures (IVIVE) in humans, which can be achieved through the use of a PBPK/PD model. Exposure scenarios for chemicals in the PBPK/PD model will consider both placental and lactational transfer of chemicals, with a focus on age dependent dosimetry during fetal development and after birth for a nursing infant. This talk proposes a universal life-stage computational model that incorporates changing physiological parameters to link environmental exposures to in vitro levels of HTS assays related to a developmental toxicological AOP for vascular disruption. In vitro toxicity endpoints discussed are based on two mechanisms: 1) Fetal vascular disruption, and 2) Neurodevelopmental toxicity induced by altering thyroid hormone levels in neonates via inhibition of thyroperoxidase in the thyroid gland. Application of our Life-stage computati

A tiered approach for integrating exposure and dosimetry with ...

EPA Pesticide Factsheets

High-throughput (HT) risk screening approaches apply in vitro dose-response data to estimate potential health risks that arise from exposure to chemicals. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the perturbations of biological mechanisms that lead to apical adverse health outcomes in living organisms. The chemical-agnostic Adverse Outcome Pathway (AOP) framework addresses this uncertainty by acting as a scaffold onto which pathway-based data can be arranged to aid in the understanding of in vitro toxicity testing results. In addition, risk estimation also requires reconciling chemical concentrations sufficient to produce bioactivity in vitro with concentrations that trigger a molecular initiating event (MIE) at the relevant biological target in vivo. Such target site exposures (TSEs) can be estimated using computational models to integrate exposure information with a chemical’s absorption, distribution, metabolism, and elimination (ADME) processes. In this presentation, the utility of a tiered approach for integrating exposure, ADME, and hazard into risk-based decision making will be demonstrated using several case studies, along with the investigation of how uncertainties in exposure and ADME might impact risk estimates. These case studies involve 1) identifying and prioritizing chemicals capable of altering biological pathways based on their potential to reach an in vivo target; 2) evaluating the infl

Human health risk assessment of triclosan in land-applied biosolids.

PubMed

Verslycke, Tim; Mayfield, David B; Tabony, Jade A; Capdevielle, Marie; Slezak, Brian

2016-09-01

Triclosan (5-chloro-2-[2,4-dichlorophenoxy]-phenol) is an antimicrobial agent found in a variety of pharmaceutical and personal care products. Numerous studies have examined the occurrence and environmental fate of triclosan in wastewater, biosolids, biosolids-amended soils, and plants and organisms exposed to biosolid-amended soils. Triclosan has a propensity to adhere to organic carbon in biosolids and biosolid-amended soils. Land application of biosolids containing triclosan has the potential to contribute to multiple direct and indirect human health exposure pathways. To estimate exposures and human health risks from biosolid-borne triclosan, a risk assessment was conducted in general accordance with the methodology incorporated into the US Environmental Protection Agency's Part 503 biosolids rule. Human health exposures to biosolid-borne triclosan were estimated on the basis of published empirical data or modeled using upper-end environmental partitioning estimates. Similarly, a range of published triclosan human health toxicity values was evaluated. Margins of safety were estimated for 10 direct and indirect exposure pathways, both individually and combined. The present risk assessment found large margins of safety (>1000 to >100 000) for potential exposures to all pathways, even under the most conservative exposure and toxicity assumptions considered. The human health exposures and risks from biosolid-borne triclosan are concluded to be de minimis. Environ Toxicol Chem 2016;35:2358-2367. © 2016 SETAC. © 2016 SETAC.

Validation of a novel air toxic risk model with air monitoring.

PubMed

Pratt, Gregory C; Dymond, Mary; Ellickson, Kristie; Thé, Jesse

2012-01-01

Three modeling systems were used to estimate human health risks from air pollution: two versions of MNRiskS (for Minnesota Risk Screening), and the USEPA National Air Toxics Assessment (NATA). MNRiskS is a unique cumulative risk modeling system used to assess risks from multiple air toxics, sources, and pathways on a local to a state-wide scale. In addition, ambient outdoor air monitoring data were available for estimation of risks and comparison with the modeled estimates of air concentrations. Highest air concentrations and estimated risks were generally found in the Minneapolis-St. Paul metropolitan area and lowest risks in undeveloped rural areas. Emissions from mobile and area (nonpoint) sources created greater estimated risks than emissions from point sources. Highest cancer risks were via ingestion pathway exposures to dioxins and related compounds. Diesel particles, acrolein, and formaldehyde created the highest estimated inhalation health impacts. Model-estimated air concentrations were generally highest for NATA and lowest for the AERMOD version of MNRiskS. This validation study showed reasonable agreement between available measurements and model predictions, although results varied among pollutants, and predictions were often lower than measurements. The results increased confidence in identifying pollutants, pathways, geographic areas, sources, and receptors of potential concern, and thus provide a basis for informing pollution reduction strategies and focusing efforts on specific pollutants (diesel particles, acrolein, and formaldehyde), geographic areas (urban centers), and source categories (nonpoint sources). The results heighten concerns about risks from food chain exposures to dioxins and PAHs. Risk estimates were sensitive to variations in methodologies for treating emissions, dispersion, deposition, exposure, and toxicity. © 2011 Society for Risk Analysis.

Reactive Aggression and Posttraumatic Stress in Adolescents Affected by Hurricane Katrina

ERIC Educational Resources Information Center

Marsee, Monica A.

2008-01-01

The current study tests a theoretical model illustrating a potential pathway to reactive aggression through exposure to a traumatic event (Hurricane Katrina) in 166 adolescents (61% female, 63% Caucasian) recruited from high schools on the Gulf Coast of Mississippi. Results support an association between exposure to Hurricane Katrina and reactive…

Transcriptional Modulation of the ERK1/2 MAPK and NF-kB pathways in Human Urothelial cells after trivalent arsenical exposure: Implications for urinary bladder cancer

EPA Science Inventory

Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk ofurinary bladder (DB) cancers in humans. Rodent models administered particular arsenicals have indicated urothelial necrosis followed by regenerative proliferation i...

Monitoring UV-induced signalling pathways in an ex vivo skin organ culture model using phospho-antibody array.

PubMed

Lenain, Christelle; Gamboa, Bastien; Perrin, Agnes; Séraïdaris, Alexia; Bertino, Béatrice; Rival, Yves; Bernardi, Mathieu; Piwnica, David; Méhul, Bruno

2018-05-01

We investigated UV-induced signalling in an ex vivo skin organ culture model using phospho-antibody array. Phosphorylation modulations were analysed in time-course experiments following exposure to solar-simulated UV and validated by Western blot analyses. We found that UV induced P-p38 and its substrates, P-ERK1/2 and P-AKT, which were previously shown to be upregulated by UV in cultured keratinocytes and in vivo human skin. This indicates that phospho-antibody array applied to ex vivo skin organ culture is a relevant experimental system to investigate signalling events following perturbations. As the identified proteins are components of pathways implicated in skin tumorigenesis, UV-exposed skin organ culture model could be used to investigate the effect on these pathways of NMSC cancer drug candidates. In addition, we found that phospho-HCK is induced upon UV exposure, producing a new candidate for future studies investigating its role in the skin response to UV and UV-induced carcinogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Predicting Residential Exposure to Phthalate Plasticizer Emitted from Vinyl Flooring: Sensitivity, Uncertainty, and Implications for Biomonitoring

PubMed Central

Xu, Ying; Cohen Hubal, Elaine A.; Little, John C.

2010-01-01

Background Because of the ubiquitous nature of phthalates in the environment and the potential for adverse human health effects, an urgent need exists to identify the most important sources and pathways of exposure. Objectives Using emissions of di(2-ethylhexyl) phthalate (DEHP) from vinyl flooring (VF) as an illustrative example, we describe a fundamental approach that can be used to identify the important sources and pathways of exposure associated with phthalates in indoor material. Methods We used a three-compartment model to estimate the emission rate of DEHP from VF and the evolving exposures via inhalation, dermal absorption, and oral ingestion of dust in a realistic indoor setting. Results A sensitivity analysis indicates that the VF source characteristics (surface area and material-phase concentration of DEHP), as well as the external mass-transfer coefficient and ventilation rate, are important variables that influence the steady-state DEHP concentration and the resulting exposure. In addition, DEHP is sorbed by interior surfaces, and the associated surface area and surface/air partition coefficients strongly influence the time to steady state. The roughly 40-fold range in predicted exposure reveals the inherent difficulty in using biomonitoring to identify specific sources of exposure to phthalates in the general population. Conclusions The relatively simple dependence on source and chemical-specific transport parameters suggests that the mechanistic modeling approach could be extended to predict exposures arising from other sources of phthalates as well as additional sources of other semivolatile organic compounds (SVOCs) such as biocides and flame retardants. This modeling approach could also provide a relatively inexpensive way to quantify exposure to many of the SVOCs used in indoor materials and consumer products. PMID:20123613

Predicting residential exposure to phthalate plasticizer emitted from vinyl flooring: sensitivity, uncertainty, and implications for biomonitoring.

PubMed

Xu, Ying; Cohen Hubal, Elaine A; Little, John C

2010-02-01

Because of the ubiquitous nature of phthalates in the environment and the potential for adverse human health effects, an urgent need exists to identify the most important sources and pathways of exposure. Using emissions of di(2-ethylhexyl) phthalate (DEHP) from vinyl flooring (VF) as an illustrative example, we describe a fundamental approach that can be used to identify the important sources and pathways of exposure associated with phthalates in indoor material. We used a three-compartment model to estimate the emission rate of DEHP from VF and the evolving exposures via inhalation, dermal absorption, and oral ingestion of dust in a realistic indoor setting. A sensitivity analysis indicates that the VF source characteristics (surface area and material-phase concentration of DEHP), as well as the external mass-transfer coefficient and ventilation rate, are important variables that influence the steady-state DEHP concentration and the resulting exposure. In addition, DEHP is sorbed by interior surfaces, and the associated surface area and surface/air partition coefficients strongly influence the time to steady state. The roughly 40-fold range in predicted exposure reveals the inherent difficulty in using biomonitoring to identify specific sources of exposure to phthalates in the general population. The relatively simple dependence on source and chemical-specific transport parameters suggests that the mechanistic modeling approach could be extended to predict exposures arising from other sources of phthalates as well as additional sources of other semivolatile organic compounds (SVOCs) such as biocides and flame retardants. This modeling approach could also provide a relatively inexpensive way to quantify exposure to many of the SVOCs used in indoor materials and consumer products.

FUGACITY-BASED INDOOR RESIDENTIAL PESTICIDE FATE MODEL

EPA Science Inventory

Dermal and non-dietary pathways are possibly important for exposure to pesticides used in residences. Limited data have been collected on pesticide concentrations in residential air and surfaces following application. Models may be useful for interpreting these data and to make...

The Effect of Microplastic on the Uptake of Chemicals by the Lugworm Arenicola marina (L.) under Environmentally Relevant Exposure Conditions

PubMed Central

2017-01-01

It has been hypothesized that ingestion of microplastic increases exposure of aquatic organisms to hydrophobic contaminants. To date, most laboratory studies investigated chemical transfer from ingested microplastic without taking other exposure pathways into account. Therefore, we studied the effect of polyethylene (PE) microplastic in sediment on PCB uptake by Arenicola marina as a model species, quantifying uptake fluxes from all natural exposure pathways. PCB concentrations in sediment, biota lipids (Clip) and porewater measured with passive samplers were used to derive lipid-normalized bioaccumulation metrics Clip, Biota sediment accumulation factor (BSAF), Bioaccumulation factor (BAF) and the Biota plastic accumulation factor (BPAF). Small effects of PE addition were detected suggesting slightly increased or decreased bioaccumulation. However, the differences decreased in magnitude dependent on the metric used to assess bioaccumulation, in the order: Clip > BSAF > BPAF > BAF, and were nonsignificant for BAF. The fact that BAF, that is, normalization of Clip on porewater concentration, largely removed all effects of PE, shows that PE did not act as a measurable vector of PCBs. Biodynamic model analysis confirmed that PE ingestion contributed marginally to bioaccumulation. This work confirmed model-based predictions on the limited relevance of microplastic for bioaccumulation under environmentally realistic conditions, and illustrated the importance of assessing exposure through all media in microplastic bioaccumulation studies. PMID:28682597

The Effect of Microplastic on the Uptake of Chemicals by the Lugworm Arenicola marina (L.) under Environmentally Relevant Exposure Conditions.

PubMed

Besseling, Ellen; Foekema, Edwin M; van den Heuvel-Greve, Martine J; Koelmans, Albert A

2017-08-01

It has been hypothesized that ingestion of microplastic increases exposure of aquatic organisms to hydrophobic contaminants. To date, most laboratory studies investigated chemical transfer from ingested microplastic without taking other exposure pathways into account. Therefore, we studied the effect of polyethylene (PE) microplastic in sediment on PCB uptake by Arenicola marina as a model species, quantifying uptake fluxes from all natural exposure pathways. PCB concentrations in sediment, biota lipids (C lip ) and porewater measured with passive samplers were used to derive lipid-normalized bioaccumulation metrics C lip , Biota sediment accumulation factor (BSAF), Bioaccumulation factor (BAF) and the Biota plastic accumulation factor (BPAF). Small effects of PE addition were detected suggesting slightly increased or decreased bioaccumulation. However, the differences decreased in magnitude dependent on the metric used to assess bioaccumulation, in the order: C lip > BSAF > BPAF > BAF, and were nonsignificant for BAF. The fact that BAF, that is, normalization of C lip on porewater concentration, largely removed all effects of PE, shows that PE did not act as a measurable vector of PCBs. Biodynamic model analysis confirmed that PE ingestion contributed marginally to bioaccumulation. This work confirmed model-based predictions on the limited relevance of microplastic for bioaccumulation under environmentally realistic conditions, and illustrated the importance of assessing exposure through all media in microplastic bioaccumulation studies.

Modelling effects of chemical exposure on birds wintering in agricultural landscapes: The western burrowing owl (Athene cunicularia hypugaea) as a case study

USGS Publications Warehouse

Engelman, Catherine A.; Grant, William E.; Mora, Miguel A.; Woodin, Marc

2012-01-01

We describe an ecotoxicological model that simulates the sublethal and lethal effects of chronic, low-level, chemical exposure on birds wintering in agricultural landscapes. Previous models estimating the impact on wildlife of chemicals used in agro-ecosystems typically have not included the variety of pathways, including both dermal and oral, by which individuals are exposed. The present model contains four submodels simulating (1) foraging behavior of individual birds, (2) chemical applications to crops, (3) transfers of chemicals among soil, insects, and small mammals, and (4) transfers of chemicals to birds via ingestion and dermal exposure. We demonstrate use of the model by simulating the impacts of a variety of commonly used herbicides, insecticides, growth regulators, and defoliants on western burrowing owls (Athene cunicularia hypugaea) that winter in agricultural landscapes in southern Texas, United States. The model generated reasonable movement patterns for each chemical through soil, water, insects, and rodents, as well as into the owl via consumption and dermal absorption. Sensitivity analysis suggested model predictions were sensitive to uncertainty associated with estimates of chemical half-lives in birds, soil, and prey, sensitive to parameters associated with estimating dermal exposure, and relatively insensitive to uncertainty associated with details of chemical application procedures (timing of application, amount of drift). Nonetheless, the general trends in chemical accumulations and the relative impacts of the various chemicals were robust to these parameter changes. Simulation results suggested that insecticides posed a greater potential risk to owls of both sublethal and lethal effects than do herbicides, defoliants, and growth regulators under crop scenarios typical of southern Texas, and that use of multiple indicators, or endpoints provided a more accurate assessment of risk due to agricultural chemical exposure. The model should prove useful in helping prioritize the chemicals and transfer pathways targeted in future studies and also, as these new data become available, in assessing the relative danger to other birds of exposure to different types of agricultural chemicals.

Chemical and metabolomic screens identify novel biomarkers and antidotes for cyanide exposure

PubMed Central

Nath, Anjali K.; Roberts, Lee D.; Liu, Yan; Mahon, Sari B.; Kim, Sonia; Ryu, Justine H.; Werdich, Andreas; Januzzi, James L.; Boss, Gerry R.; Rockwood, Gary A.; MacRae, Calum A.; Brenner, Matthew; Gerszten, Robert E.; Peterson, Randall T.

2013-01-01

Exposure to cyanide causes a spectrum of cardiac, neurological, and metabolic dysfunctions that can be fatal. Improved cyanide antidotes are needed, but the ideal biological pathways to target are not known. To understand better the metabolic effects of cyanide and to discover novel cyanide antidotes, we developed a zebrafish model of cyanide exposure and scaled it for high-throughput chemical screening. In a screen of 3120 small molecules, we discovered 4 novel antidotes that block cyanide toxicity. The most potent antidote was riboflavin. Metabolomic profiling of cyanide-treated zebrafish revealed changes in bile acid and purine metabolism, most notably by an increase in inosine levels. Riboflavin normalizes many of the cyanide-induced neurological and metabolic perturbations in zebrafish. The metabolic effects of cyanide observed in zebrafish were conserved in a rabbit model of cyanide toxicity. Further, humans treated with nitroprusside, a drug that releases nitric oxide and cyanide ions, display increased circulating bile acids and inosine. In summary, riboflavin may be a novel treatment for cyanide toxicity and prophylactic measure during nitroprusside treatment, inosine may serve as a biomarker of cyanide exposure, and metabolites in the bile acid and purine metabolism pathways may shed light on the pathways critical to reversing cyanide toxicity.—Nath, A. K., Roberts, L. D., Liu, Y., Mahon, S. B., Kim, S., Ryu, J. H., Werdich, A., Januzzi, J. L., Boss, G. R., Rockwood, G. A., MacRae, C. A., Brenner, M., Gerszten, R. E., Peterson, R. T. Chemical and metabolomic screens identify novel biomarkers and antidotes for cyanide exposure. PMID:23345455

System-based identification of toxicity pathways associated with multi-walled carbon nanotube-induced pathological responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Snyder-Talkington, Brandi N.; Dymacek, Julian; Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300

2013-10-15

The fibrous shape and biopersistence of multi-walled carbon nanotubes (MWCNT) have raised concern over their potential toxicity after pulmonary exposure. As in vivo exposure to MWCNT produced a transient inflammatory and progressive fibrotic response, this study sought to identify significant biological processes associated with lung inflammation and fibrosis pathology data, based upon whole genome mRNA expression, bronchoaveolar lavage scores, and morphometric analysis from C57BL/6J mice exposed by pharyngeal aspiration to 0, 10, 20, 40, or 80 μg MWCNT at 1, 7, 28, or 56 days post-exposure. Using a novel computational model employing non-negative matrix factorization and Monte Carlo Markov Chainmore » simulation, significant biological processes with expression similar to MWCNT-induced lung inflammation and fibrosis pathology data in mice were identified. A subset of genes in these processes was determined to be functionally related to either fibrosis or inflammation by Ingenuity Pathway Analysis and was used to determine potential significant signaling cascades. Two genes determined to be functionally related to inflammation and fibrosis, vascular endothelial growth factor A (vegfa) and C-C motif chemokine 2 (ccl2), were confirmed by in vitro studies of mRNA and protein expression in small airway epithelial cells exposed to MWCNT as concordant with in vivo expression. This study identified that the novel computational model was sufficient to determine biological processes strongly associated with the pathology of lung inflammation and fibrosis and could identify potential toxicity signaling pathways and mechanisms of MWCNT exposure which could be used for future animal studies to support human risk assessment and intervention efforts. - Highlights: • A novel computational model identified toxicity pathways matching in vivo pathology. • Systematic identification of MWCNT-induced biological processes in mouse lungs • MWCNT-induced functional networks of lung inflammation and fibrosis were revealed. • Two functional, representative genes, ccl2 and vegfa, were validated in vitro.« less

Integration of Life-Stage Physiologically Based Pharmacokinetic Models with Adverse Outcome Pathways and Environmental Exposure Models to Screen for Environmental Hazards

EPA Science Inventory

A Life-stage Physiologically-Based Pharmacokinetic (PBPK) model was developed to include descriptions of several life-stage events such as pregnancy, fetal development, the neonate and child growth. The overall modeling strategy was used for in vitro to in vivo (IVIVE) extrapolat...

A Review of Nonoccupational Pathways for Pesticide Exposure in Women Living in Agricultural Areas

PubMed Central

Friesen, Melissa C.; Hoppin, Jane A.; Hines, Cynthia J.; Thomas, Kent; Freeman, Laura E. Beane

2015-01-01

Background Women living in agricultural areas may experience high pesticide exposures compared with women in urban or suburban areas because of their proximity to farm activities. Objective Our objective was to review the evidence in the published literature for the contribution of nonoccupational pathways of pesticide exposure in women living in North American agricultural areas. Methods We evaluated the following nonoccupational exposure pathways: paraoccupational (i.e., take-home or bystander exposure), agricultural drift, residential pesticide use, and dietary ingestion. We also evaluated the role of hygiene factors (e.g., house cleaning, shoe removal). Results Among 35 publications identified (published 1995–2013), several reported significant or suggestive (p < 0.1) associations between paraoccupational (n = 19) and agricultural drift (n = 10) pathways and pesticide dust or biomarker levels, and 3 observed that residential use was associated with pesticide concentrations in dust. The 4 studies related to ingestion reported low detection rates of most pesticides in water; additional studies are needed to draw conclusions about the importance of this pathway. Hygiene factors were not consistently linked to exposure among the 18 relevant publications identified. Conclusions Evidence supported the importance of paraoccupational, drift, and residential use pathways. Disentangling exposure pathways was difficult because agricultural populations are concurrently exposed to pesticides via multiple pathways. Most evidence was based on measurements of pesticides in residential dust, which are applicable to any household member and are not specific to women. An improved understanding of nonoccupational pesticide exposure pathways in women living in agricultural areas is critical for studying health effects in women and for designing effective exposure-reduction strategies. Citation Deziel NC, Friesen MC, Hoppin JA, Hines CJ, Thomas K, Beane Freeman LE. 2015. A review of nonoccupational pathways for pesticide exposure in women living in agricultural areas. Environ Health Perspect 123:515–524; http://dx.doi.org/10.1289/ehp.1408273 PMID:25636067

Installation Restoration Program. Remedial Investigation Report: Minnesota Air National Guard Base Duluth International Airport, Duluth, Minnesota. Volume 7

DTIC Science & Technology

1990-01-01

Selection of Indicator Chemicals 6-36 6.2.2 Estimation of Exposure Point Concentrations or Emission Rates 6-38 6.2.2.1 Exposure Pathway Analysis 6-38...Exposure Point Concentrations or Emission Rates 6-50 j 6.3.2.1 Exposure Pathway Analysis 6-52 6.3.2.2 Exposure Point Concentrations 6-55 6.3.2.3...Exposure Point Concentrations or Emission Rates 6-62 6.4.2.1 Exposure Pathway Analysis 6-62 6.4.2.2 Exposure Point Concentrations 6-69 6.4.2.3

Completing the Link between Exposure Science and ...

EPA Pesticide Factsheets

Driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making. The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports G

Assessing Risks to Sea Otters and the Exxon Valdez Oil Spill: New Scenarios, Attributable Risk, and Recovery

PubMed Central

Harwell, Mark A.; Gentile, John H.

2014-01-01

The Exxon Valdez oil spill occurred more than two decades ago, and the Prince William Sound ecosystem has essentially recovered. Nevertheless, discussion continues on whether or not localized effects persist on sea otters (Enhydra lutris) at northern Knight Island (NKI) and, if so, what are the associated attributable risks. A recent study estimated new rates of sea otter encounters with subsurface oil residues (SSOR) from the oil spill. We previously demonstrated that a potential pathway existed for exposures to polycyclic aromatic hydrocarbons (PAHs) and conducted a quantitative ecological risk assessment using an individual-based model that simulated this and other plausible exposure pathways. Here we quantitatively update the potential for this exposure pathway to constitute an ongoing risk to sea otters using the new estimates of SSOR encounters. Our conservative model predicted that the assimilated doses of PAHs to the 1-in-1000th most-exposed sea otters would remain 1–2 orders of magnitude below the chronic effects thresholds. We re-examine the baseline estimates, post-spill surveys, recovery status, and attributable risks for this subpopulation. We conclude that the new estimated frequencies of encountering SSOR do not constitute a plausible risk for sea otters at NKI and these sea otters have fully recovered from the oil spill. PMID:24587690

Development of a pathway model to assess the exposure of European pine trees to pine wood nematode via the trade of wood.

PubMed

Douma, J C; van der Werf, W; Hemerik, L; Magnusson, C; Robinet, C

2017-04-01

Pine wood nematode (PWN), Bursaphelenchus xylophilus, is a threat for pine species (Pinus spp.) throughout the world. The nematode is native to North America, and invaded Japan, China, Korea, and Taiwan, and more recently Portugal and Spain. PWN enters new areas through trade in wood products. Once established, eradication is not practically feasible. Therefore, preventing entry of PWN into new areas is crucial. Entry risk analysis can assist in targeting management to reduce the probability of entry. Assessing the entry of PWN is challenging due to the complexity of the wood trade and the wood processing chain. In this paper, we develop a pathway model that describes the wood trade and wood processing chain to determine the structure of the entry process. We consider entry of PWN through imported coniferous wood from China, a possible origin of Portuguese populations, to Europe. We show that exposure increased over years due to an increase in imports of sawn wood. From 2000 to 2012, Europe received an estimated 84 PWN propagules from China, 88% of which arose from imported sawn wood and 12% from round wood. The region in Portugal where the PWN was first reported is among those with the highest PWN transfer per unit of imported wood due to a high host cover and vector activity. An estimated 62% of PWN is expected to enter in countries where PWN is not expected to cause the wilt of pine trees because of low summer temperatures (e.g., Belgium, Sweden, Norway). In these countries, PWN is not easily detected, and such countries can thus serve as potential reservoirs of PWN. The model identifies ports and regions with high exposure, which helps targeting monitoring and surveillance, even in areas where wilt disease is not expected to occur. In addition, we show that exposure is most efficiently reduced by additional treatments in the country of origin, and/or import wood from PWN-free zones. Pathway modelling assists plant health managers in analyzing risks along the pathway and planning measures for enhancing biosecurity. © 2016 by the Ecological Society of America.

INDIRECT EXPOSURE ASSESSMENT AT THE U.S. EPA

EPA Science Inventory

In the early 1980s, exposures and subsequent health impact assessments from contaminants emitted into the air from stationary sources focused on the inhalation pathway. This 'direct' pathway of exposure was thought to be the most critical pathway, as it is for many contaminants. ...

EPA EcoBox Tools by Exposure Pathways - Exposure Pathways In ERA

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

A Review of Health Risks and Pathways for Exposure to Wastewater Use in Agriculture

PubMed Central

Dickin, Sarah K.; Schuster-Wallace, Corinne J.; Qadir, Manzoor; Pizzacalla, Katherine

2016-01-01

Background: Wastewater is increasingly being used in the agricultural sector to cope with the depletion of freshwater resources as well as water stress linked to changing climate conditions. As wastewater irrigation expands, research focusing on the human health risks is critical because exposure to a range of contaminants must be weighed with the benefits to food security, nutrition and livelihoods. Objectives: The goal of this paper was to review research examining health risks and exposure pathways associated with wastewater irrigation to identify research trends and gaps. Methods: We conducted a review of the literature and identified a total of 126 studies published from 1995 to 2013. Findings were summarized based on several themes including types of exposure pathways, wastewater contaminants, methodological approaches and the geographical distribution of research. Results: Only 23 studies used epidemiological methods, while most research applied alternative methods to estimate risk, such as quantitative risk assessment models or comparisons of crop contamination to established guidelines for wastewater reuse. A geographic breakdown demonstrated a focus on microbiological contaminants in specific regions such as sub-Saharan Africa and Southeast Asia, despite growing chemical risks associated with rapid urbanization and industrialization that may change the types and distribution of wastewater contaminants. Conclusions: To provide a more comprehensive understanding of the health risks of wastewater use in agriculture, future research should consider multiple exposure routes, long-term health implications, and increase the range of contaminants studied, particularly in regions heavily dependent on wastewater irrigation. Citation: Dickin SK, Schuster-Wallace CJ, Qadir M, Pizzacalla K. 2016. A review of health risks and pathways for exposure to wastewater use in agriculture. Environ Health Perspect 124:900–909; http://dx.doi.org/10.1289/ehp.1509995 PMID:26824464

A Review of Health Risks and Pathways for Exposure to Wastewater Use in Agriculture.

PubMed

Dickin, Sarah K; Schuster-Wallace, Corinne J; Qadir, Manzoor; Pizzacalla, Katherine

2016-07-01

Wastewater is increasingly being used in the agricultural sector to cope with the depletion of freshwater resources as well as water stress linked to changing climate conditions. As wastewater irrigation expands, research focusing on the human health risks is critical because exposure to a range of contaminants must be weighed with the benefits to food security, nutrition and livelihoods. The goal of this paper was to review research examining health risks and exposure pathways associated with wastewater irrigation to identify research trends and gaps. We conducted a review of the literature and identified a total of 126 studies published from 1995 to 2013. Findings were summarized based on several themes including types of exposure pathways, wastewater contaminants, methodological approaches and the geographical distribution of research. Only 23 studies used epidemiological methods, while most research applied alternative methods to estimate risk, such as quantitative risk assessment models or comparisons of crop contamination to established guidelines for wastewater reuse. A geographic breakdown demonstrated a focus on microbiological contaminants in specific regions such as sub-Saharan Africa and Southeast Asia, despite growing chemical risks associated with rapid urbanization and industrialization that may change the types and distribution of wastewater contaminants. To provide a more comprehensive understanding of the health risks of wastewater use in agriculture, future research should consider multiple exposure routes, long-term health implications, and increase the range of contaminants studied, particularly in regions heavily dependent on wastewater irrigation. Dickin SK, Schuster-Wallace CJ, Qadir M, Pizzacalla K. 2016. A review of health risks and pathways for exposure to wastewater use in agriculture. Environ Health Perspect 124:900-909; http://dx.doi.org/10.1289/ehp.1509995.

A quantitative assessment of risks of heavy metal residues in laundered shop towels and their use by workers.

PubMed

Connor, Kevin; Magee, Brian

2014-10-01

This paper presents a risk assessment of exposure to metal residues in laundered shop towels by workers. The concentrations of 27 metals measured in a synthetic sweat leachate were used to estimate the releasable quantity of metals which could be transferred to workers' skin. Worker exposure was evaluated quantitatively with an exposure model that focused on towel-to-hand transfer and subsequent hand-to-food or -mouth transfers. The exposure model was based on conservative, but reasonable assumptions regarding towel use and default exposure factor values from the published literature or regulatory guidance. Transfer coefficients were derived from studies representative of the exposures to towel users. Contact frequencies were based on assumed high-end use of shop towels, but constrained by a theoretical maximum dermal loading. The risk estimates for workers developed for all metals were below applicable regulatory risk benchmarks. The risk assessment for lead utilized the Adult Lead Model and concluded that predicted lead intakes do not constitute a significant health hazard based on potential worker exposures. Uncertainties are discussed in relation to the overall confidence in the exposure estimates developed for each exposure pathway and the likelihood that the exposure model is under- or overestimating worker exposures and risk. Copyright © 2014 Elsevier Inc. All rights reserved.

Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teeguarden, Justin G.; Tan, Yu-Mei; Edwards, Stephen W.

Driven by major scientific advances in analytical methods, biomonitoring, and computational exposure assessment, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the computationally enabled “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) conceptmore » in the toxicological sciences. The AEP framework offers an intuitive approach to successful organization of exposure science data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathway and adverse outcome pathways, completing the source to outcome continuum and setting the stage for more efficient integration of exposure science and toxicity testing information. Together these frameworks form and inform a decision making framework with the flexibility for risk-based, hazard-based or exposure-based decisions.« less

Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Yoke-Chen; Wang, James D.; Svoboda, Kathy K.

The endoplasmic reticulum (ER) stress response is a cell survival pathway upregulated when cells are under severe stress. Severely damaged mouse ear skin exposed to the vesicant, sulfur mustard (bis-2-chloroethyl sulfide, SM), resulted in increased expression of ER chaperone proteins that accompany misfolded and incorrectly made proteins targeted for degradation. Time course studies with SM using the mouse ear vesicant model (MEVM) showed progressive histopathologic changes including edema, separation of the epidermis from the dermis, persistent inflammation, upregulation of laminin γ2 (one of the chains of laminin-332, a heterotrimeric skin glycoprotein required for wound repair), and delayed wound healing frommore » 24 h to 168 h post exposure. This was associated with time related increased expression of the cell survival ER stress marker, GRP78/BiP, and the ER stress apoptosis marker, GADD153/CHOP, suggesting simultaneous activation of both cell survival and non-mitochondrial apoptosis pathways. Dual immunofluorescence labeling of a keratinocyte migration promoting protein, laminin γ2 and GRP78/BIP, showed colocalization of the two molecules 72 h post exposure indicating that the laminin γ2 was misfolded after SM exposure and trapped within the ER. Taken together, these data show that ER stress is induced in mouse skin within 24 h of vesicant exposure in a defensive response to promote cell survival; however, it appears that this response is rapidly overwhelmed by the apoptotic pathway as a consequence of severe SM-induced injury. - Highlights: ► We demonstrated ER stress response in the mouse ear vesicant model. ► We described the asymmetrical nature of wound repair in the MEVM. ► We identified the distribution of various ER stress markers in the MEVM.« less

10 CFR 50.47 - Emergency plans.

Code of Federal Regulations, 2011 CFR

2011-01-01

... clear instruction to the populace within the plume exposure pathway Emergency Planning Zone have been... protective actions has been developed for the plume exposure pathway EPZ for emergency workers and the public... and in place, and protective actions for the ingestion exposure pathway EPZ appropriate to the locale...

Changes in gene expression in chronic allergy mouse model exposed to natural environmental PM2.5-rich ambient air pollution.

PubMed

Ouyang, Yuhui; Xu, Zhaojun; Fan, Erzhong; Li, Ying; Miyake, Kunio; Xu, Xianyan; Zhang, Luo

2018-04-20

Particulate matter (PM) air pollution has been associated with an increase in the incidence of chronic allergic diseases; however, the mechanisms underlying the effect of exposure to natural ambient air pollution in chronic allergic diseases have not been fully elucidated. In the present study, we aimed to investigate the cellular responses induced by exposure to natural ambient air pollution, employing a mouse model of chronic allergy. The results indicated that exposure to ambient air pollution significantly increased the number of eosinophils in the nasal mucosa. The modulation of gene expression profile identified a set of regulated genes, and the Triggering Receptor Expressed on Myeloid cells1(TREM1) signaling canonical pathway was increased after exposure to ambient air pollution. In vitro, PM2.5 increased Nucleotide-binding oligomerization domain-containing protein 1 (Nod1) and nuclear factor (NF)-κB signaling pathway activation in A549 and HEK293 cell cultures. These results suggest a novel mechanism by which, PM2.5 in ambient air pollution may stimulate the innate immune system through the PM2.5-Nod1-NF-κB axis in chronic allergic disease.

20170312 - Adverse Outcome Pathway (AOP) framework for ...

EPA Pesticide Factsheets

Vascular development commences with de novo assembly of a primary capillary plexus (vasculogenesis) followed by its expansion (angiogenesis) and maturation (angio-adaptation) into a hierarchical system of arteries and veins. These processes are tightly regulated by genetic signals and environmental factors linked to morphogenesis and microphysiology. Gestational exposure to some chemicals disrupts vascular development leading to adverse outcomes. To broadly assess consequences of gestational toxicant exposure on vascular development, an Adverse Outcome Pathway (AOP) framework was constructed that integrates data from ToxCast high-throughput screening (HTS) assays with pathway-level information from the literature and public databases. The AOP-based model resolved the ToxCast library (1065 compounds) into a matrix based on several dozen molecular functions critical for developmental angiogenesis. A sample of 38 ToxCast chemicals selected across the matrix tested model performance. Putative vascular disrupting chemical (pVDC) bioactivity was assessed by multiple laboratories utilizing diverse angiogenesis assays, including: transgenic zebrafish, complex human cell co-cultures, engineered microscale systems, and human-synthetic models. The ToxCast pVDC signature predicted vascular disruption in a manner that was chemical-specific and assay-dependent. An AOP for developmental vascular toxicity was constructed that focuses on inhibition of VEGF receptor (VEGFR2). Thi

Adverse Outcome Pathway (AOP) framework for embryonic ...

EPA Pesticide Factsheets

Vascular development commences with de novo assembly of a primary capillary plexus (vasculogenesis) followed by its expansion (angiogenesis) and maturation (angio-adaptation) into a hierarchical system of arteries and veins. These processes are tightly regulated by genetic signals and environmental factors linked to morphogenesis and microphysiology. Gestational exposure to some chemicals disrupts vascular development leading to adverse outcomes. To broadly assess consequences of gestational toxicant exposure on vascular development, an Adverse Outcome Pathway (AOP) framework was constructed that integrates data from ToxCast high-throughput screening (HTS) assays with pathway-level information from the literature and public databases. The AOP-based model resolved the ToxCast library (1065 compounds) into a matrix based on several dozen molecular functions critical for developmental angiogenesis. A sample of 38 ToxCast chemicals selected across the matrix tested model performance. Putative vascular disrupting chemical (pVDC) bioactivity was assessed by multiple laboratories utilizing diverse angiogenesis assays, including: transgenic zebrafish, complex human cell co-cultures, engineered microscale systems, and human-synthetic models. The ToxCast pVDC signature predicted vascular disruption in a manner that was chemical-specific and assay-dependent. An AOP for developmental vascular toxicity was constructed that focuses on inhibition of VEGF receptor (VEGFR2). Thi

Chlorpyrifos PBPK/PD model for multiple routes of exposure.

PubMed

Poet, Torka S; Timchalk, Charles; Hotchkiss, Jon A; Bartels, Michael J

2014-10-01

1. Chlorpyrifos (CPF) is an important pesticide used to control crop insects. Human Exposures to CPF will occur primarily through oral exposure to residues on foods. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model has been developed that describes the relationship between oral, dermal and inhalation doses of CPF and key events in the pathway for cholinergic effects. The model was built on a prior oral model that addressed age-related changes in metabolism and physiology. This multi-route model was developed in rats and humans to validate all scenarios in a parallelogram design. 2. Critical biological effects from CPF exposure require metabolic activation to CPF oxon, and small amounts of metabolism in tissues will potentially have a great effect on pharmacokinetics and pharmacodynamic outcomes. Metabolism (bioactivation and detoxification) was therefore added in diaphragm, brain, lung and skin compartments. Pharmacokinetic data are available for controlled human exposures via the oral and dermal routes and from oral and inhalation studies in rats. The validated model was then used to determine relative dermal versus inhalation uptake from human volunteers exposed to CPF in an indoor scenario.

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2013 CFR

2013-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2010 CFR

2010-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2011 CFR

2011-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2014 CFR

2014-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2012 CFR

2012-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

Assessing Residential Exposure Risk from Spills of Flowback Water from Marcellus Shale Hydraulic Fracturing Activity

PubMed Central

Abualfaraj, Noura; Olson, Mira S.

2018-01-01

Identifying sources of concern and risk from shale gas development, particularly from the hydraulic fracturing process, is an important step in better understanding sources of uncertainty within the industry. In this study, a risk assessment of residential exposure pathways to contaminated drinking water is carried out. In this model, it is assumed that a drinking water source is contaminated by a spill of flowback water; probability distributions of spill size and constituent concentrations are fit to historical datasets and Monte Carlo simulation was used to calculate a distribution of risk values for two scenarios: (1) use of a contaminated reservoir for residential drinking water supply and (2) swimming in a contaminated pond. The swimming scenario did not produce risks of concern from a single exposure of 1 h duration, but 11 such 1-h exposures did produce risks of 10−6 due to radionuclide exposure. The drinking water scenario over a 30-year exposure duration produced cancer risk values exceeding 10−6 for arsenic, benzene, benzo(a)pyrene, heptachlor, heptachlor epoxide, pentachlorophenol, and vinyl chloride. However, this extended exposure duration is probably not realistic for exposure by a spill event. Radionuclides produced risks in the residential drinking water scenario of 10−6 in just 8 h, a much more realistic timeline for continual exposure due to a spill event. In general, for contaminants for which inhalation exposure was applicable, this pathway produced the highest risks with exposure from ingestion posing the next greatest risk to human health followed by dermal absorption (or body emersion for radionuclides). Considering non-carcinogenic effects, only barium and thallium exceed target limits, where the ingestion pathway seems to be of greater concern than dermal exposure. Exposure to radionuclides in flowback water, particularly through the inhalation route, poses a greater threat to human health than other contaminants examined in this assessment and should be the focus of risk assessment and risk mitigation efforts. PMID:29641504

Assessing Residential Exposure Risk from Spills of Flowback Water from Marcellus Shale Hydraulic Fracturing Activity.

PubMed

Abualfaraj, Noura; Gurian, Patrick L; Olson, Mira S

2018-04-11

Identifying sources of concern and risk from shale gas development, particularly from the hydraulic fracturing process, is an important step in better understanding sources of uncertainty within the industry. In this study, a risk assessment of residential exposure pathways to contaminated drinking water is carried out. In this model, it is assumed that a drinking water source is contaminated by a spill of flowback water; probability distributions of spill size and constituent concentrations are fit to historical datasets and Monte Carlo simulation was used to calculate a distribution of risk values for two scenarios: (1) use of a contaminated reservoir for residential drinking water supply and (2) swimming in a contaminated pond. The swimming scenario did not produce risks of concern from a single exposure of 1 h duration, but 11 such 1-h exposures did produce risks of 10 -6 due to radionuclide exposure. The drinking water scenario over a 30-year exposure duration produced cancer risk values exceeding 10 -6 for arsenic, benzene, benzo(a)pyrene, heptachlor, heptachlor epoxide, pentachlorophenol, and vinyl chloride. However, this extended exposure duration is probably not realistic for exposure by a spill event. Radionuclides produced risks in the residential drinking water scenario of 10 -6 in just 8 h, a much more realistic timeline for continual exposure due to a spill event. In general, for contaminants for which inhalation exposure was applicable, this pathway produced the highest risks with exposure from ingestion posing the next greatest risk to human health followed by dermal absorption (or body emersion for radionuclides). Considering non-carcinogenic effects, only barium and thallium exceed target limits, where the ingestion pathway seems to be of greater concern than dermal exposure. Exposure to radionuclides in flowback water, particularly through the inhalation route, poses a greater threat to human health than other contaminants examined in this assessment and should be the focus of risk assessment and risk mitigation efforts.

Zebrafish as a model to study the role of DNA methylation in environmental toxicology.

PubMed

Kamstra, Jorke H; Aleström, Peter; Kooter, Jan M; Legler, Juliette

2015-11-01

Environmental epigenetics is a rapidly growing field which studies the effects of environmental factors such as nutrition, stress, and exposure to compounds on epigenetic gene regulation. Recent studies have shown that exposure to toxicants in vertebrates is associated with changes in DNA methylation, a major epigenetic mechanism affecting gene transcription. Zebra fish, a well-known model in toxicology and developmental biology, are emerging as a model species in environmental epigenetics despite their evolutionary distance to rodents and humans. In this review, recent insights in DNA methylation during zebra fish development are discussed and compared to mammalian models in order to evaluate zebra fish as a model to study the role of DNA methylation in environmental toxicology. Differences exist in DNA methylation reprogramming during early development, whereas in later developmental stages, tissue distribution of both 5-methylcytosine and 5-hydroxymethylcytosine seems more conserved between species, as well as basic DNA (de)methylation mechanisms. All DNA methyl transferases identified so far in mammals are present in zebra fish, as well as a number of major demethylation pathways. However, zebra fish appear to lack some methylation pathways present in mammals, such as parental imprinting. Several studies report effects on DNA methylation in zebra fish following exposure to environmental contaminants, such as arsenic, benzo[a]pyrene, and tris(1,3-dichloro-2-propyl)phosphate. Though more research is needed to examine heritable effects of contaminant exposure on DNA methylation, recent data suggests the usefulness of the zebra fish as a model in environmental epigenetics.

Exposure pathway evaluations for sites that processed asbestos-contaminated vermiculite.

PubMed

Anderson, Barbara A; Dearwent, Steve M; Durant, James T; Dyken, Jill J; Freed, Jennifer A; Moore, Susan McAfee; Wheeler, John S

2005-01-01

The Agency for Toxic Substances and Disease Registry (ATSDR) is currently evaluating the potential public health impacts associated with the processing of asbestos-contaminated vermiculite at various facilities around the country. Vermiculite ore contaminated with significant levels of asbestos was mined and milled in Libby, Montana, from the early 1920s until 1990. The majority of the Libby ore was then shipped to processing facilities for exfoliation. ATSDR initiated the National Asbestos Exposure Review (NAER) to identify and evaluate exposure pathways associated with these processing facilities. This manuscript details ATSDR's phased approach in addressing exposure potential around these sites. As this is an ongoing project, only the results from a selected set of completed site analyses are presented. Historical occupational exposures are the most significant exposure pathway for the site evaluations completed to date. Former workers also probably brought asbestos fibers home on their clothing, shoes, and hair, and their household contacts may have been exposed. Currently, most site-related worker and community exposure pathways have been eliminated. One community exposure pathway of indeterminate significance is the current exposure of individuals through direct contact with waste rock brought home for personal use as fill material, driveway surfacing, or soil amendment. Trace levels of asbestos are present in soil at many of the sites and buried waste rock has been discovered at a few sites; therefore, future worker and community exposure associated with disturbing on-site soil during construction or redevelopment at these sites is also a potential exposure pathway.

Developing confidence in adverse outcome pathway-based ...

EPA Pesticide Factsheets

An adverse outcome pathway (AOP) description linking inhibition of aromatase (cytochrome P450 [cyp] 19) to reproductive dysfunction was reviewed for scientific and technical quality and endorsed by the OECD. An intended application of the AOP framework is to support the use of mechanistic or pathway-based data to infer or predict chemical hazards and apical adverse outcomes. As part of this work, ToxCast high throughput screening data were used to identify a chemicals’ ability to inhibit aromatase activity in vitro. Twenty-four hour in vivo exposures, focused on effects on production and circulating concentrations of 17β-estradiol (E2), key events in the AOP, were conducted to verify in vivo activity. Based on these results, imazalil was selected as a case study chemical to test an AOP-based hazard prediction. A computational model of the fish hypothalamic-pituitary-gonadal-liver axis and a statistically-based model of oocyte growth dynamics were used to predict impacts of different concentrations of imazalil on multiple key events along the AOP, assuming continuous exposure for 21 d. Results of the model simulations were used to select test concentrations and design a fathead minnow reproduction study in which fish were exposed to 20, 60, or 200 µg imazalil/L for durations of 2.5, 10, or 21d. Within 60 h of exposure, female fathead minnows showed significant reductions in ex vivo production of E2, circulating E2 concentrations, and significant increases in

Developing confidence in adverse outcome pathway-based ...

EPA Pesticide Factsheets

An adverse outcome pathway (AOP) description linking inhibition of aromatase (cytochrome P450 [cyp] 19) to reproductive dysfunction was reviewed for scientific and technical quality and endorsed by the OECD (https://aopwiki.org/wiki/index.php/Aop:25). An intended application of the AOP framework is to support the use of mechanistic or pathway-based data to infer or predict chemical hazards and apical adverse outcomes. As part of this work, ToxCast high throughput screening data were used to identify a chemicals’ ability to inhibit aromatase activity in vitro. Twenty-four hour in vivo exposures, focused on effects on production and circulating concentrations of 17â-estradiol (E2), key events in the AOP, were conducted to verify in vivo activity. Based on these results, imazalil was selected as a case study chemical to test an AOP-based hazard prediction. A computational model of the fish hypothalamic-pituitary-gonadal-liver axis and a statistically-based model of oocyte growth dynamics were used to predict impacts of different concentrations of imazalil on multiple key events along the AOP, assuming continuous exposure for 21 d. Results of the model simulations were used to select test concentrations and design a fathead minnow reproduction study in which fish were exposed to 20, 60, or 200 µg imazalil/L for durations of 2.5, 10, or 21d. Within 60 h of exposure, female fathead minnows showed significant reductions in ex vivo production of E2, circulating E2 c

UV exposure, genetic targets in melanocytic tumors and transgenic mouse models.

PubMed

de Gruijl, Frank R; van Kranen, Henk J; van Schanke, Arne

2005-01-01

The genetic changes and corruption of kinase activity in melanomas appear to revolve around a central axis: mitogenic signaling along the RAS pathway down to transcription regulation by pRB. Epidemiological studies point to the importance of ultraviolet (UV) radiation in the etiology of melanoma, but where and how UV radiation is targeted to contribute to the oncogenic signaling remains obscure. Animal models of melanoma genesis could serve to clarify this issue, but many of these models are not responsive to UV exposure. Most interesting advances have been made by using transgenic mice that carry genetic defects that are known to be relevant to human melanoma: specifically, dysfunction in the tumor suppressive action of p16INK4a or a receptor tyrosine kinase/RAS pathway, that is constitutively activated in melanocytes. The latter types of mice appear to be most responsive to (neonatal) UV exposure. Whether this is due to a general increase in target cells by melanocytosis and a paucity or complete lack of pigment, or a possible UV-induced response of the promoter-enhancer of the transgene or a genuinely independent and additional genetic alteration caused by UV exposure needs to be established. Importantly, the full effect of UV radiation needs to be ascertained in mice with different pigmentation by varying the wavelengths, UV-B versus UV-A1, and the exposure schedules, i.e. neonatal versus adult and chronic versus intermittent overexposure. Intermittent UV-B overexposure deserves special attention because it most strongly evokes proliferative responses in melanocytes.

Herpes simplex virus triggers activation of calcium-signaling pathways

PubMed Central

Cheshenko, Natalia; Del Rosario, Brian; Woda, Craig; Marcellino, Daniel; Satlin, Lisa M.; Herold, Betsy C.

2003-01-01

The cellular pathways required for herpes simplex virus (HSV) invasion have not been defined. To test the hypothesis that HSV entry triggers activation of Ca2+-signaling pathways, the effects on intracellular calcium concentration ([Ca2+]i) after exposure of cells to HSV were examined. Exposure to virus results in a rapid and transient increase in [Ca2+]i. Pretreatment of cells with pharmacological agents that block release of inositol 1,4,5-triphosphate (IP3)–sensitive endoplasmic reticulum stores abrogates the response. Moreover, treatment of cells with these pharmacological agents inhibits HSV infection and prevents focal adhesion kinase (FAK) phosphorylation, which occurs within 5 min after viral infection. Viruses deleted in glycoprotein L or glycoprotein D, which bind but do not penetrate, fail to induce a [Ca2+]i response or trigger FAK phosphorylation. Together, these results support a model for HSV infection that requires activation of IP3-responsive Ca2+-signaling pathways and that is associated with FAK phosphorylation. Defining the pathway of viral invasion may lead to new targets for anti-viral therapy. PMID:14568989

Cigarette smoke induced urocystic epithelial mesenchymal transition via MAPK pathways.

PubMed

Yu, Dexin; Geng, Hao; Liu, Zhiqi; Zhao, Li; Liang, Zhaofeng; Zhang, Zhiqiang; Xie, Dongdong; Wang, Yi; Zhang, Tao; Min, Jie; Zhong, Caiyun

2017-01-31

Cigarette smoke has been shown to be a major risk factor for bladder cancer. Epithelial-mesenchymal transition (EMT) is a crucial process in cancer development. The role of MAPK pathways in regulating cigarette smoke-triggered urocystic EMT remains to be elucidated. Human normal urothelial cells and BALB/c mice were used as in vitro and in vivo cigarette smoke exposure models. Exposure of human normal urothelial cells to cigarette smoke induced morphological change, enhanced migratory and invasive capacities, reduced epithelial marker expression and increased mesenchymal marker expression, along with the activation of MAPK pathways. Moreover, we revealed that ERK1/2 and p38 inhibitors, but rather JNK inhibitor, effectively attenuated cigarette smoke-induced urocystic EMT. Importantly, the regulatory function of ERK1/2 and p38 pathways in cigarette smoke-triggered urocystic EMT was further confirmed in mice exposed to CS for 12 weeks. These findings could provide new insight into the molecular mechanisms of cigarette smoke-associated bladder cancer development as well as its potential intervention.

Political violence exposure, adolescent school violence, and drug use: The mediating role of school support and posttraumatic stress.

PubMed

Fang, Lin; Schiff, Miriam; Benbenishty, Rami

2016-01-01

Adolescents may engage in risk behaviors to cope with the negative psychological impacts resulting from exposure to political violence. Guided by the Deterioration Deterrence Model and General Strain Theory, the present study assessed the mediating role of school support and posttraumatic stress (PTS) on two adolescent risk behaviors (i.e., school violence and drug use) among Arab and Jewish Israeli adolescents. We analyzed data from a nationally representative survey that consisted of 4,733 Israeli high school students (54.5% females; 63.2% Jewish) following the Second Lebanon War. Structural equation modeling using weighted data bootstrapped with 2,000 iterations evaluated the mediated effects of school support and PTS. The results showed that both school support and PTS mediated the pathways from political violence exposure to school violence and drug use. However, although school support and PTS fully mediated the relationship between political violence exposure and these risk behaviors for Jewish students, school support and PTS only partially mediated the relationships for Arab students. While school support can help decrease the detrimental effect of exposure to terrorism and war, Israeli adolescents exposed to more political violence may perceive receiving less school support than those experiencing less exposure. Findings of this study provide evidence for the theorized mediated pathways between political violence exposure and adolescent risk behaviors by PTS and school support. The study serves as a basis for future research that can unpack the relationship between exposure to political violence and adolescent risk-taking behaviors. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Relative Contributions of Agricultural Drift, Para-Occupational ...

EPA Pesticide Factsheets

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. Methods: From studies in North American agricultural areas published from 1995-2015, we abstracted dust pesticide concentrations reported as summary statistics (e.g., geometric means (GM)). We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). Results: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (inter-quartile range of published data) based on 52 statistics from 7 studies. For the para-occupational pathway, GMs were 2.3 times higher (95% confidence interval [CI]: 1.5-3.3; 15 statistics, 5 studies) in homes of farmers who applied pesticides more versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95%CI: 1.1-1.4) and 1.5 (95%CI: 1.2-1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for

Multiple pathway asbestos exposure assessment for a Superfund community.

PubMed

Noonan, Curtis W; Conway, Kathrene; Landguth, Erin L; McNew, Tracy; Linker, Laura; Pfau, Jean; Black, Brad; Szeinuk, Jaime; Flores, Raja

2015-01-01

Libby, MT, USA, was the home to workers at a historical vermiculite mining facility and served as the processing and distribution center for this industrial product that was contaminated with amphibole asbestos. Several pathways of environmental asbestos exposure to the general population have been identified. The local clinic and health screening program collects data from participants on past occupational and environmental exposures to vermiculite and asbestos. Health studies among this population have demonstrated associations between amphibole exposure and health outcomes, but critical questions regarding the nature and level of exposure associated with specific outcomes remain unanswered. The objective of this study was to develop a comprehensive exposure assessment approach that integrates information on individuals' contact frequency with multiple exposure pathways. For 3031 participants, we describe cumulative exposure metrics for environmental exposures, occupational exposures, and residents' contact with carry-home asbestos from household workers. As expected, cumulative exposures for all three occupational categories were higher among men compared with women, and cumulative exposures for household contact and environmental pathways were higher among women. The comprehensive exposure assessment strategies will advance health studies and risk assessment approaches in this population with a complex history of both occupational and environmental asbestos exposure.

Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Nanoparticle Titanium Dioxide

EPA Science Inventory

Identification of toxicity pathways linked to chemical -exposure is critical for a better understanding of biological effects of the exposure, toxic mechanisms, and for enhancement of the prediction of chemical toxicity and adverse health outcomes. To identify toxicity pathways a...

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2011 CFR

2011-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2014 CFR

2014-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2013 CFR

2013-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2010 CFR

2010-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2012 CFR

2012-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

Human primordial germ cell formation is diminished by exposure to environmental toxicants acting through the AHR signaling pathway.

PubMed

Kee, Kehkooi; Flores, Martha; Cedars, Marcelle I; Reijo Pera, Renee A

2010-09-01

Historically, effects of environmental toxicants on human development have been deduced via epidemiological studies because direct experimental analysis has not been possible. However, in recent years, the derivation of human pluripotent stem cells has provided a potential experimental system to directly probe human development. Here, we used human embryonic stem cells (hESCs) to study the effect of environmental toxicants on human germ cell development, with a focus on differentiation of the founding population of primordial germ cells (PGCs), which will go on to form the oocytes of the adult. We demonstrate that human PGC numbers are specifically reduced by exposure to polycyclic aromatic hydrocarbons (PAHs), a group of toxicants common in air pollutants released from gasoline combustion or tobacco smoke. Further, we demonstrate that the adverse effects of PAH exposure are mediated through the aromatic hydrocarbon receptor (AHR) and BAX pathway. This study demonstrates the utility of hESCs as a model system for direct examination of the molecular and genetic pathways of environmental toxicants on human germ cell development.

The Virtual Liver Project: Modeling Tissue Response To Chemicals Through Multiscale Simulation

EPA Science Inventory

The US EPA Virtual Liver Project is aimed at simulating the risk of toxic effects from environmental chemicals in silico. The computational systems model of organ injury due to chronic chemical exposure is based on: (i) the dynamics of perturbed molecular pathways, (ii) their lin...

Causal pathways linking environmental change with health behaviour change: Natural experimental study of new transport infrastructure and cycling to work.

PubMed

Prins, R G; Panter, J; Heinen, E; Griffin, S J; Ogilvie, D B

2016-06-01

Mechanisms linking changes to the environment with changes in physical activity are poorly understood. Insights into mechanisms of interventions can help strengthen causal attribution and improve understanding of divergent response patterns. We examined the causal pathways linking exposure to new transport infrastructure with changes in cycling to work. We used baseline (2009) and follow-up (2012) data (N=469) from the Commuting and Health in Cambridge natural experimental study (Cambridge, UK). Exposure to new infrastructure in the form of the Cambridgeshire Guided Busway was defined using residential proximity. Mediators studied were changes in perceptions of the route to work, theory of planned behaviour constructs and self-reported use of the new infrastructure. Outcomes were modelled as an increase, decrease or no change in weekly cycle commuting time. We used regression analyses to identify combinations of mediators forming potential pathways between exposure and outcome. We then tested these pathways in a path model and stratified analyses by baseline level of active commuting. We identified changes in perceptions of the route to work, and use of the cycle path, as potential mediators. Of these potential mediators, only use of the path significantly explained (85%) the effect of the infrastructure in increasing cycling. Path use also explained a decrease in cycling among more active commuters. The findings strengthen the causal argument that changing the environment led to changes in health-related behaviour via use of the new infrastructure, but also show how some commuters may have spent less time cycling as a result. Copyright © 2016. Published by Elsevier Inc.

SAGE Analysis of Transcriptome Responses in Arabidopsis Roots Exposed to 2,4,6-Trinitrotoluene1

PubMed Central

Ekman, Drew R.; Lorenz, W. Walter; Przybyla, Alan E.; Wolfe, N. Lee; Dean, Jeffrey F.D.

2003-01-01

Serial analysis of gene expression was used to profile transcript levels in Arabidopsis roots and assess their responses to 2,4,6-trinitrotoluene (TNT) exposure. SAGE libraries representing control and TNT-exposed seedling root transcripts were constructed, and each was sequenced to a depth of roughly 32,000 tags. More than 19,000 unique tags were identified overall. The second most highly induced tag (27-fold increase) represented a glutathione S-transferase. Cytochrome P450 enzymes, as well as an ABC transporter and a probable nitroreductase, were highly induced by TNT exposure. Analyses also revealed an oxidative stress response upon TNT exposure. Although some increases were anticipated in light of current models for xenobiotic metabolism in plants, evidence for unsuspected conjugation pathways was also noted. Identifying transcriptome-level responses to TNT exposure will better define the metabolic pathways plants use to detoxify this xenobiotic compound, which should help improve phytoremediation strategies directed at TNT and other nitroaromatic compounds. PMID:14551330

Differential reconstructed gene interaction networks for deriving toxicity threshold in chemical risk assessment.

PubMed

Yang, Yi; Maxwell, Andrew; Zhang, Xiaowei; Wang, Nan; Perkins, Edward J; Zhang, Chaoyang; Gong, Ping

2013-01-01

Pathway alterations reflected as changes in gene expression regulation and gene interaction can result from cellular exposure to toxicants. Such information is often used to elucidate toxicological modes of action. From a risk assessment perspective, alterations in biological pathways are a rich resource for setting toxicant thresholds, which may be more sensitive and mechanism-informed than traditional toxicity endpoints. Here we developed a novel differential networks (DNs) approach to connect pathway perturbation with toxicity threshold setting. Our DNs approach consists of 6 steps: time-series gene expression data collection, identification of altered genes, gene interaction network reconstruction, differential edge inference, mapping of genes with differential edges to pathways, and establishment of causal relationships between chemical concentration and perturbed pathways. A one-sample Gaussian process model and a linear regression model were used to identify genes that exhibited significant profile changes across an entire time course and between treatments, respectively. Interaction networks of differentially expressed (DE) genes were reconstructed for different treatments using a state space model and then compared to infer differential edges/interactions. DE genes possessing differential edges were mapped to biological pathways in databases such as KEGG pathways. Using the DNs approach, we analyzed a time-series Escherichia coli live cell gene expression dataset consisting of 4 treatments (control, 10, 100, 1000 mg/L naphthenic acids, NAs) and 18 time points. Through comparison of reconstructed networks and construction of differential networks, 80 genes were identified as DE genes with a significant number of differential edges, and 22 KEGG pathways were altered in a concentration-dependent manner. Some of these pathways were perturbed to a degree as high as 70% even at the lowest exposure concentration, implying a high sensitivity of our DNs approach. Findings from this proof-of-concept study suggest that our approach has a great potential in providing a novel and sensitive tool for threshold setting in chemical risk assessment. In future work, we plan to analyze more time-series datasets with a full spectrum of concentrations and sufficient replications per treatment. The pathway alteration-derived thresholds will also be compared with those derived from apical endpoints such as cell growth rate.

Helminth–host immunological interactions: prevention and control of immune-mediated diseases

PubMed Central

Elliott, David E.; Weinstock, Joel V.

2013-01-01

Exposure to commensal and pathogenic organisms strongly influences our immune system. Exposure to helminths was frequent before humans constructed their current highly hygienic environment. Today, in highly industrialized countries, contact between humans and helminths is rare. Congruent with the decline in helminth infections is an increase in the prevalence of autoimmune and inflammatory disease. It is possible that exclusion of helminths from the environment has permitted the emergence of immune-mediated disease. We review the protective effects of helminths on expression of inflammatory bowel disease, multiple sclerosis, and animal models of these and other inflammatory diseases. We also review the immune pathways altered by helminths that may afford protection from these illnesses. Helminth exposure tends to inhibit IFN-γ and IL-17 production, promote IL-4, IL-10, and TGF-β release, induce CD4+ T cell Foxp3 expression, and generate regulatory macrophages, dendritic cells, and B cells. Helminths enable protective pathways that may vary by specific species and disease model. Helminths or their products likely have therapeutic potential to control or prevent immune-mediated illness. PMID:22239614

A quantitative visual dashboard to explore exposures to ...

EPA Pesticide Factsheets

The Exposure Prioritization (Ex Priori) model features a simplified, quantitative visual dashboard to explore exposures across chemical space. Diverse data streams are integrated within the interface such that different exposure scenarios for “individual,” “population,” or “professional” time-use profiles can be interchanged to tailor exposure and quantitatively explore multi-chemical signatures of exposure, internalized dose (uptake), body burden, and elimination. Ex Priori will quantitatively extrapolate single-point estimates of both exposure and internal dose for multiple exposure scenarios, factors, products, and pathways. Currently, EPA is investigating its usefulness in life cycle analysis, insofar as its ability to enhance exposure factors used in calculating characterization factors for human health. Presented at 2016 Annual ISES Meeting held in Utrecht, The Netherlands, from 9-13 October 2016.

44 CFR 350.5 - Criteria for review and approval of State and local radiological emergency plans and preparedness.

Code of Federal Regulations, 2013 CFR

2013-10-01

... populace within the plume exposure pathway Emergency Planning Zone have been established. (6) Provisions... plume exposure pathway EPZ for emergency workers and the public. Guidelines for the choice of protective... actions for the ingestion exposure pathway EPZ appropriate to the locale have been developed. (11) Means...

44 CFR 350.5 - Criteria for review and approval of State and local radiological emergency plans and preparedness.

Code of Federal Regulations, 2012 CFR

2012-10-01

... populace within the plume exposure pathway Emergency Planning Zone have been established. (6) Provisions... plume exposure pathway EPZ for emergency workers and the public. Guidelines for the choice of protective... actions for the ingestion exposure pathway EPZ appropriate to the locale have been developed. (11) Means...

44 CFR 350.5 - Criteria for review and approval of State and local radiological emergency plans and preparedness.

Code of Federal Regulations, 2014 CFR

2014-10-01

... populace within the plume exposure pathway Emergency Planning Zone have been established. (6) Provisions... plume exposure pathway EPZ for emergency workers and the public. Guidelines for the choice of protective... actions for the ingestion exposure pathway EPZ appropriate to the locale have been developed. (11) Means...

System-based Identification of Toxicity Pathways Associated With Multi-Walled Carbon Nanotube-Induced Pathological Responses

PubMed Central

Snyder-Talkington, Brandi N.; Dymacek, Julian; Porter, Dale W.; Wolfarth, Michael G.; Mercer, Robert R.; Pacurari, Maricica; Denvir, James; Castranova, Vincent; Qian, Yong; Guo, Nancy L.

2014-01-01

The fibrous shape and biopersistence of multi-walled carbon nanotubes (MWCNT) have raised concern over their potential toxicity after pulmonary exposure. As in vivo exposure to MWCNT produced a transient inflammatory and progressive fibrotic response, this study sought to identify significant biological processes associated with lung inflammation and fibrosis pathology data, based upon whole genome mRNA expression, bronchoaveolar lavage scores, and morphometric analysis from C57BL/6J mice exposed by pharyngeal aspiration to 0, 10, 20, 40, or 80 µg MWCNT at 1, 7, 28, or 56 days post-exposure. Using a novel computational model employing non-negative matrix factorization and Monte Carlo Markov Chain simulation, significant biological processes with expression similar to MWCNT-induced lung inflammation and fibrosis pathology data in mice were identified. A subset of genes in these processes was determined to be functionally related to either fibrosis or inflammation by Ingenuity Pathway Analysis and were used to determine potential significant signaling cascades. Two genes determined to be functionally related to inflammation and fibrosis, vascular endothelial growth factor A (vegfa) and C-C motif chemokine 2 (ccl2), were confirmed by in vitro studies of mRNA and protein expression in small airway epithelial cells exposed to MWCNT as concordant with in vivo expression. This study identified that the novel computational model was sufficient to determine biological processes strongly associated with the pathology of lung inflammation and fibrosis and could identify potential toxicity signaling pathways and mechanisms of MWCNT exposure which could be used for future animal studies to support human risk assessment and intervention efforts. PMID:23845593

Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Jintao; Zhu, Dexiao; Zhang, Jing

Methamphetamine (MA) is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to MA causes psychosis and increases the risk of Parkinson's disease. Lithium (Li) is a known mood stabilizer and has neuroprotective effects. Previous studies suggest that MA exposure decreases the phosphorylation of Akt/GSK3β pathway in vivo, whereas Li facilitates the phosphorylation of Akt/GSK3β pathway. Moreover, GSK3β and mTOR are implicated in the locomotor sensitization induced by psychostimulants and mTOR plays a critical role in MA induced toxicity. However, the effect of MA on Akt/GSK3β/mTOR pathway has not been fully investigated in vitro. Here, we found that MA exposure significantly dephosphorylated Akt/GSK3β/mTOR pathwaymore » in PC12 cells. In addition, Li remarkably attenuated the dephosphorylation effect of MA exposure on Akt/GSK3β/mTOR pathway. Furthermore, Li showed obvious protective effects against MA toxicity and LY294002 (Akt inhibitor) suppressed the protective effects of Li. Together, MA exposure dephosphorylates Akt/GSK3β/mTOR pathway in vitro, while lithium protects against MA-induced neurotoxicity via phosphorylation of Akt/GSK3β/mTOR pathway. - Highlights: • Lithium protects against methamphetamine-induced neurotoxicity in vitro. • Methamphetamine exposure dephosphorylates Akt/GSK3β/mTOR pathway. • Lithium attenuates methamphetamine-induced toxicity via phosphorylating Akt/GSK3β/mTOR pathway.« less

Investigation and health risk assessment of heavy metals in soils from partial areas of Daye city, china

NASA Astrophysics Data System (ADS)

Xiao, M. S.; Li, F.; Zhang, J. D.; Lin, S. Y.; Zhuang, Z. Y.; Wu, Z. X.

2017-05-01

Heavy metals (Cu and Pb) in four sampling sites from parts areas of Daye city were collected. Concentrations of Cu and Pb in soils in sampling sites were detected, the enrichment degree was measured by geo-accumulation index, and the human health risks were calculated by applying the human health risk assessment model. The results show that the concentrations of Cu and Pb of soils in some areas are much more than Daye City, Hubei Province soil background value. The concentration of Cu and Pb in Xiaganwan soil sample has a higher value and the concentration of Cu (110.17 mg·kg-1) exceeds the soil environmental quality standards. The values of Igeo of Cu and Pb in the soil in some areas of Daye city are 1 except Xiaganwan sample is 2. For human health risk assessment, the non-cancer risk of Cu in three routes of exposure is less than Pb. The non-cancer risk both adults and children are less than 1 and show a general trend of HQ in oral ingestion exposure pathway > HQ in inhalation exposure pathway>HQ in skin contact exposure pathway. It will not cause significant non-carcinogenic health effects on the human body.

Multi-pathway exposure modelling of chemicals in cosmetics ...

EPA Pesticide Factsheets

We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based on the chemical mass originally applied via a product, multiplied by the product intake fractions (PiF, the fraction of a chemical in a product that is taken in by exposed persons) to yield intake rates. The average PiFs for the evaluated chemicals in shampoo ranged from 3 × 10− 4 up to 0.3 for rapidly absorbed ingredients. Average intake rates ranged between nano- and micrograms per kilogram bodyweight per day; the order of chemical prioritization was strongly affected by the ingredient concentration in shampoo. Dermal intake and inhalation (for 20% of the evaluated chemicals) during use dominated exposure, while the skin permeation coefficient dominated the estimated uncertainties. The fraction of chemical taken in by a shampoo user often exceeded, by orders of magnitude, the aggregated fraction taken in by the population through post-use environmental emissions. Chemicals with relatively high octanol-water partitioning and/or volatility, and low molecular weight tended to have higher use stage exposure. Chemicals with low intakes during use (< 1%) and subsequent high post-use emissions, however, may yield comparable intake for a member of the general population. The pre

Testing pathways linking exposure to community violence and sexual behaviors among African American youth.

PubMed

Voisin, Dexter R; Hotton, Anna L; Neilands, Torsten B

2014-09-01

Exposure to community violence and HIV sexual risks are two major public health concerns among youth. This study tests various pathways linking exposure to community violence and sexual behaviors among African American adolescents. Using a sample of 563 (61% females) African American youth attending high school we examined whether problematic psychological symptoms, low school engagement, and/or negative perceptions of peer norms about safer sex functioned as pathways linking exposure to community violence and sexual behaviors. Major findings indicated that, for boys, the relationship between exposure to community violence and sexual début and sexual risk behaviors were linked by aggression. In addition, the relationship between exposure to community violence and sexual risk behaviors were linked by negative perceptions of peer attitudes about safer sex. For girls, the relationship between exposure to community violence and sexual début was linked by aggression and negative perceptions of peer attitudes about safer sex. These findings provide support for pathways linking exposure to community violence to sexual behaviors.

Testing Pathways Linking Exposure to Community Violence and Sexual Behaviors Among African American Youth

PubMed Central

Hotton, Anna L.; Neilands, Torsten B.

2014-01-01

Exposure to community violence and HIV sexual risks are two major public health concerns among youth. This study tests various pathways linking exposure to community violence and sexual behaviors among African American adolescents. Using a sample of 563 (61 % females) African American youth attending high school we examined whether problematic psychological symptoms, low school engagement, and/or negative perceptions of peer norms about safer sex functioned as pathways linking exposure to community violence and sexual behaviors. Major findings indicated that, for boys, the relationship between exposure to community violence and sexual début and sexual risk behaviors were linked by aggression. In addition, the relationship between exposure to community violence and sexual risk behaviors were linked by negative perceptions of peer attitudes about safer sex. For girls, the relationship between exposure to community violence and sexual début was linked by aggression and negative perceptions of peer attitudes about safer sex. These findings provide support for pathways linking exposure to community violence to sexual behaviors. PMID:24327295

Emsoft User's Guide and Modeling Software (1997)

EPA Science Inventory

Chemicals that readily vaporize at relatively low temperatures can migrate from contaminated soils into the atmosphere via a process called volatilization. Volatilization represents a potentially significant exposure pathway because humans can come in contact with volatilized com...

Emsoft User's Guide and Modeling Software (2002 Update)

EPA Science Inventory

Chemicals that readily vaporize at relatively low temperatures can migrate from contaminated soils into the atmosphere via a process called volatilization. Volatilization represents a potentially significant exposure pathway because humans can come in contact with volatilized com...

Three multimedia models used at hazardous and radioactive waste sites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moskowitz, P.D.; Pardi, R.; Fthenakis, V.M.

1996-02-01

Multimedia models are used commonly in the initial phases of the remediation process where technical interest is focused on determining the relative importance of various exposure pathways. This report provides an approach for evaluating and critically reviewing the capabilities of multimedia models. This study focused on three specific models MEPAS Version 3.0, MMSOILS Version 2.2, and PRESTO-EPA-CPG Version 2.0. These models evaluate the transport and fate of contaminants from source to receptor through more than a single pathway. The presence of radioactive and mixed wastes at a site poses special problems. Hence, in this report, restrictions associated with the selectionmore » and application of multimedia models for sites contaminated with radioactive and mixed wastes are highlighted. This report begins with a brief introduction to the concept of multimedia modeling, followed by an overview of the three models. The remaining chapters present more technical discussions of the issues associated with each compartment and their direct application to the specific models. In these analyses, the following components are discussed: source term; air transport; ground water transport; overland flow, runoff, and surface water transport; food chain modeling; exposure assessment; dosimetry/risk assessment; uncertainty; default parameters. The report concludes with a description of evolving updates to the model; these descriptions were provided by the model developers.« less

Green tea catechin intervention of reactive oxygen species-mediated ERK pathway activation and chronically induced breast cell carcinogenesis

PubMed Central

Rathore, Kusum; Choudhary, Shambhunath; Odoi, Agricola; Wang, Hwa-Chain R.

2012-01-01

Long-term exposure to low doses of environmental carcinogens contributes to sporadic human breast cancers. Epidemiologic and experimental studies indicate that green tea catechins (GTCs) may intervene with breast cancer development. We have been developing a chronically induced breast cell carcinogenesis model wherein we repeatedly expose non-cancerous, human breast epithelial MCF10A cells to bioachievable picomolar concentrations of environmental carcinogens, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), to progressively induce cellular acquisition of cancer-associated properties, as measurable end points. The model is then used as a target to identify non-cytotoxic preventive agents effective in suppression of cellular carcinogenesis. Here, we demonstrate, for the first time, a two-step strategy that initially used end points that were transiently induced by short-term exposure to NNK and B[a]P as targets to detect GTCs capable of blocking the acquisition of cancer-associated properties and subsequently used end points constantly induced by long-term exposure to carcinogens as targets to verify GTCs capable of suppressing carcinogenesis. We detected that short-term exposure to NNK and B[a]P resulted in elevation of reactive oxygen species (ROS), leading to Raf-independent extracellular signal-regulated kinase (ERK) pathway activation and subsequent induction of cell proliferation and DNA damage. These GTCs, at non-cytotoxic levels, were able to suppress chronically induced cellular carcinogenesis by blocking carcinogen-induced ROS elevation, ERK activation, cell proliferation and DNA damage in each exposure cycle. Our model may help accelerate the identification of preventive agents to intervene in carcinogenesis induced by long-term exposure to environmental carcinogens, thereby safely and effectively reducing the health risk of sporadic breast cancer. PMID:22045026

The potential impacts of 21st century climatic and population changes on human exposure to the virus vector mosquito Aedes aegypti.

PubMed

Monaghan, A J; Sampson, K M; Steinhoff, D F; Ernst, K C; Ebi, K L; Jones, B; Hayden, M H

2018-02-01

The mosquito Aedes (Ae). aegypti transmits the viruses that cause dengue and chikungunya, two globally-important vector-borne diseases. We investigate how choosing alternate emissions and/or socioeconomic pathways may modulate future human exposure to Ae. aegypti . Occurrence patterns for Ae. aegypti for 2061-2080 are mapped globally using empirically downscaled air temperature and precipitation projections from the Community Earth System Model, for the Representative Concentration Pathway (RCP) 4.5 and 8.5 scenarios. Population growth is quantified using gridded global population projections consistent with two Shared Socioeconomic Pathways (SSPs), SSP3 and SSP5. Change scenarios are compared to a 1950-2000 reference period. A global land area of 56.9 M km 2 is climatically suitable for Ae. aegypti during the reference period, and is projected to increase by 8% (RCP4.5) to 13% (RCP8.5) by 2061-2080. The annual average number of people exposed globally to Ae. aegypti for the reference period is 3794 M, a value projected to statistically significantly increase by 298-460 M (8-12%) by 2061-2080 if only climate change is considered, and by 4805-5084 M (127-134%) for SSP3 and 2232-2483 M (59-65%) for SSP5 considering both climate and population change (lower and upper values of each range represent RCP4.5 and RCP8.5 respectively). Thus, taking the lower-emissions RCP4.5 pathway instead of RCP8.5 may mitigate future human exposure to Ae. aegypti globally, but the effect of population growth on exposure will likely be larger. Regionally, Australia, Europe and North America are projected to have the largest percentage increases in human exposure to Ae. aegypti considering only climate change.

Role of hippocampal β-adrenergic and glucocorticoid receptors in the novelty-induced enhancement of fear extinction.

PubMed

Liu, Jian-Feng; Yang, Chang; Deng, Jia-Hui; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao; Shi, Hai-Shui; Meng, Shi-Qiu; Chai, Bai-Sheng; Fang, Qin; Chai, Ning; Xue, Yan-Xue; Sun, Jia; Chen, Chen; Wang, Xue-Yi; Wang, Ji-Shi; Lu, Lin

2015-05-27

Fear extinction forms a new memory but does not erase the original fear memory. Exposure to novelty facilitates transfer of short-term extinction memory to long-lasting memory. However, the underlying cellular and molecular mechanisms are still unclear. Using a classical contextual fear-conditioning model, we investigated the effect of novelty on long-lasting extinction memory in rats. We found that exposure to a novel environment but not familiar environment 1 h before or after extinction enhanced extinction long-term memory (LTM) and reduced fear reinstatement. However, exploring novelty 6 h before or after extinction had no such effect. Infusion of the β-adrenergic receptor (βAR) inhibitor propranolol and glucocorticoid receptor (GR) inhibitor RU486 into the CA1 area of the dorsal hippocampus before novelty exposure blocked the effect of novelty on extinction memory. Propranolol prevented activation of the hippocampal PKA-CREB pathway, and RU486 prevented activation of the hippocampal extracellular signal-regulated kinase 1/2 (Erk1/2)-CREB pathway induced by novelty exposure. These results indicate that the hippocampal βAR-PKA-CREB and GR-Erk1/2-CREB pathways mediate the extinction-enhancing effect of novelty exposure. Infusion of RU486 or the Erk1/2 inhibitor U0126, but not propranolol or the PKA inhibitor Rp-cAMPS, into the CA1 before extinction disrupted the formation of extinction LTM, suggesting that hippocampal GR and Erk1/2 but not βAR or PKA play critical roles in this process. These results indicate that novelty promotes extinction memory via hippocampal βAR- and GR-dependent pathways, and Erk1/2 may serve as a behavioral tag of extinction. Copyright © 2015 the authors 0270-6474/15/358308-14$15.00/0.

A changing climate: impacts on human exposures to O3 using ...

EPA Pesticide Factsheets

Predicting the impacts of changing climate on human exposure to air pollution requires future scenarios that account for changes in ambient pollutant concentrations, population sizes and distributions, and housing stocks. An integrated methodology to model changes in human exposures due to these impacts was developed by linking climate, air quality, land-use, and human exposure models. This methodology was then applied to characterize changes in predicted human exposures to O3 under multiple future scenarios. Regional climate projections for the U.S. were developed by downscaling global circulation model (GCM) scenarios for three of the Intergovernmental Panel on Climate Change’s (IPCC’s) Representative Concentration Pathways (RCPs) using the Weather Research and Forecasting (WRF) model. The regional climate results were in turn used to generate air quality (concentration) projections using the Community Multiscale Air Quality (CMAQ) model. For each of the climate change scenarios, future U.S. census-tract level population distributions from the Integrated Climate and Land Use Scenarios (ICLUS) model for four future scenarios based on the IPCC’s Special Report on Emissions Scenarios (SRES) storylines were used. These climate, air quality, and population projections were used as inputs to EPA’s Air Pollutants Exposure (APEX) model for 12 U.S. cities. Probability density functions show changes in the population distribution of 8 h maximum daily O3 exposur

Halobenzoquinone-Induced Alteration of Gene Expression Associated with Oxidative Stress Signaling Pathways.

PubMed

Li, Jinhua; Moe, Birget; Liu, Yanming; Li, Xing-Fang

2018-06-05

Halobenzoquinones (HBQs) are emerging disinfection byproducts (DBPs) that effectively induce reactive oxygen species and oxidative damage in vitro. However, the impacts of HBQs on oxidative-stress-related gene expression have not been investigated. In this study, we examined alterations in the expression of 44 genes related to oxidative-stress-induced signaling pathways in human uroepithelial cells (SV-HUC-1) upon exposure to six HBQs. The results show the structure-dependent effects of HBQs on the studied gene expression. After 2 h of exposure, the expression levels of 9 to 28 genes were altered, while after 8 h of exposure, the expression levels of 29 to 31 genes were altered. Four genes ( HMOX1, NQO1, PTGS2, and TXNRD1) were significantly upregulated by all six HBQs at both exposure time points. Ingenuity pathway analysis revealed that the Nrf2 pathway was significantly responsive to HBQ exposure. Other canonical pathways responsive to HBQ exposure included GSH redox reductions, superoxide radical degradation, and xenobiotic metabolism signaling. This study has demonstrated that HBQs significantly alter the gene expression of oxidative-stress-related signaling pathways and contributes to the understanding of HBQ-DBP-associated toxicity.

Physiologically-based Pharmacokinetic(PBPK) Models Application to Screen Environmental Hazards Related to Adverse Outcome Pathways(AOPs)

EPA Science Inventory

PBPK models are useful in estimating exposure levels based on in vitro to in vivo extrapolation (IVIVE) calculations. Linkage of large sets of chemically screened vitro signature effects to in vivo adverse outcomes using IVIVE is central to the concepts of toxicology in the 21st ...

Modeling the impact of growth and leptin deficits on the neuronal regulation of blood pressure.

PubMed

Steinbrekera, Baiba; Roghair, Robert

2016-11-01

The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency and aberration in sex hormone levels. As a neurotrophic hormone that is intimately involved in the cardiovascular regulation and whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus a therapeutic agent. As a product of maternal and late fetal adipocytes and the placenta, circulating leptin typically surges late in gestation and declines after delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish the circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction-adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates the leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation. © 2016 Society for Endocrinology.

Modeling the Impact of Growth and Leptin Deficits on the Neuronal Regulation of Blood Pressure

PubMed Central

Steinbrekera, Baiba; Roghair, Robert

2016-01-01

The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency, and aberration in sex hormone levels. As a neurotrophic hormone intimately involved in cardiovascular regulation whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus therapeutic agent. As a product of maternal and late fetal adipocytes as well as the placenta, circulating leptin typically surges late in gestation and declines following delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction-adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation. PMID:27613336

DESIGN STRATEGY FOR ASSESSING MULTI-PATHWAY EXPOSURE FOR CHILDREN: THE MINNESOTA CHILDREN'S PESTICIDE EXPOSURE STUDY (MNCPES)

EPA Science Inventory

Although children are exposed to a variety of environmental hazards, including pesticides, there is a scarcity of information available to estimate exposures realistically. This article reports on one of the first attempts to measure multi-pathway pesticide exposures in a popu...

Petroleum Release Assessment and Impacts of Weather Extremes

EPA Science Inventory

Contaminated ground water and vapor intrusion are two major exposure pathways of concern at petroleum release sites. EPA has recently developed a model for petroleum vapor intrusion, called PVIScreen, which incorporates variability and uncertainty in input parameters. This ap...

MATHEMATICAL MODEL OF METABOLIC PATHWAYS OF STEROIDOGENESIS TO PREDICT MOLECULAR RESPONSE FOR ENDOCRINE DISRUPTING CHEMICALS.

EPA Science Inventory

There is increasing evidence that exposure to endocrine disrupting chemicals (EDCs) in the environment can induce adverse effects on reproduction and development in both humans and wildlife, mediated through hormonal disturbances.

Evolution of Antibody-Drug Conjugate Tumor Disposition Model to Predict Preclinical Tumor Pharmacokinetics of Trastuzumab-Emtansine (T-DM1).

PubMed

Singh, Aman P; Maass, Katie F; Betts, Alison M; Wittrup, K Dane; Kulkarni, Chethana; King, Lindsay E; Khot, Antari; Shah, Dhaval K

2016-07-01

A mathematical model capable of accurately characterizing intracellular disposition of ADCs is essential for a priori predicting unconjugated drug concentrations inside the tumor. Towards this goal, the objectives of this manuscript were to: (1) evolve previously published cellular disposition model of ADC with more intracellular details to characterize the disposition of T-DM1 in different HER2 expressing cell lines, (2) integrate the improved cellular model with the ADC tumor disposition model to a priori predict DM1 concentrations in a preclinical tumor model, and (3) identify prominent pathways and sensitive parameters associated with intracellular activation of ADCs. The cellular disposition model was augmented by incorporating intracellular ADC degradation and passive diffusion of unconjugated drug across tumor cells. Different biomeasures and chemomeasures for T-DM1, quantified in the companion manuscript, were incorporated into the modified model of ADC to characterize in vitro pharmacokinetics of T-DM1 in three HER2+ cell lines. When the cellular model was integrated with the tumor disposition model, the model was able to a priori predict tumor DM1 concentrations in xenograft mice. Pathway analysis suggested different contribution of antigen-mediated and passive diffusion pathways for intracellular unconjugated drug exposure between in vitro and in vivo systems. Global and local sensitivity analyses revealed that non-specific deconjugation and passive diffusion of the drug across tumor cell membrane are key parameters for drug exposure inside a cell. Finally, a systems pharmacokinetic model for intracellular processing of ADCs has been proposed to highlight our current understanding about the determinants of ADC activation inside a cell.

How cigarette smoking may increase the risk of anxiety symptoms and anxiety disorders: a critical review of biological pathways

PubMed Central

Moylan, Steven; Jacka, Felice N; Pasco, Julie A; Berk, Michael

2013-01-01

Multiple studies have demonstrated an association between cigarette smoking and increased anxiety symptoms or disorders, with early life exposures potentially predisposing to enhanced anxiety responses in later life. Explanatory models support a potential role for neurotransmitter systems, inflammation, oxidative and nitrosative stress, mitochondrial dysfunction, neurotrophins and neurogenesis, and epigenetic effects, in anxiety pathogenesis. All of these pathways are affected by exposure to cigarette smoke components, including nicotine and free radicals. This review critically examines and summarizes the literature exploring the role of these systems in increased anxiety and how exposure to cigarette smoke may contribute to this pathology at a biological level. Further, this review explores the effects of cigarette smoke on normal neurodevelopment and anxiety control, suggesting how exposure in early life (prenatal, infancy, and adolescence) may predispose to higher anxiety in later life. A large heterogenous literature was reviewed that detailed the association between cigarette smoking and anxiety symptoms and disorders with structural brain changes, inflammation, and cell-mediated immune markers, markers of oxidative and nitrosative stress, mitochondrial function, neurotransmitter systems, neurotrophins and neurogenesis. Some preliminary data were found for potential epigenetic effects. The literature provides some support for a potential interaction between cigarette smoking, anxiety symptoms and disorders, and the above pathways; however, limitations exist particularly in delineating causative effects. The literature also provides insight into potential effects of cigarette smoke, in particular nicotine, on neurodevelopment. The potential treatment implications of these findings are discussed in regards to future therapeutic targets for anxiety. The aforementioned pathways may help mediate increased anxiety seen in people who smoke. Further research into the specific actions of nicotine and other cigarette components on these pathways, and how these pathways interact, may provide insights that lead to new treatment for anxiety and a greater understanding of anxiety pathogenesis. PMID:23785661

Coal seam gas water: potential hazards and exposure pathways in Queensland.

PubMed

Navi, Maryam; Skelly, Chris; Taulis, Mauricio; Nasiri, Shahram

2015-01-01

The extraction of coal seam gas (CSG) produces large volumes of potentially contaminated water. It has raised concerns about the environmental health impacts of the co-produced CSG water. In this paper, we review CSG water contaminants and their potential health effects in the context of exposure pathways in Queensland's CSG basins. The hazardous substances associated with CSG water in Queensland include fluoride, boron, lead and benzene. The exposure pathways for CSG water are (1) water used for municipal purposes; (2) recreational water activities in rivers; (3) occupational exposures; (4) water extracted from contaminated aquifers; and (5) indirect exposure through the food chain. We recommend mapping of exposure pathways into communities in CSG regions to determine the potentially exposed populations in Queensland. Future efforts to monitor chemicals of concern and consolidate them into a central database will build the necessary capability to undertake a much needed environmental health impact assessment.

Chemical-agnostic hazard prediction: statistical inference of in vitro toxicity pathways from proteomics responses to chemical mixtures

EPA Science Inventory

Toxicity pathways have been defined as normal cellular pathways that, when sufficiently perturbed as a consequence of chemical exposure, lead to an adverse outcome. If an exposure alters one or more normal biological pathways to an extent that leads to an adverse toxicity outcome...

Application of a framework for extrapolating chemical effects ...

EPA Pesticide Factsheets

Cross-species extrapolation of toxicity data from limited surrogate test organisms to all wildlife with potential of chemical exposure remains a key challenge in ecological risk assessment. A number of factors affect extrapolation, including the chemical exposure, pharmacokinetics, life-stage, and pathway similarities/differences. Here we propose a framework using a tiered approach for species extrapolation that enables a transparent weight-of-evidence driven evaluation of pathway conservation (or lack thereof) in the context of adverse outcome pathways. Adverse outcome pathways describe the linkages from a molecular initiating event, defined as the chemical-biomolecule interaction, through subsequent key events leading to an adverse outcome of regulatory concern (e.g., mortality, reproductive dysfunction). Tier 1 of the extrapolation framework employs in silico evaluations of sequence and structural conservation of molecules (e.g., receptors, enzymes) associated with molecular initiating events or upstream key events. Such evaluations make use of available empirical and sequence data to assess taxonomic relevance. Tier 2 uses in vitro bioassays, such as enzyme inhibition/activation, competitive receptor binding, and transcriptional activation assays to explore functional conservation of pathways across taxa. Finally, Tier 3 provides a comparative analysis of in vivo responses between species utilizing well-established model organisms to assess departure from

Chemical-agnostic hazard prediction: statistical inference of in ...

EPA Pesticide Factsheets

Toxicity pathways have been defined as normal cellular pathways that, when sufficiently perturbed as a consequence of chemical exposure, lead to an adverse outcome. If an exposure alters one or more normal biological pathways to an extent that leads to an adverse toxicity outcome, a significant correlation must exist between the exposure, the extent of pathway alteration, and the degree of adverse outcome. Biological pathways are regulated at multiple levels, including transcriptional, post-transcriptional, post-translational, and targeted degradation, each of which can affect the levels and extents of modification of proteins involved in the pathways. Significant alterations of toxicity pathways resulting from changes in regulation at any of these levels therefore are likely to be detectable as alterations in the proteome. We hypothesize that significant correlations between exposures, adverse outcomes, and changes in the proteome have the potential to identify putative toxicity pathways, facilitating selection of candidate targets for high throughput screening, even in the absence of a priori knowledge of either the specific pathways involved or the specific agents inducing the pathway alterations. We explored this hypothesis in vitro in BEAS-2B human airway epithelial cells exposed to different concentrations of Ni2+, Cd2+, and Cr6+, alone and in defined mixtures. Levels and phosphorylation status of a variety of signaling pathway proteins and cytokines were

Circular RNA expression profiles in hippocampus from mice with perinatal glyphosate exposure.

PubMed

Yu, Ning; Tong, Yun; Zhang, Danni; Zhao, Shanshan; Fan, Xinli; Wu, Lihui; Ji, Hua

2018-07-02

Glyphosate is the active ingredient in numerous herbicide formulations. The roles of glyphosate in embryo-toxicity and neurotoxicity have been reported in human and animal models. Recently, several studies have reported evidence linking neurodevelopmental disorders (NDDs) with gestational glyphosate exposure. However, the role of glyphosate in neuronal development is still not fully understood. Our previous study found that perinatal glyphosate exposure resulted in differential microRNA expression in the prefrontal cortex of mouse offspring. However, the mechanism of glyphosate-induced neurotoxicity in the developing brain is still not fully understood. Considering the pivotal role of Circular RNAs (circRNAs) in the regulation of gene expression, a circRNA microarray method was used in this study to investigate circRNA expression changes in the hippocampus of mice with perinatal glyphosate exposure. The circRNA microarrays revealed that 663 circRNAs were significantly altered in the perinatal glyphosate exposure group compared with the control group. Among them, 330 were significantly upregulated, and the other 333 were downregulated. Furthermore, the relative expression levels of mmu-circRNA-014015, mmu-circRNA-28128 and mmu-circRNA-29837 were verified using quantitative real-time polymerase chain reaction (qRT-PCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that stress-associated steroid metabolism pathways, such as aldosterone synthesis and secretion pathways, may be involved in the neurotoxicity of glyphosate. These results showed that circRNAs are aberrantly expressed in the hippocampus of mice with perinatal glyphosate exposure and play potential roles in glyphosate-induced neurotoxicity. Copyright © 2018 Elsevier Inc. All rights reserved.

Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ovacik, Meric A.; Sen, Banalata; Euling, Susan Y.

Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significancemore » analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

M.A. Wasiolek

Inhalation exposure pathway modeling has recently been investigated as one of the tasks of the BIOPROTA Project (BIOPROTA 2005). BIOPROTA was set up to address the key uncertainties in long term assessments of contaminant releases into the environment arising from radioactive waste disposal. Participants of this international Project include national authorities and agencies, both regulators and operators, with responsibility for achieving safe and acceptable radioactive waste management. The objective of the inhalation task was to investigate the calculation of doses arising from inhalation of particles suspended from soils within which long-lived radionuclides, particularly alpha emitters, had accumulated. It was recognizedmore » that site-specific conditions influence the choice of conceptual model and input parameter values. Therefore, one of the goals of the task was to identify the circumstances in which different processes included in specific inhalation exposure pathway models were important. This paper discusses evaluation of processes and modeling assumptions specific to the proposed repository at Yucca Mountain as compared to the typical approaches and other models developed for different assessments and project specific contexts. Inhalation of suspended particulates that originate from contaminated soil is an important exposure pathway, particularly for exposure to actinides such as uranium, neptunium and plutonium. Radionuclide accumulation in surface soil arises from irrigation of soil with contaminated water over many years. The level of radionuclide concentration in surface soil depends on the assumed duration of irrigation. Irrigation duration is one of the parameters used on biosphere models and it depends on a specific assessment context. It is one of the parameters addressed in this paper from the point of view of assessment context for the proposed repository at Yucca Mountain. The preferred model for the assessment of inhalation exposure uses atmospheric mass loading approach, which is based on the mass of airborne particulates per unit volume of air that is inhaled by the receptor. This type of model was used by the majority of the BIOPROTA inhalation task participants and is also used in the Yucca Mountain model. Although the mass loading model is conceptually straightforward, there are some considerations that need to be included when using this model. Small particles have larger surface to volume ratio than large particles and this ratio increases in inverse proportion to the particle size. This is particularly important for elements such as plutonium, which have high sorption coefficients, and thus are preferentially attached to small particles of soil. Suspended particulates originating from soil are composed of particles smaller than average soil particles and thus, on average, have larger available surface area, and consequently activity, per unit mass than that of soil. The increase of radionuclide concentration of suspended particulates compared with that of underlying soil is quantified in terms of the enhancement factor, which is included in the inhalation model for the Yucca Mountain repository. In this paper, the use of the enhancement factor in the inhalation exposure models is discussed. Then, enhancement factor values used in the Yucca Mountain model are discussed from the perspective of site-specific conditions as well as the microenvironmental approach to modeling inhalation exposure of the receptor: The receptor can spend specified time in several environments, each of them characterized by an occupancy time, suspended particulate level, enhancement factor and breathing rate. The environment where inhalation exposure is the highest is associated with the receptor being active outdoors and involved in activities that generate high levels of dust by using farm equipment, walking, or conducting other outdoor activities. I n summary, it is important to recognize that site-specific conditions play an important role in constructing conceptual and mathematical models of inhalation exposure.« less

Temporal effects in porcine skin following bromine vapor exposure.

PubMed

Price, Jennifer A; Rogers, James V; Wendling, Morgan Q S; Plahovinsak, Jennifer L; Perry, Mark R; Reid, Frances M; Kiser, Robyn C; Graham, John S

2011-09-01

Bromine is an industrial chemical that causes severe cutaneous burns. When selecting or developing effective treatments for bromine burns, it is important to understand the molecular mechanisms of tissue damage and wound healing. This study investigated the effect of cutaneous bromine vapor exposure on gene expression using a weanling swine burn model by microarray analysis. Ventral abdominal sites were exposed to a mean calculated bromine vapor concentration of 0.51 g/L for 7 or 17 min. At 6 h, 48 h, and 7 days post-exposure, total RNA from skin samples was isolated, processed, and analyzed with Affymetrix GeneChip® Porcine Genome Arrays (N = 3 per experimental group). Differences in gene expression were observed with respect to exposure duration and sampling time. Ingenuity Pathways Analysis (IPA) revealed four common biological functions (cancer, cellular movement, cell-to-cell signaling and interaction, and tissue development) among the top ten functions of each experimental group, while canonical pathway analysis revealed 9 genes (ARG2, CCR1, HMOX1, ATF2, IL-8, TIMP1, ESR1, HSPAIL, and SELE) that were commonly shared among four significantly altered signaling pathways. Among these, the transcripts encoding HMOX1 and ESR1 were identified using IPA as common potential therapeutic targets for Phase II/III clinical trial or FDA-approved drugs. The present study describes the transcriptional responses to cutaneous bromine vapor exposure identifying molecular networks and genes that could serve as targets for developing therapeutics for bromine-induced skin injury.

Peripheral Blood Signatures of Lead Exposure

PubMed Central

LaBreche, Heather G.; Meadows, Sarah K.; Nevins, Joseph R.; Chute, John P.

2011-01-01

Background Current evidence indicates that even low-level lead (Pb) exposure can have detrimental effects, especially in children. We tested the hypothesis that Pb exposure alters gene expression patterns in peripheral blood cells and that these changes reflect dose-specific alterations in the activity of particular pathways. Methodology/Principal Finding Using Affymetrix Mouse Genome 430 2.0 arrays, we examined gene expression changes in the peripheral blood of female Balb/c mice following exposure to per os lead acetate trihydrate or plain drinking water for two weeks and after a two-week recovery period. Data sets were RMA-normalized and dose-specific signatures were generated using established methods of supervised classification and binary regression. Pathway activity was analyzed using the ScoreSignatures module from GenePattern. Conclusions/Significance The low-level Pb signature was 93% sensitive and 100% specific in classifying samples a leave-one-out crossvalidation. The high-level Pb signature demonstrated 100% sensitivity and specificity in the leave-one-out crossvalidation. These two signatures exhibited dose-specificity in their ability to predict Pb exposure and had little overlap in terms of constituent genes. The signatures also seemed to reflect current levels of Pb exposure rather than past exposure. Finally, the two doses showed differential activation of cellular pathways. Low-level Pb exposure increased activity of the interferon-gamma pathway, whereas high-level Pb exposure increased activity of the E2F1 pathway. PMID:21829687

Latent variable models for gene-environment interactions in longitudinal studies with multiple correlated exposures.

PubMed

Tao, Yebin; Sánchez, Brisa N; Mukherjee, Bhramar

2015-03-30

Many existing cohort studies designed to investigate health effects of environmental exposures also collect data on genetic markers. The Early Life Exposures in Mexico to Environmental Toxicants project, for instance, has been genotyping single nucleotide polymorphisms on candidate genes involved in mental and nutrient metabolism and also in potentially shared metabolic pathways with the environmental exposures. Given the longitudinal nature of these cohort studies, rich exposure and outcome data are available to address novel questions regarding gene-environment interaction (G × E). Latent variable (LV) models have been effectively used for dimension reduction, helping with multiple testing and multicollinearity issues in the presence of correlated multivariate exposures and outcomes. In this paper, we first propose a modeling strategy, based on LV models, to examine the association between repeated outcome measures (e.g., child weight) and a set of correlated exposure biomarkers (e.g., prenatal lead exposure). We then construct novel tests for G × E effects within the LV framework to examine effect modification of outcome-exposure association by genetic factors (e.g., the hemochromatosis gene). We consider two scenarios: one allowing dependence of the LV models on genes and the other assuming independence between the LV models and genes. We combine the two sets of estimates by shrinkage estimation to trade off bias and efficiency in a data-adaptive way. Using simulations, we evaluate the properties of the shrinkage estimates, and in particular, we demonstrate the need for this data-adaptive shrinkage given repeated outcome measures, exposure measures possibly repeated and time-varying gene-environment association. Copyright © 2014 John Wiley & Sons, Ltd.

Pathways to Well-Being in Later Life: Socioeconomic and Health Determinants Across the Life Course of Australian Baby Boomers.

PubMed

Kendig, Hal; Loh, Vanessa; O'Loughlin, Kate; Byles, Julie; Nazroo, James Y

2016-01-01

In many countries like Australia and the United States, baby boomers are referred to as the 'lucky cohort', yet there has been little research on the origins and extent of inequalities within this cohort. This study uses path analysis to investigate direct and indirect effects of childhood and adult socioeconomic status and health on two subjective well-being measures: quality of life and life satisfaction. Retrospective life course data were obtained for 1,261 people aged 60 to 64 in the 2011-12 Life Histories and Health survey, a sub-study of the Australian 45 and Up Study. Supporting an accumulation model, the number of negative childhood and adult exposures were inversely related to both types of well-being. Consistent with a critical period model, childhood exposures had small but significant effects on subjective well-being and were relatively more important for quality of life than for life satisfaction. However, these childhood effects were largely indirect and significantly mediated by more proximal adult exposures, providing support for a pathway model. A key implication of this research is that the critical period for later life well-being is significant in adulthood rather than childhood, suggesting that there may be key opportunities for improving individuals' later life well-being far beyond the early, formative years. This research highlights the importance of understanding how earlier life exposures impact experiences in later life, and investing in health and socioeconomic opportunities to reduce inequalities across all stages of life.

Nano-risk Science: application of toxicogenomics in an adverse outcome pathway framework for risk assessment of multi-walled carbon nanotubes.

PubMed

Labib, Sarah; Williams, Andrew; Yauk, Carole L; Nikota, Jake K; Wallin, Håkan; Vogel, Ulla; Halappanavar, Sabina

2016-03-15

A diverse class of engineered nanomaterials (ENMs) exhibiting a wide array of physical-chemical properties that are associated with toxicological effects in experimental animals is in commercial use. However, an integrated framework for human health risk assessment (HHRA) of ENMs has yet to be established. Rodent 2-year cancer bioassays, clinical chemistry, and histopathological endpoints are still considered the 'gold standard' for detecting substance-induced toxicity in animal models. However, the use of data derived from alternative toxicological tools, such as genome-wide expression profiling and in vitro high-throughput assays, are gaining acceptance by the regulatory community for hazard identification and for understanding the underlying mode-of-action. Here, we conducted a case study to evaluate the application of global gene expression data in deriving pathway-based points of departure (PODs) for multi-walled carbon nanotube (MWCNT)-induced lung fibrosis, a non-cancer endpoint of regulatory importance. Gene expression profiles from the lungs of mice exposed to three individual MWCNTs with different physical-chemical properties were used within the framework of an adverse outcome pathway (AOP) for lung fibrosis to identify key biological events linking MWCNT exposure to lung fibrosis. Significantly perturbed pathways were categorized along the key events described in the AOP. Benchmark doses (BMDs) were calculated for each perturbed pathway and were used to derive transcriptional BMDs for each MWCNT. Similar biological pathways were perturbed by the different MWCNT types across the doses and post-exposure time points studied. The pathway BMD values showed a time-dependent trend, with lower BMDs for pathways perturbed at the earlier post-exposure time points (24 h, 3d). The transcriptional BMDs were compared to the apical BMDs derived by the National Institute for Occupational Safety and Health (NIOSH) using alveolar septal thickness and fibrotic lesions endpoints. We found that regardless of the type of MWCNT, the BMD values for pathways associated with fibrosis were 14.0-30.4 μg/mouse, which are comparable to the BMDs derived by NIOSH for MWCNT-induced lung fibrotic lesions (21.0-27.1 μg/mouse). The results demonstrate that transcriptomic data can be used to as an effective mechanism-based method to derive acceptable levels of exposure to nanomaterials in product development when epidemiological data are unavailable.

Benzo[a]pyrene affects Jurkat T cells in the activated state via the antioxidant response element dependent Nrf2 pathway leading to decreased IL-2 secretion and redirecting glutamine metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murugaiyan, Jayaseelan; Rockstroh, Maxie; Wagner, Juliane

2013-06-15

There is a clear evidence that environmental pollutants, such as benzo[a]pyrene (B[a]P), can have detrimental effects on the immune system, whereas the underlying mechanisms still remain elusive. Jurkat T cells share many properties with native T lymphocytes and therefore are an appropriate model to analyze the effects of environmental pollutants on T cells and their activation. Since environmental compounds frequently occur at low, not acute toxic concentrations, we analyzed the effects of two subtoxic concentrations, 50 nM and 5 μM, on non- and activated cells. B[a]P interferes directly with the stimulation process as proven by an altered IL-2 secretion. Furthermore,more » B[a]P exposure results in significant proteomic changes as shown by DIGE analysis. Pathway analysis revealed an involvement of the AhR independent Nrf2 pathway in the altered processes observed in unstimulated and stimulated cells. A participation of the Nrf2 pathway in the change of IL-2 secretion was confirmed by exposing cells to the Nrf2 activator tBHQ. tBHQ and 5 μM B[a]P caused similar alterations of IL-2 secretion and glutamine/glutamate metabolism. Moreover, the proteome changes in unstimulated cells point towards a modified regulation of the cytoskeleton and cellular stress response, which was proven by western blotting. Additionally, there is a strong evidence for alterations in metabolic pathways caused by B[a]P exposure in stimulated cells. Especially the glutamine/glutamate metabolism was indicated by proteome pathway analysis and validated by metabolite measurements. The detrimental effects were slightly enhanced in stimulated cells, suggesting that stimulated cells are more vulnerable to the environmental pollutant model compound B[a]P. - Highlights: • B[a]P affects the proteome of Jurkat T cells also at low concentrations. • Exposure to B[a]P (50 nM, 5 μM) did not change Jurkat T cell viability. • Both B[a]P concentrations altered the IL-2 secretion of stimulated cells. • 608 different protein spots of Jurkat T cells were quantified using 2-DE-DIGE. • Pathway analysis identified Nrf2 and AhR pathway as regulated.« less

HUMAN EXPOSURE MODELING FOR CUMULATIVE RISK

EPA Science Inventory

US EPA's Office of Research and Development (ORD) has identified cumulative risk assessment as a priority research area. This is because humans and other organisms are exposed to a multitude of chemicals, physical agents, and other stressors through multiple pathways, routes, an...

The injury of fine particulate matter from cooking oil fumes on umbilical cord blood vessels in vitro.

PubMed

Hou, Lijuan; Zhang, Jian; Zhang, Chao; Xu, Yachun; Zhu, Xiaoxia; Yao, Cijiang; Liu, Ying; Li, Tao; Cao, Jiyu

2017-01-01

Cooking oil fumes (COFs) derived PM 2.5 is the major source of indoor air pollution in Asia. For this, a pregnant rat model within different doses of cooking oil fumes (COFs) derived PM 2.5 was established in pregnancy in our research. Our previous studies have showed that exposure to COFs-derived PM 2.5 was related to adverse pregnancy outcomes. However, the mechanisms of signaling pathways remain unknown. Therefore, this study aimed to investigate the underlying mechanisms induced by COFs-derived PM2.5 injury on umbilical cord blood vessels (UCs) in vitro. Exposure to COFs-derived PM 2.5 resulted in changing the expression of eNOS, ET-1, ETRA, and ETRB. In additions, western blot analysis indicated that the HIF-1α/iNOS/NO signaling pathway and VEGF/VEGFR1/iNOS signaling pathway were involved in UCs injury triggered by COFs-derived PM 2.5 . In conclusion, our data suggested that exposure to COFs-derived PM 2.5 resulted in increasing of oxidative stress and inflammation, as well as dysfunction of UCs. Copyright © 2016 Elsevier B.V. All rights reserved.

10 CFR 50.47 - Emergency plans.

Code of Federal Regulations, 2014 CFR

2014-01-01

... to the populace within the plume exposure pathway Emergency Planning Zone have been established. (6... has been developed for the plume exposure pathway EPZ for emergency workers and the public. In... pathway EPZ appropriate to the locale have been developed. (11) Means for controlling radiological...

10 CFR 50.47 - Emergency plans.

Code of Federal Regulations, 2013 CFR

2013-01-01

... to the populace within the plume exposure pathway Emergency Planning Zone have been established. (6... has been developed for the plume exposure pathway EPZ for emergency workers and the public. In... pathway EPZ appropriate to the locale have been developed. (11) Means for controlling radiological...

10 CFR 50.47 - Emergency plans.

Code of Federal Regulations, 2012 CFR

2012-01-01

... to the populace within the plume exposure pathway Emergency Planning Zone have been established. (6... has been developed for the plume exposure pathway EPZ for emergency workers and the public. In... pathway EPZ appropriate to the locale have been developed. (11) Means for controlling radiological...

Inflammatory and Repair Pathways Induced in Human Bronchoalveolar Lavage Cells with Ozone Inhalation

PubMed Central

Wong, Hofer; Tenney, Rachel; Chen, Chun; Stiner, Rachel; Balmes, John R.; Paquet, Agnès C.; Arjomandi, Mehrdad

2015-01-01

Background Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury. Methods To examine the responses of airway cells to ozone-induced oxidative injury, 19 subjects (7 with asthma) were exposed to clean air (0ppb), medium (100ppb), and high (200ppb) ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL) 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG) in epithelial injury was evaluated in an in vitro model of injury [16HBE14o- cell line scratch assay]. Results Ozone exposure caused a dose-dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up-regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an α9β1 integrin-dependent manner. Conclusions Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury. PMID:26035830

Modeling methylene chloride exposure-reduction options for home paint-stripper users.

PubMed

Riley, D M; Small, M J; Fischhoff, B

2000-01-01

Home improvement is a popular activity, but one that can also involve exposure to hazardous substances. Paint stripping is of particular concern because of the high potential exposures to methylene chloride, a solvent that is a potential human carcinogen and neurotoxicant. This article presents a general methodology for evaluating the effectiveness of behavioral interventions for reducing these risks. It doubles as a model that assesses exposure patterns, incorporating user time-activity patterns and risk-mitigation strategies. The model draws upon recent innovations in indoor air-quality modeling to estimate exposure through inhalation and dermal pathways to paint-stripper users. It is designed to use data gathered from home paint-stripper users about room characteristics, amount of stripper used, time-activity patterns and exposure-reduction strategies (e.g., increased ventilation and modification in the timing of stripper application, scraping, and breaks). Results indicate that the effectiveness of behavioral interventions depends strongly on characteristics of the room (e.g., size, number and size of doors and windows, base air-exchange rates). The greatest simple reduction in exposure is achieved by using an exhaust fan in addition to opening windows and doors. These results can help identify the most important information for product labels and other risk-communication materials.

Urban gardens: Lead exposure, recontamination mechanisms, and implications for remediation design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clark, Heather F.; Hausladen, Debra M.; Brabander, Daniel J.

2008-07-15

Environmental lead contamination is prevalent in urban areas where soil represents a significant sink and pathway of exposure. This study characterizes the speciation of lead that is relevant to local recontamination and to human exposure in the backyard gardens of Roxbury and Dorchester, MA, USA. One hundred forty-one backyard gardens were tested by X-ray fluorescence, and 81% of gardens have lead levels above the US EPA action limit of 400 {mu}g/g. Raised gardening beds are the in situ exposure reduction method used in the communities to promote urban gardening. Raised beds were tested for lead and the results showed thatmore » the lead concentration increased from an initial range of 150{+-}40 {mu}g/g to an average of 336 {mu}g/g over 4 years. The percent distribution of lead in the fine grain soil (<100 {mu}m) and the trace metal signature of the raised beds support the conclusion that the mechanism of recontamination is wind-transported particles. Scanning electron microscopy and sequential extraction were used to characterize the speciation of lead, and the trace metal signature of the fine grain soil in both gardens and raised gardening beds is characteristic of lead-based paint. This study demonstrates that raised beds are a limited exposure reduction method and require maintenance to achieve exposure reduction goals. An exposure model was developed based on a suite of parameters that combine relevant values from the literature with site-specific quantification of exposure pathways. This model suggests that consumption of homegrown produce accounts for only 3% of children's daily exposure of lead while ingestion of fine grained soil (<100 {mu}m) accounts for 82% of the daily exposure. This study indicates that urban lead remediation on a yard-by-yard scale requires constant maintenance and that remediation may need to occur on a neighborhood-wide scale.« less

Urban gardens: lead exposure, recontamination mechanisms, and implications for remediation design.

PubMed

Clark, Heather F; Hausladen, Debra M; Brabander, Daniel J

2008-07-01

Environmental lead contamination is prevalent in urban areas where soil represents a significant sink and pathway of exposure. This study characterizes the speciation of lead that is relevant to local recontamination and to human exposure in the backyard gardens of Roxbury and Dorchester, MA, USA. One hundred forty-one backyard gardens were tested by X-ray fluorescence, and 81% of gardens have lead levels above the US EPA action limit of 400 microg/g. Raised gardening beds are the in situ exposure reduction method used in the communities to promote urban gardening. Raised beds were tested for lead and the results showed that the lead concentration increased from an initial range of 150+/-40 microg/g to an average of 336 microg/g over 4 years. The percent distribution of lead in the fine grain soil (<100 microm) and the trace metal signature of the raised beds support the conclusion that the mechanism of recontamination is wind-transported particles. Scanning electron microscopy and sequential extraction were used to characterize the speciation of lead, and the trace metal signature of the fine grain soil in both gardens and raised gardening beds is characteristic of lead-based paint. This study demonstrates that raised beds are a limited exposure reduction method and require maintenance to achieve exposure reduction goals. An exposure model was developed based on a suite of parameters that combine relevant values from the literature with site-specific quantification of exposure pathways. This model suggests that consumption of homegrown produce accounts for only 3% of children's daily exposure of lead while ingestion of fine grained soil (<100 microm) accounts for 82% of the daily exposure. This study indicates that urban lead remediation on a yard-by-yard scale requires constant maintenance and that remediation may need to occur on a neighborhood-wide scale.

Time series models of environmental exposures: Good predictions or good understanding.

PubMed

Barnett, Adrian G; Stephen, Dimity; Huang, Cunrui; Wolkewitz, Martin

2017-04-01

Time series data are popular in environmental epidemiology as they make use of the natural experiment of how changes in exposure over time might impact on disease. Many published time series papers have used parameter-heavy models that fully explained the second order patterns in disease to give residuals that have no short-term autocorrelation or seasonality. This is often achieved by including predictors of past disease counts (autoregression) or seasonal splines with many degrees of freedom. These approaches give great residuals, but add little to our understanding of cause and effect. We argue that modelling approaches should rely more on good epidemiology and less on statistical tests. This includes thinking about causal pathways, making potential confounders explicit, fitting a limited number of models, and not over-fitting at the cost of under-estimating the true association between exposure and disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Biomarkers of environmental benzene exposure.

PubMed Central

Weisel, C; Yu, R; Roy, A; Georgopoulos, P

1996-01-01

Environmental exposures to benzene result in increases in body burden that are reflected in various biomarkers of exposure, including benzene in exhaled breath, benzene in blood and urinary trans-trans-muconic acid and S-phenylmercapturic acid. A review of the literature indicates that these biomarkers can be used to distinguish populations with different levels of exposure (such as smokers from nonsmokers and occupationally exposed from environmentally exposed populations) and to determine differences in metabolism. Biomarkers in humans have shown that the percentage of benzene metabolized by the ring-opening pathway is greater at environmental exposures than that at higher occupational exposures, a trend similar to that found in animal studies. This suggests that the dose-response curve is nonlinear; that potential different metabolic mechanisms exist at high and low doses; and that the validity of a linear extrapolation of adverse effects measured at high doses to a population exposed to lower, environmental levels of benzene is uncertain. Time-series measurements of the biomarker, exhaled breath, were used to evaluate a physiologically based pharmacokinetic (PBPK) model. Biases were identified between the PBPK model predictions and experimental data that were adequately described using an empirical compartmental model. It is suggested that a mapping of the PBPK model to a compartmental model can be done to optimize the parameters in the PBPK model to provide a future framework for developing a population physiologically based pharmacokinetic model. PMID:9118884

Approaches to Children’s Exposure Assessment: Case Study with Diethylhexylphthalate (DEHP)

PubMed Central

Ginsberg, Gary; Ginsberg, Justine; Foos, Brenda

2016-01-01

Children’s exposure assessment is a key input into epidemiology studies, risk assessment and source apportionment. The goals of this article are to describe a methodology for children’s exposure assessment that can be used for these purposes and to apply the methodology to source apportionment for the case study chemical, diethylhexylphthalate (DEHP). A key feature is the comparison of total (aggregate) exposure calculated via a pathways approach to that derived from a biomonitoring approach. The 4-step methodology and its results for DEHP are: (1) Prioritization of life stages and exposure pathways, with pregnancy, breast-fed infants, and toddlers the focus of the case study and pathways selected that are relevant to these groups; (2) Estimation of pathway-specific exposures by life stage wherein diet was found to be the largest contributor for pregnant women, breast milk and mouthing behavior for the nursing infant and diet, house dust, and mouthing for toddlers; (3) Comparison of aggregate exposure by pathways vs biomonitoring-based approaches wherein good concordance was found for toddlers and pregnant women providing confidence in the exposure assessment; (4) Source apportionment in which DEHP presence in foods, children’s products, consumer products and the built environment are discussed with respect to early life mouthing, house dust and dietary exposure. A potential fifth step of the method involves the calculation of exposure doses for risk assessment which is described but outside the scope for the current case study. In summary, the methodology has been used to synthesize the available information to identify key sources of early life exposure to DEHP. PMID:27376320

DOE Office of Scientific and Technical Information (OSTI.GOV)

Evans, M.V., E-mail: evans.marina@epa.go; Caldwell, J.C.

Dichloromethane (DCM, methylene chloride) is a lipophilic volatile compound readily absorbed and then metabolized to several metabolites that may lead to chronic toxicity in different target organs. Physiologically based pharmacokinetic (PBPK) models are useful tools for calculation of internal and target organ doses of parent compound and metabolites. PBPK models, coupled with in vivo inhalation gas-uptake data, can be useful to estimate total metabolism. Previously, such an approach was used to make predictions regarding the metabolism and to make subsequent inferences of DCM's mode of action for toxicity. However, current evidence warrants re-examination of this approach. The goal of thismore » work was to examine two different hypotheses for DCM metabolism in mice. One hypothesis describes two metabolic pathways: one involving cytochrome P450 2E1 (CYP2E1) and a second glutathione (GSH). The second metabolic hypothesis describes only one pathway mediated by CYP2E1 that includes multiple binding sites. The results of our analysis show that the in vivo gas-uptake data fit both hypotheses well and the traditional analysis of the chamber concentration data is not sufficient to distinguish between them. Gas-uptake data were re-analyzed by construction of a velocity plot as a function of increasing DCM initial concentration. The velocity (slope) analysis revealed that there are two substantially different phases in velocity, one rate for lower exposures and a different rate for higher exposures. The concept of a 'metabolic switch,' namely that due to conformational changes in the enzyme after one site is occupied - a different metabolic rate is seen - is also consistent with the experimental data. Our analyses raise questions concerning the importance of GSH metabolism for DCM. Recent research results also question the importance of this pathway in the toxicity of DCM. GSH-related DNA adducts were not formed after in vivo DCM exposure in mice and DCM-induced DNA damage has been detected in human lung cultures without GSH metabolism. In summary, a revised/updated metabolic hypothesis for DCM has been examined using in vivo inhalation data in mice combined with PBPK modeling that is consistent with up-to-date models of the active site for CYP2E1 and suggests that this pathway is the major metabolizing pathway for DCM metabolism.« less

Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells.

PubMed

Limonciel, Alice; Wilmes, Anja; Aschauer, Lydia; Radford, Robert; Bloch, Katarzyna M; McMorrow, Tara; Pfaller, Walter; van Delft, Joost H; Slattery, Craig; Ryan, Michael P; Lock, Edward A; Jennings, Paul

2012-11-01

Potassium bromate (KBrO(3)) is an oxidising agent that has been widely used in the food and cosmetic industries. It has shown to be both a nephrotoxin and a renal carcinogen in in vivo and in vitro models. Here, we investigated the effects of KBrO(3) in the human and rat proximal tubular cell lines RPTEC/TERT1 and NRK-52E. A genome-wide transcriptomic screen was carried out from cells exposed to a sub-lethal concentration of KBrO(3) for 6, 24 and 72 h. Pathway analysis identified "glutathione metabolism", "Nrf2-mediated oxidative stress" and "tight junction (TJ) signalling" as the most enriched pathways. TJ signalling was less impacted in the rat model, and further studies revealed low transepithelial electrical resistance (TEER) and an absence of several TJ proteins in NRK-52E cells. In RPTEC/TERT1 cells, KBrO(3) exposure caused a decrease in TEER and resulted in altered expression of several TJ proteins. N-Acetylcysteine co-incubation prevented these effects. These results demonstrate that oxidative stress has, in conjunction with the activation of the cytoprotective Nrf2 pathway, a dramatic effect on the expression of tight junction proteins. The further understanding of the cross-talk between these two pathways could have major implications for epithelial repair, carcinogenesis and metastasis.

MicroRNA Regulation of Host Immune Responses following Fungal Exposure.

PubMed

Croston, Tara L; Lemons, Angela R; Beezhold, Donald H; Green, Brett J

2018-01-01

Fungal bioaerosols are ubiquitous in the environment and human exposure can result in a variety of health effects ranging from systemic, subcutaneous, and cutaneous infections to respiratory morbidity including allergy, asthma, and hypersensitivity pneumonitis. Recent research has focused on the role of microRNAs (miRNAs) following fungal exposure and is overlooked, yet important, group of regulators capable of influencing fungal immune responses through a variety of cellular mechanisms. These small non-coding ribose nucleic acids function to regulate gene expression at the post-transcriptional level and have been shown to participate in multiple disease pathways including cancer, heart disease, apoptosis, as well as immune responses to microbial hazards and occupational allergens. Recent animal model studies have characterized miRNAs following the exposure to inflammatory stimuli. Studies focused on microbial exposure, including bacterial infections, as well as exposure to different allergens have shown miRNAs, such as miR-21, miR-146, miR-132, miR-155, and the let-7 family members, to be involved in immune and inflammatory responses. Interestingly, the few studies have assessed that the miRNA profiles following fungal exposure have identified the same critical miRNAs that have been characterized in other inflammatory-mediated and allergy-induced experimental models. Review of available in vitro , animal and human studies of exposures to Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Paracoccidioides brasiliensis , and Stachybotrys chartarum identified several miRNAs that were shared between responses to these species including miR-125 a/b (macrophage polarization/activation), miR-132 [toll-like receptor (TLR)2-mediated signaling], miR-146a (TLR mediated signaling, alternative macrophage activation), and miR-29a/b (natural killer cell function, C-leptin signaling, inhibition of Th1 immune response). Although these datasets provide preliminary insight into the role of miRNAs in fungal exposed models, interpretation of miRNA datasets can be challenging for researchers. To assist in navigating this rapidly evolving field, the aim of this review is to describe miRNAs in the framework of host recognition mechanisms and provide initial insight into the regulatory pathways in response to fungal exposure.

AOP Knowledge Base/Wiki Tool Set

EPA Science Inventory

Utilizing ToxCast Data and Lifestage Physiologically-Based Pharmacokinetic (PBPK) models to Drive Adverse Outcome Pathways (AOPs)-Based Margin of Exposures (ABME) to Chemicals. Hisham A. El-Masri1, Nicole C. Klienstreur2, Linda Adams1, Tamara Tal1, Stephanie Padilla1, Kristin Is...

RISK 0301 - MOLECULAR MODELING

EPA Science Inventory

Risk assessment practices, in general, for a range of diseases now encourages the use of mechanistic data to enhance the ability to predict responses at low, environmental exposures. In particular, the pathway from normal biology to pathologic state can be dcscribed by a set of m...

Dose–response analysis of phthalate effects on gene expression in rat whole embryo culture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Robinson, Joshua F.; Department of Toxicogenomics, Maastricht University, Maastricht; Verhoef, Aart

2012-10-01

The rat postimplantation whole embryo culture (WEC) model serves as a potential screening tool for developmental toxicity. In this model, cultured rat embryos are exposed during early embryogenesis and evaluated for morphological effects. The integration of molecular-based markers may lead to improved objectivity, sensitivity and predictability of WEC in assessing developmental toxic properties of compounds. In this study, we investigated the concentration-dependent effects of two phthalates differing in potency, mono(2-ethylhexyl) phthalate (MEHP) and monomethyl phthalate (MMP, less toxic), on the transcriptome in WEC to examine gene expression in relation with dysmorphogenesis. MEHP was more potent than MMP in inducing genemore » expression changes as well as changes on morphology. MEHP induced significant enrichment of cholesterol/lipid/steroid (CLS) metabolism and apoptosis pathways which was associated with developmental toxicity. Regulation of genes within CLS metabolism pathways represented the most sensitive markers of MEHP exposure, more sensitive than classical morphological endpoints. As shown in direct comparisons with toxicogenomic in vivo studies, alterations in the regulation of CLS metabolism pathways has been previously identified to be associated with developmental toxicity due to phthalate exposure in utero. Our results support the application of WEC as a model to examine relative phthalate potency through gene expression and morphological responses. Additionally, our results further define the applicability domain of the WEC model for developmental toxicological investigations. -- Highlights: ► We examine the effect of two phthalates on gene expression and morphology in WEC. ► MEHP is more potent than MMP in inducing gene expression changes and dysmorphogenesis. ► MEHP significantly disrupts cholesterol metabolism pathways in a dose-dependent manner. ► Specific phthalate-related mechanisms in WEC are relevant to mechanisms in vivo.« less

Radiation Quality Effects on Transcriptome Profiles in 3-d Cultures After Particle Irradiation

NASA Technical Reports Server (NTRS)

Patel, Z. S.; Kidane, Y. H.; Huff, J. L.

2014-01-01

In this work, we evaluate the differential effects of low- and high-LET radiation on 3-D organotypic cultures in order to investigate radiation quality impacts on gene expression and cellular responses. Reducing uncertainties in current risk models requires new knowledge on the fundamental differences in biological responses (the so-called radiation quality effects) triggered by heavy ion particle radiation versus low-LET radiation associated with Earth-based exposures. We are utilizing novel 3-D organotypic human tissue models that provide a format for study of human cells within a realistic tissue framework, thereby bridging the gap between 2-D monolayer culture and animal models for risk extrapolation to humans. To identify biological pathway signatures unique to heavy ion particle exposure, functional gene set enrichment analysis (GSEA) was used with whole transcriptome profiling. GSEA has been used extensively as a method to garner biological information in a variety of model systems but has not been commonly used to analyze radiation effects. It is a powerful approach for assessing the functional significance of radiation quality-dependent changes from datasets where the changes are subtle but broad, and where single gene based analysis using rankings of fold-change may not reveal important biological information. We identified 45 statistically significant gene sets at 0.05 q-value cutoff, including 14 gene sets common to gamma and titanium irradiation, 19 gene sets specific to gamma irradiation, and 12 titanium-specific gene sets. Common gene sets largely align with DNA damage, cell cycle, early immune response, and inflammatory cytokine pathway activation. The top gene set enriched for the gamma- and titanium-irradiated samples involved KRAS pathway activation and genes activated in TNF-treated cells, respectively. Another difference noted for the high-LET samples was an apparent enrichment in gene sets involved in cycle cycle/mitotic control. It is plausible that the enrichment in these particular pathways results from the complex DNA damage resulting from high-LET exposure where repair processes are not completed during the same time scale as the less complex damage resulting from low-LET radiation.

Zebrafish Get Connected: Investigating Neurotransmission Targets and Alterations in Chemical Toxicity

PubMed Central

Horzmann, Katharine A.; Freeman, Jennifer L.

2016-01-01

Neurotransmission is the basis of neuronal communication and is critical for normal brain development, behavior, learning, and memory. Exposure to drugs and chemicals can alter neurotransmission, often through unknown pathways and mechanisms. The zebrafish (Danio rerio) model system is increasingly being used to study the brain and chemical neurotoxicity. In this review, the major neurotransmitter systems, including glutamate, GABA, dopamine, norepinephrine, serotonin, acetylcholine, histamine, and glutamate are surveyed and pathways of synthesis, transport, metabolism, and action are examined. Differences between human and zebrafish neurochemical pathways are highlighted. We also review techniques for evaluating neurological function, including the measurement of neurotransmitter levels, assessment of gene expression through transcriptomic analysis, and the recording of neurobehavior. Finally examples of chemical toxicity studies evaluating alterations in neurotransmitter systems in the zebrafish model are reviewed. PMID:28730152

INDIRECT EXPOSURE ASSESSMENT AT THE UNITED STATES ENRONMENTAL PROTECTION AGENCY

EPA Science Inventory

In the early 1980s, expousres and subsequent health impact assessments from contaminants emitted into the air from stationary sources focused on the inhalation pathway. This 'direct' pathway of exposure was thought to be the most critical pathway, as it is for many contaminants. ...

Transcriptomic Analysis of Lung Tissue from Cigarette Smoke-Induced Emphysema Murine Models and Human Chronic Obstructive Pulmonary Disease Show Shared and Distinct Pathways.

PubMed

Yun, Jeong H; Morrow, Jarrett; Owen, Caroline A; Qiu, Weiliang; Glass, Kimberly; Lao, Taotao; Jiang, Zhiqiang; Perrella, Mark A; Silverman, Edwin K; Zhou, Xiaobo; Hersh, Craig P

2017-07-01

Although cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD), the underlying molecular mechanisms for the significant variability in developing COPD in response to CS are incompletely understood. We performed lung gene expression profiling of two different wild-type murine strains (C57BL/6 and NZW/LacJ) and two genetic models with mutations in COPD genome-wide association study genes (HHIP and FAM13A) after 6 months of chronic CS exposure and compared the results to human COPD lung tissues. We identified gene expression patterns that correlate with severity of emphysema in murine and human lungs. Xenobiotic metabolism and nuclear erythroid 2-related factor 2-mediated oxidative stress response were commonly regulated molecular response patterns in C57BL/6, Hhip +/- , and Fam13a -/- murine strains exposed chronically to CS. The CS-resistant Fam13a -/- mouse and NZW/LacJ strain revealed gene expression response pattern differences. The Fam13a -/- strain diverged in gene expression compared with C57BL/6 control only after CS exposure. However, the NZW/LacJ strain had a unique baseline expression pattern, enriched for nuclear erythroid 2-related factor 2-mediated oxidative stress response and xenobiotic metabolism, and converged to a gene expression pattern similar to the more susceptible wild-type C57BL/6 after CS exposure. These results suggest that distinct molecular pathways may account for resistance to emphysema. Surprisingly, there were few genes commonly modulated in mice and humans. Our study suggests that gene expression responses to CS may be largely species and model dependent, yet shared pathways could provide biologically significant insights underlying individual susceptibility to CS.

Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model?

PubMed Central

Doktorova, T. Y.; Yildirimman, Reha; Ceelen, Liesbeth; Vilardell, Mireia; Vanhaecke, Tamara; Vinken, Mathieu; Ates, Gamze; Heymans, Anja; Gmuender, Hans; Bort, Roque; Corvi, Raffaella; Phrakonkham, Pascal; Li, Ruoya; Mouchet, Nicolas; Chesne, Christophe; van Delft, Joost; Kleinjans, Jos; Castell, Jose; Herwig, Ralf; Rogiers, Vera

2014-01-01

The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in vitro cell culture models for identifying organotypical genotoxic- and non-genotoxic carcinogen-specific gene signatures. Here the performance of its gene classifier, derived from exposure of metabolically competent human HepaRG cells to prototypical non-carcinogens (10 compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the gene and the pathway level by using independent biostatistical approaches showed a distinct separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to 88 % correct prediction). The most characteristic pathway responding to genotoxic exposure was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three compounds, from the set of 30 compounds, by three independent laboratories. Subsequent classification of these compounds resulted in correct prediction of the genotoxicants. As expected, results on the non-genotoxic carcinogens and the non-carcinogens were less predictive. In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model provides a potential weight of evidence approach for the evaluation of the genotoxic potential of chemical substances. PMID:26417288

A Pilot Study on Integrating Videography and Environmental Microbial Sampling to Model Fecal Bacterial Exposures in Peri-Urban Tanzania.

PubMed

Julian, Timothy R; Pickering, Amy J

2015-01-01

Diarrheal diseases are a leading cause of under-five mortality and morbidity in sub-Saharan Africa. Quantitative exposure modeling provides opportunities to investigate the relative importance of fecal-oral transmission routes (e.g. hands, water, food) responsible for diarrheal disease. Modeling, however, requires accurate descriptions of individuals' interactions with the environment (i.e., activity data). Such activity data are largely lacking for people in low-income settings. In the present study, we collected activity data and microbiological sampling data to develop a quantitative microbial exposure model for two female caretakers in peri-urban Tanzania. Activity data were combined with microbiological data of contacted surfaces and fomites (e.g. broom handle, soil, clothing) to develop example exposure profiles describing second-by-second estimates of fecal indicator bacteria (E. coli and enterococci) concentrations on the caretaker's hands. The study demonstrates the application and utility of video activity data to quantify exposure factors for people in low-income countries and apply these factors to understand fecal contamination exposure pathways. This study provides both a methodological approach for the design and implementation of larger studies, and preliminary data suggesting contacts with dirt and sand may be important mechanisms of hand contamination. Increasing the scale of activity data collection and modeling to investigate individual-level exposure profiles within target populations for specific exposure scenarios would provide opportunities to identify the relative importance of fecal-oral disease transmission routes.

Salicylic acid induces vanillin synthesis through the phospholipid signaling pathway in Capsicum chinense cell cultures

PubMed Central

Rodas-Junco, Beatriz A; Cab-Guillen, Yahaira; Muñoz-Sanchez, J Armando; Vázquez-Flota, Felipe; Monforte-Gonzalez, Miriam; Hérnandez-Sotomayor, S M Teresa

2013-01-01

Signal transduction via phospholipids is mediated by phospholipases such as phospholipase C (PLC) and D (PLD), which catalyze hydrolysis of plasma membrane structural phospholipids. Phospholipid signaling is also involved in plant responses to phytohormones such as salicylic acid (SA). The relationships between phospholipid signaling, SA, and secondary metabolism are not fully understood. Using a Capsicum chinense cell suspension as a model, we evaluated whether phospholipid signaling modulates SA-induced vanillin production through the activation of phenylalanine ammonia lyase (PAL), a key enzyme in the biosynthetic pathway. Salicylic acid was found to elicit PAL activity and consequently vanillin production, which was diminished or reversed upon exposure to the phosphoinositide-phospholipase C (PI-PLC) signaling inhibitors neomycin and U73122. Exposure to the phosphatidic acid inhibitor 1-butanol altered PLD activity and prevented SA-induced vanillin production. Our results suggest that PLC and PLD-generated secondary messengers may be modulating SA-induced vanillin production through the activation of key biosynthetic pathway enzymes.

Human Health Risk Assessment Calculator. In: SMARTe20ll, EPA/600/C-10/007

EPA Science Inventory

This calculator is aimed at supporting a human health risk assessment. Risk scenarios can be built by combining various health effects, exposure pathways, exposure parameters, and analytes. Scenario risk are calculated for each exposure pathway and analyte combination. The out...

The pathway to grandparenting stress: trauma, relational conflict, and emotional well-being.

PubMed

Sprang, Ginny; Choi, Moon; Eslinger, Jessica G; Whitt-Woosley, Adrienne L

2015-01-01

This paper examines the mediating effect of child-grandparent conflict on the relationship between child trauma exposure and grandparenting stress. Data was collected from a sample of custodial grandparents who participated in kinship care or relative caregiving programs (n = 251). Grandparenting stress was measured with Parenting Stress Scale (Berry & Jones, 1995 ) modified for grandparents. A series of regression models and structural equation models (SEM) were used to test the relationship between the number of different types of child trauma exposures and grandparenting stress, and to examine the mediating effect of child-grandparent conflicts on the relationship. Almost three-fourths (72%) of children had experienced at least one type of traumatic exposure. The SEM model shows that child's trauma exposure indirectly affected grandparenting stress, mediated by child-grandparenting conflicts though no direct path between the child's trauma exposure variable and grandparenting stress was found. A higher level of child-grandparent conflicts was also associated with a lower level of emotional well-being among custodial grandparents. Based on these findings, recommendations are made about how to tailor a trauma-informed approach to the needs of custodial grandparents.

Examining the effects of emotional and cognitive desensitization to community violence exposure in male adolescents of color.

PubMed

Gaylord-Harden, Noni K; So, Suzanna; Bai, Grace J; Tolan, Patrick H

2017-01-01

The current study examined pathways in a model of desensitization, the Pathologic Adaptation Model, in adolescent males of color. Specifically, the current study examined depressive symptoms and deviant beliefs as mediators of the association between community violence exposure and subsequent violent behavior. The current study included 250 African-American (67%) and Latino (33%) male adolescents (T1 mean age = 15.32) from the Chicago Youth Development Study. Consistent with the Pathologic Adaptation Model, results demonstrated that depressive symptoms mediated the association between the quadratic violence exposure term in middle adolescence and violent behaviors in late adolescence, but the direction of the mediation effect was dependent upon the levels of violence exposure in middle adolescence. However, deviant beliefs were not found to be a significant mediator. Emotional desensitization effects may increase the likelihood of violence perpetration in adolescent males exposed to community violence, and the implications for future research and intervention efforts are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Examining the Effects of Emotional and Cognitive Desensitization to Community Violence Exposure in Male Adolescents of Color

PubMed Central

Gaylord-Harden, Noni K.; So, Suzanna; Bai, Grace J.; Tolan, Patrick H.

2016-01-01

Objective The current study examined pathways in a model of desensitization, the Pathologic Adaptation Model, in adolescent males of color. Specifically, the current study examined depressive symptoms and deviant beliefs as mediators of the association between community violence exposure and subsequent violent behavior. Method The current study included 250 African American (67%) and Latino (33%) male adolescents (T1 mean age = 15.32) from the Chicago Youth Development Study. Results Consistent with the Pathologic Adaptation Model, results demonstrated that depressive symptoms mediated the association between the quadratic violence exposure term in middle adolescence and violent behaviors in late adolescence, but the direction of the mediation effect was dependent upon the levels of violence exposure in middle adolescence. However, deviant beliefs were not found to be a significant mediator. Conclusion Emotional desensitization effects may increase the likelihood of violence perpetration in adolescent males exposed to community violence, and the implications for future research and intervention efforts are discussed. PMID:27977283

Frameworks for organizing exposure and toxicity data - the Aggregate Exposure Pathway (AEP) and the Adverse Outcome Pathway (AOP)

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework organizes existing knowledge regarding a series of biological events, starting with a molecular initiating event (MIE) and ending at an adverse outcome. The AOP framework provides a biological context to interpret in vitro toxicity dat...

Tobacco Smoke Exposure and Altered Nasal Responses to Live Attenuated Influenza Virus

EPA Science Inventory

Background: Epidemiologic evidence links tobacco smoke and increased risk for influenza in humans, but the specific host defense pathways involved are unclear. Objective. Develop a model to examine influenza-induced innate immune responses in humans and test the hypothesis that ...

Clustering and optimal arrangement of enzymes in reaction-diffusion systems.

PubMed

Buchner, Alexander; Tostevin, Filipe; Gerland, Ulrich

2013-05-17

Enzymes within biochemical pathways are often colocalized, yet the consequences of specific spatial enzyme arrangements remain poorly understood. We study the impact of enzyme arrangement on reaction efficiency within a reaction-diffusion model. The optimal arrangement transitions from a cluster to a distributed profile as a single parameter, which controls the probability of reaction versus diffusive loss of pathway intermediates, is varied. We introduce the concept of enzyme exposure to explain how this transition arises from the stochastic nature of molecular reactions and diffusion.

Applying high resolution mass spectrometry and network analysis to assess exposure to a novel androgen, spironolactone, on metabolic pathways in fish

EPA Science Inventory

Although metabolomics can successfully detect effects from overall contaminant exposure, its ability to elucidate specific metabolic pathways impacted by those exposures can be hindered by bottlenecks in metabolite identification. However, improved analytical approaches that com...

A Review of Non-occupational Pathways for Pesticide Exposure in Women Living in Agricultural Areas

EPA Science Inventory

Women living in agricultural areas may experience relatively high pesticide exposures compared to women in urban or suburban areas due to their proximity to farm activities. However, exposure pathways in these women are not well-characterized. We reviewed the evidence for the con...

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data

EPA Science Inventory

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified rel...

Metal-induced Dysregulation of the NF-kB Pathway in a Detroit Michigan's Children Cohort

EPA Science Inventory

Heavy metal exposure can have adverse effects on childhood development, and early life exposures have been shown to modify key biological pathways. We set out to evaluate the genome-wide effects of metals exposure in the Mechanistic Indicators of Childhood Asthma (MICA) study, wh...

Intracellular signal modulation by nanomaterials.

PubMed

Hussain, Salik; Garantziotis, Stavros; Rodrigues-Lima, Fernando; Dupret, Jean-Marie; Baeza-Squiban, Armelle; Boland, Sonja

2014-01-01

A thorough understanding of the interactions of nanomaterials with biological systems and the resulting activation of signal transduction pathways is essential for the development of safe and consumer friendly nanotechnology. Here we present an overview of signaling pathways induced by nanomaterial exposures and describe the possible correlation of their physicochemical characteristics with biological outcomes. In addition to the hierarchical oxidative stress model and a review of the intrinsic and cell-mediated mechanisms of reactive oxygen species (ROS) generating capacities of nanomaterials, we also discuss other oxidative stress dependent and independent cellular signaling pathways. Induction of the inflammasome, calcium signaling, and endoplasmic reticulum stress are reviewed. Furthermore, the uptake mechanisms can be of crucial importance for the cytotoxicity of nanomaterials and membrane-dependent signaling pathways have also been shown to be responsible for cellular effects of nanomaterials. Epigenetic regulation by nanomaterials, effects of nanoparticle-protein interactions on cell signaling pathways, and the induction of various cell death modalities by nanomaterials are described. We describe the common trigger mechanisms shared by various nanomaterials to induce cell death pathways and describe the interplay of different modalities in orchestrating the final outcome after nanomaterial exposures. A better understanding of signal modulations induced by nanomaterials is not only essential for the synthesis and design of safer nanomaterials but will also help to discover potential nanomedical applications of these materials. Several biomedical applications based on the different signaling pathways induced by nanomaterials are already proposed and will certainly gain a great deal of attraction in the near future.

Intracellular Signal Modulation by Nanomaterials

PubMed Central

Hussain, Salik; Garantziotis, Stavros; Rodrigues-Lima, Fernando; Dupret, Jean-Marie; Baeza-Squiban, Armelle; Boland, Sonja

2016-01-01

A thorough understanding of the interactions of nanomaterials with biological systems and the resulting activation of signal transduction pathways is essential for the development of safe and consumer friendly nanotechnology. Here we present an overview of signaling pathways induced by nanomaterial exposures and describe the possible correlation of their physicochemical characteristics with biological outcomes. In addition to the hierarchical oxidative stress model and a review of the intrinsic and cell-mediated mechanisms of reactive Oxygen species (ROS) generating capacities of nanomaterials, we also discuss other oxidative stress dependent and independent cellular signaling pathways. Induction of the inflammasome, calcium signaling, and endoplasmic reticulum stress are reviewed. Furthermore, the uptake mechanisms can crucially affect the cytotoxicity of nanomaterials and membrane-dependent signaling pathways can be responsible for cellular effects of nanomaterials. Epigenetic regulation by nanomaterials effects of nanoparticle-protein interactions on cell signaling pathways, and the induction of various cell death modalities by nanomaterials are described. We describe the common trigger mechanisms shared by various nanomaterials to induce cell death pathways and describe the interplay of different modalities in orchestrating the final outcome after nanomaterial exposures. A better understanding of signal modulations induced by nanomaterials is not only essential for the synthesis and design of safer nanomaterials but will also help to discover potential nanomedical applications of these materials. Several biomedical applications based on the different signaling pathways induced by nanomaterials are already proposed and will certainly gain a great deal of attraction in the near future. PMID:24683030

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kodali, Vamsi; Littke, Matthew H.; Tilton, Susan C.

Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pretreatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pretreatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in responsemore » to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pretreatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from an M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNFα production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Finally, nanotoxicology screening strategies should therefore consider how exposure to these materials alters susceptibility to other environmental exposures.« less

Human health risk assessment: models for predicting the effective exposure duration of on-site receptors exposed to contaminated groundwater.

PubMed

Baciocchi, Renato; Berardi, Simona; Verginelli, Iason

2010-09-15

Clean-up of contaminated sites is usually based on a risk-based approach for the definition of the remediation goals, which relies on the well known ASTM-RBCA standard procedure. In this procedure, migration of contaminants is described through simple analytical models and the source contaminants' concentration is supposed to be constant throughout the entire exposure period, i.e. 25-30 years. The latter assumption may often result over-protective of human health, leading to unrealistically low remediation goals. The aim of this work is to propose an alternative model taking in account the source depletion, while keeping the original simplicity and analytical form of the ASTM-RBCA approach. The results obtained by the application of this model are compared with those provided by the traditional ASTM-RBCA approach, by a model based on the source depletion algorithm of the RBCA ToolKit software and by a numerical model, allowing to assess its feasibility for inclusion in risk analysis procedures. The results discussed in this work are limited to on-site exposure to contaminated water by ingestion, but the approach proposed can be extended to other exposure pathways. Copyright 2010 Elsevier B.V. All rights reserved.

40 CFR 300.420 - Remedial site evaluation.

Code of Federal Regulations, 2010 CFR

2010-07-01

... existing information about a release such as information on the pathways of exposure, exposure targets, and... known contaminants; (iii) A description of pathways of migration of contaminants; (iv) An identification...

40 CFR 300.420 - Remedial site evaluation.

Code of Federal Regulations, 2011 CFR

2011-07-01

... existing information about a release such as information on the pathways of exposure, exposure targets, and... known contaminants; (iii) A description of pathways of migration of contaminants; (iv) An identification...

40 CFR 300.420 - Remedial site evaluation.

Code of Federal Regulations, 2012 CFR

2012-07-01

... existing information about a release such as information on the pathways of exposure, exposure targets, and... known contaminants; (iii) A description of pathways of migration of contaminants; (iv) An identification...

Transcriptome response of the foundation plant Spartina alterniflora to the Deepwater Horizon oil spill.

PubMed

Alvarez, Mariano; Ferreira de Carvalho, Julie; Salmon, Armel; Ainouche, Malika L; Cavé-Radet, Armand; El Amrani, Abdelhak; Foster, Tammy E; Moyer, Sydney; Richards, Christina L

2018-06-04

Despite the severe impacts of the Deepwater Horizon oil spill, the foundation plant species Spartina alterniflora proved resilient to heavy oiling, providing an opportunity to identify mechanisms of response to the anthropogenic stress of crude oil exposure. We assessed plants from oil-affected and unaffected populations using a custom DNA microarray to identify genomewide transcription patterns and gene expression networks that respond to crude oil exposure. In addition, we used T-DNA insertion lines of the model grass Brachypodium distachyon to assess the contribution of four novel candidate genes to crude oil response. Responses in S. alterniflora to hydrocarbon exposure across the transcriptome as well as xenobiotic specific response pathways had little overlap with those previously identified in the model plant Arabidopsis thaliana. Among T-DNA insertion lines of B. distachyon, we found additional support for two candidate genes, one (ATTPS21) involved in volatile production, and the other (SUVH5) involved in epigenetic regulation of gene expression, that may be important in the response to crude oil. The architecture of crude oil response in S. alterniflora is unique from that of the model species A. thaliana, suggesting that xenobiotic response may be highly variable across plant species. In addition, further investigations of regulatory networks may benefit from more information about epigenetic response pathways. © 2018 John Wiley & Sons Ltd.

10 CFR 50.33 - Contents of applications; general information.

Code of Federal Regulations, 2013 CFR

2013-01-01

... within the plume exposure pathway emergency planning zone (EPZ), 4 as well as the plans of State governments wholly or partially within the ingestion pathway EPZ. 5 If the application is for an early site... plume exposure pathway EPZ for nuclear power reactors shall consist of an area about 10 miles (16 km) in...

10 CFR 50.33 - Contents of applications; general information.

Code of Federal Regulations, 2014 CFR

2014-01-01

... within the plume exposure pathway emergency planning zone (EPZ), 4 as well as the plans of State governments wholly or partially within the ingestion pathway EPZ. 5 If the application is for an early site... plume exposure pathway EPZ for nuclear power reactors shall consist of an area about 10 miles (16 km) in...

10 CFR 50.33 - Contents of applications; general information.

Code of Federal Regulations, 2012 CFR

2012-01-01

... within the plume exposure pathway emergency planning zone (EPZ), 4 as well as the plans of State governments wholly or partially within the ingestion pathway EPZ. 5 If the application is for an early site... plume exposure pathway EPZ for nuclear power reactors shall consist of an area about 10 miles (16 km) in...

10 CFR 50.33 - Contents of applications; general information.

Code of Federal Regulations, 2011 CFR

2011-01-01

... within the plume exposure pathway emergency planning zone (EPZ), 4 as well as the plans of State governments wholly or partially within the ingestion pathway EPZ. 5 If the application is for an early site... plume exposure pathway EPZ for nuclear power reactors shall consist of an area about 10 miles (16 km) in...

CalTOX (registered trademark), A multimedia total exposure model spreadsheet user's guide. Version 4.0(Beta)

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKone, T.E.; Enoch, K.G.

2002-08-01

CalTOX has been developed as a set of spreadsheet models and spreadsheet data sets to assist in assessing human exposures from continuous releases to multiple environmental media, i.e. air, soil, and water. It has also been used for waste classification and for setting soil clean-up levels at uncontrolled hazardous wastes sites. The modeling components of CalTOX include a multimedia transport and transformation model, multi-pathway exposure scenario models, and add-ins to quantify and evaluate uncertainty and variability. All parameter values used as inputs to CalTOX are distributions, described in terms of mean values and a coefficient of variation, rather than asmore » point estimates or plausible upper values such as most other models employ. This probabilistic approach allows both sensitivity and uncertainty analyses to be directly incorporated into the model operation. This manual provides CalTOX users with a brief overview of the CalTOX spreadsheet model and provides instructions for using the spreadsheet to make deterministic and probabilistic calculations of source-dose-risk relationships.« less

Modeling the impact of climate change in Germany with biosphere models for long-term safety assessment of nuclear waste repositories.

PubMed

Staudt, C; Semiochkina, N; Kaiser, J C; Pröhl, G

2013-01-01

Biosphere models are used to evaluate the exposure of populations to radionuclides from a deep geological repository. Since the time frame for assessments of long-time disposal safety is 1 million years, potential future climate changes need to be accounted for. Potential future climate conditions were defined for northern Germany according to model results from the BIOCLIM project. Nine present day reference climate regions were defined to cover those future climate conditions. A biosphere model was developed according to the BIOMASS methodology of the IAEA and model parameters were adjusted to the conditions at the reference climate regions. The model includes exposure pathways common to those reference climate regions in a stylized biosphere and relevant to the exposure of a hypothetical self-sustaining population at the site of potential radionuclide contamination from a deep geological repository. The end points of the model are Biosphere Dose Conversion factors (BDCF) for a range of radionuclides and scenarios normalized for a constant radionuclide concentration in near-surface groundwater. Model results suggest an increased exposure of in dry climate regions with a high impact of drinking water consumption rates and the amount of irrigation water used for agriculture. Copyright © 2012 Elsevier Ltd. All rights reserved.

The cumulative MeHg and PCBs exposure and risk of tribal ...

EPA Pesticide Factsheets

Studies have shown that the U.S. population continues to be exposed to methyl mercury (MeHg) and polychlorinated biphenyls (PCBs) due to the long half-life of those environmental contaminants. Fish intake of Tribal populations is much higher than the U.S. general population due to dietary habits and unique cultural practices. Large fish tissue concentration data sets from the Environmental Protections Agency’s (EPA’s) Office of Water, USGS’s EMMMA program, and other data sources, were integrated, analyzed, and combined with recent tribal fish intake data for exposure analyses using the dietary module within EPA’s SHEDS-Multimedia model. SHEDS-Multimedia is a physically-based, probabilistic model, which can simulate cumulative (multiple chemicals) or aggregate (single chemical) exposures over time for a population via various pathways of exposure for a variety of multimedia, multipathway environmental chemicals. Our results show that MeHg and total PCBs exposure of tribal populations from fish are about 3 to 10 and 5 to 15 times higher than the US general population, respectively, and that the estimated exposures pose potential health risks. The cumulative exposures of MeHg and total PCBs will be assessed to generate the joint exposure profiles for Tribal and US general populations. Model sensitivity analyses will identify the important contributions of the cumulative exposures of MeHg and total PCBs such as fish types, locations, and size, and key expos

Differential microRNA expression in the prefrontal cortex of mouse offspring induced by glyphosate exposure during pregnancy and lactation.

PubMed

Ji, Hua; Xu, Linhao; Wang, Zheng; Fan, Xinli; Wu, Lihui

2018-03-01

Glyphosate is the active ingredient in numerous herbicide formulations. The role of glyphosate in neurotoxicity has been reported in human and animal models. However, the detailed mechanism of the role of glyphosate in neuronal development remains unknown. Recently, several studies have reported evidence linking neurodevelopmental disorders (NDDs) with gestational glyphosate exposure. The current group previously identified microRNAs (miRNAs) that are associated with the etiology of NDDs, but their expression levels in the developing brain following glyphosate exposure have not been characterized. In the present study, miRNA expression patterns were evaluated in the prefrontal cortex (PFC) of 28 postnatal day mouse offspring following glyphosate exposure during pregnancy and lactation. An miRNA microarray detected 55 upregulated and 19 downregulated miRNAs in the PFC of mouse offspring, and 20 selected deregulated miRNAs were further evaluated by quantitative polymerase chain reaction (PCR). A total of 11 targets of these selected deregulated miRNAs were analyzed using bioinformatics. Gene Ontology (GO) terms associated with the relevant miRNAs included neurogenesis (GO:0050769), neuron differentiation (GO:0030182) and brain development (GO:0007420). The genes Cdkn1a, Numbl, Notch1, Fosl1 and Lef1 are involved in the Wnt and Notch signaling pathways, which are closely associated with neural development. PCR arrays for the mouse Wnt and Notch signaling pathways were used to validate the effects of glyphosate on the expression pattern of genes involved in the Wnt and Notch pathways. Nr4a2 and Wnt7b were downregulated, while Dkk1, Dixdc1, Runx1, Shh, Lef-1 and Axin2 were upregulated in the PFC of mice offspring following glyphosate exposure during pregnancy and lactation. These results indicated abnormalities of the Wnt/β-catenin and Notch pathways. These findings may be of particular interest for understanding the mechanism of glyphosate-induced neurotoxicity, as well as helping to clarify the association between glyphosate and NDDs.

Differential microRNA expression in the prefrontal cortex of mouse offspring induced by glyphosate exposure during pregnancy and lactation

PubMed Central

Ji, Hua; Xu, Linhao; Wang, Zheng; Fan, Xinli; Wu, Lihui

2018-01-01

Glyphosate is the active ingredient in numerous herbicide formulations. The role of glyphosate in neurotoxicity has been reported in human and animal models. However, the detailed mechanism of the role of glyphosate in neuronal development remains unknown. Recently, several studies have reported evidence linking neurodevelopmental disorders (NDDs) with gestational glyphosate exposure. The current group previously identified microRNAs (miRNAs) that are associated with the etiology of NDDs, but their expression levels in the developing brain following glyphosate exposure have not been characterized. In the present study, miRNA expression patterns were evaluated in the prefrontal cortex (PFC) of 28 postnatal day mouse offspring following glyphosate exposure during pregnancy and lactation. An miRNA microarray detected 55 upregulated and 19 downregulated miRNAs in the PFC of mouse offspring, and 20 selected deregulated miRNAs were further evaluated by quantitative polymerase chain reaction (PCR). A total of 11 targets of these selected deregulated miRNAs were analyzed using bioinformatics. Gene Ontology (GO) terms associated with the relevant miRNAs included neurogenesis (GO:0050769), neuron differentiation (GO:0030182) and brain development (GO:0007420). The genes Cdkn1a, Numbl, Notch1, Fosl1 and Lef1 are involved in the Wnt and Notch signaling pathways, which are closely associated with neural development. PCR arrays for the mouse Wnt and Notch signaling pathways were used to validate the effects of glyphosate on the expression pattern of genes involved in the Wnt and Notch pathways. Nr4a2 and Wnt7b were downregulated, while Dkk1, Dixdc1, Runx1, Shh, Lef-1 and Axin2 were upregulated in the PFC of mice offspring following glyphosate exposure during pregnancy and lactation. These results indicated abnormalities of the Wnt/β-catenin and Notch pathways. These findings may be of particular interest for understanding the mechanism of glyphosate-induced neurotoxicity, as well as helping to clarify the association between glyphosate and NDDs. PMID:29467848

Pharmaceuticals in water, fish and osprey nestlings in Delaware River and Bay

USGS Publications Warehouse

Bean, Thomas G.; Rattner, Barnett A.; Lazarus, Rebecca S.; Day, Daniel D.; Burket, S. Rebekah; Brooks, Bryan W.; Haddad, Samuel P.; Bowerman, William W.

2018-01-01

Exposure of wildlife to Active Pharmaceutical Ingredients (APIs) is likely to occur but studies of risk are limited. One exposure pathway that has received attention is trophic transfer of APIs in a water-fish-osprey food chain. Samples of water, fish plasma and osprey plasma were collected from Delaware River and Bay, and analyzed for 21 APIs. Only 2 of 21 analytes exceeded method detection limits in osprey plasma (acetaminophen and diclofenac) with plasma levels typically 2–3 orders of magnitude below human therapeutic concentrations (HTC). We built upon a screening level model used to predict osprey exposure to APIs in Chesapeake Bay and evaluated whether exposure levels could have been predicted in Delaware Bay had we just measured concentrations in water or fish. Use of surface water and BCFs did not predict API concentrations in fish well, likely due to fish movement patterns, and partitioning and bioaccumulation uncertainties associated with these ionizable chemicals. Input of highest measured API concentration in fish plasma combined with pharmacokinetic data accurately predicted that diclofenac and acetaminophen would be the APIs most likely detected in osprey plasma. For the majority of APIs modeled, levels were not predicted to exceed 1 ng/mL or method detection limits in osprey plasma. Based on the target analytes examined, there is little evidence that APIs represent a significant risk to ospreys nesting in Delaware Bay. If an API is present in fish orders of magnitude below HTC, sampling of fish-eating birds is unlikely to be necessary. However, several human pharmaceuticals accumulated in fish plasma within a recommended safety factor for HTC. It is now important to expand the scope of diet-based API exposure modeling to include alternative exposure pathways (e.g., uptake from landfills, dumps and wastewater treatment plants) and geographic locations (developing countries) where API contamination of the environment may represent greater risk.

The use of aquatic bioconcentration factors in ecological risk assessments: Confounding issues, laboratory v/s modeled results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brandt, C.; Blanton, M.L.; Dirkes, R.

1995-12-31

Bioconcentration in aquatic systems is generally taken to refer to contaminant uptake through non-ingestion pathways (i.e., dermal and respiration uptake). Ecological risk assessments performed on aquatic systems often rely on published data on bioconcentration factors to calibrate models of exposure. However, many published BCFs, especially those from in situ studies, are confounded by uptake from ingestion of prey. As part of exposure assessment and risk analysis of the Columbia River`s Hanford Reach, the authors tested a methodology to estimate radionuclide BCFs for several aquatic species in the Hanford Reach of the Columbia River. The iterative methodology solves for BCFs frommore » known body burdens and environmental media concentrations. This paper provides BCF methodology description comparisons of BCF from literature and modeled values and how they were used in the exposure assessment and risk analysis of the Columbia River`s Hanford Reach.« less

Fullerene Nanoparticles Exhibit Greater Retention in Freshwater Sediment than in Model Porous Media

EPA Science Inventory

Increasing production and use of fullerene-based nanomaterials underscore the need to determine their mobility in environmental transport pathways and potential ecological exposures. This study investigated the transport of two fullerenes (i.e., aqu/C(60) and water-soluble C(60) ...

DOSE RECONSTRUCTION FROM URINARY BIOMARKERS USING PHARMACOKINETIC MODELS

EPA Science Inventory

The use of biomarkers for human health risk assessment is attractive because they are an indicator of the dose that actually entered the body by all mechanisms. This is an important consideration given the need to include aggregate exposures from diet and other pathways for pes...

VITELLOGENIN ELISA FOR FATHEAD MINNOWS (PIMEPHALES PROMELAS) USING A COMPLETELY HOMOLOGOUS ASSAY SYSTEMS

EPA Science Inventory

The indication of vitellogenin in fish has been used as a biomarker for estrogen-receptor mediated gene induction pathways resulting from exposure to environmental estrogens. Pimephales promelas (fathead minnows) have been selected as one of the test models to investigate reprodu...

Quantitative Adverse Outcome Pathway for Neurodevelopmental Effects of Thyroid Peroxidase-Induced Thyroid Hormone Synthesis Inhibition

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development and deficiencies lead to adverse neurological outcomes in humans and in animal models. Environmental chemicals have been shown to disrupt TH levels, yet the relationship between developmental exposur...

The Genetic Basis for Variation in Sensitivity to Lead Toxicity in Drosophila melanogaster.

PubMed

Zhou, Shanshan; Morozova, Tatiana V; Hussain, Yasmeen N; Luoma, Sarah E; McCoy, Lenovia; Yamamoto, Akihiko; Mackay, Trudy F C; Anholt, Robert R H

2016-07-01

Lead toxicity presents a worldwide health problem, especially due to its adverse effects on cognitive development in children. However, identifying genes that give rise to individual variation in susceptibility to lead toxicity is challenging in human populations. Our goal was to use Drosophila melanogaster to identify evolutionarily conserved candidate genes associated with individual variation in susceptibility to lead exposure. To identify candidate genes associated with variation in susceptibility to lead toxicity, we measured effects of lead exposure on development time, viability and adult activity in the Drosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association analyses to identify candidate genes. We used mutants to assess functional causality of candidate genes and constructed a genetic network associated with variation in sensitivity to lead exposure, on which we could superimpose human orthologs. We found substantial heritabilities for all three traits and identified candidate genes associated with variation in susceptibility to lead exposure for each phenotype. The genetic architectures that determine variation in sensitivity to lead exposure are highly polygenic. Gene ontology and network analyses showed enrichment of genes associated with early development and function of the nervous system. Drosophila melanogaster presents an advantageous model to study the genetic underpinnings of variation in susceptibility to lead toxicity. Evolutionary conservation of cellular pathways that respond to toxic exposure allows predictions regarding orthologous genes and pathways across phyla. Thus, studies in the D. melanogaster model system can identify candidate susceptibility genes to guide subsequent studies in human populations. Zhou S, Morozova TV, Hussain YN, Luoma SE, McCoy L, Yamamoto A, Mackay TF, Anholt RR. 2016. The genetic basis for variation in sensitivity to lead toxicity in Drosophila melanogaster. Environ Health Perspect 124:1062-1070; http://dx.doi.org/10.1289/ehp.1510513.

Developmental Exposure to Estrogen Alters Differentiation and Epigenetic Programming in a Human Fetal Prostate Xenograft Model

PubMed Central

Saffarini, Camelia M.; McDonnell-Clark, Elizabeth V.; Amin, Ali; Huse, Susan M.; Boekelheide, Kim

2015-01-01

Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM) isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure. PMID:25799167

Evaluation of High-Throughput Chemical Exposure Models ...

EPA Pesticide Factsheets

The U.S. EPA, under its ExpoCast program, is developing high-throughput near-field modeling methods to estimate human chemical exposure and to provide real-world context to high-throughput screening (HTS) hazard data. These novel modeling methods include reverse methods to infer parent chemical exposures from biomonitoring measurements and forward models to predict multi-pathway exposures from chemical use information and/or residential media concentrations. Here, both forward and reverse modeling methods are used to characterize the relationship between matched near-field environmental (air and dust) and biomarker measurements. Indoor air, house dust, and urine samples from a sample of 120 females (aged 60 to 80 years) were analyzed. In the measured data, 78% of the residential media measurements (across 80 chemicals) and 54% of the urine measurements (across 21 chemicals) were censored, i.e. below the limit of quantification (LOQ). Because of the degree of censoring, we applied a Bayesian approach to impute censored values for 69 chemicals having at least 15% of measurements above LOQ. This resulted in 10 chemicals (5 phthalates, 5 pesticides) with matched air, dust, and urine metabolite measurements. The population medians of indoor air and dust concentrations were compared to population median exposures inferred from urine metabolites concentrations using a high-throughput reverse-dosimetry approach. Median air and dust concentrations were found to be correl

40 CFR 270.10 - General application requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... associated with transportation to or from the unit; (ii) The potential pathways of human exposure to... resulting from both direct and indirect exposure pathways. The Director may also require a permittee or...

Applying Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks to link toxicity testing data to exposure-relevant and biologically-relevant responses

EPA Science Inventory

Hazard assessment for nanomaterials often involves applying in vitro dose-response data to estimate potential health risks that arise from exposure to products that contain nanomaterials. However, much uncertainty is inherent in relating bioactivities observed in an in vitro syst...

MEASUREMENT OF MULTI-POLLUTANT AND MULTI-PATHWAY EXPOSURES IN A PROBABILITY-BASED SAMPLE OF CHILDREN: PRACTICAL STRATEGIES FOR EFFECTIVE FIELD STUDIES

EPA Science Inventory

The purpose of this manuscript is to describe the practical strategies developed for the implementation of the Minnesota Children's Pesticide Exposure Study (MNCPES), which is one of the first probability-based samples of multi-pathway and multi-pesticide exposures in children....

Cross-species integration of human health and ecological endpoints into risk assessment using the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks

EPA Science Inventory

Exposure to environmental contaminants can influence both human health and ecological endpoints. Chemical risk assessments combine exposure and toxicity data to estimate the likelihood of adverse outcomes for these endpoints, but are rarely conducted in a manner that integrates ...

What We Have Learned from Animal Models of Dry Eye

PubMed Central

Stern, Michael E.; Pflugfelder, Stephen C.

2017-01-01

Animal models have proved valuable to investigate the pathogenesis of dry eye disease, identify therapeutic targets and the efficacy of candidate therapeutics for dry eye. Pharmacological inhibition of the lacrimal functional unit and exposure of the mouse eye to desiccating stress was found to activate innate immune pathways, promote dendritic cell maturation and initiate an adaptive T cell response to ocular surface antigens. Disease relevant mediators and pathways have been identified through use of genetically altered mice, specific inhibitors and adoptive transfer of desiccating stress primed CD4+ T cells to naïve recipients. Findings from mouse models have elucidated the mechanism of action of cyclosporine A and the rationale for developing lifitegrast, the two currently approved therapeutics in the US. PMID:28282318

The effect of tributyltin chloride on Caenorhabditis elegans germline is mediated by a conserved DNA damage checkpoint pathway.

PubMed

Cheng, Zhe; Tian, Huimin; Chu, Hongran; Wu, Jianjian; Li, Yingying; Wang, Yanhai

2014-03-21

Tributyltin (TBT), one of the environmental pollutants, has been shown to impact the reproduction of animals. However, due to the lack of appropriate animal model, analysis of the affected molecular pathways in germ cells is lagging and has been particularly challenging. In the present study, we investigated the effects of tributyltin chloride (TBTCL) on the nematode Caenorhabditis elegans germline. We show that exposure of C. elegans to TBTCL causes significantly elevated level of sterility and embryonic lethality. TBTCL exposure results in an increased number of meiotic DNA double-strand breaks in germ cells, subsequently leading to activated DNA damage checkpoint. Exposing C. elegans to TBTCL causes dose- and time-dependent germline apoptosis. This apoptotic response was blocked in loss-of-function mutants of hus-1 (op241), mrt-2 (e2663) and p53/cep-1 (gk138), indicating that checkpoints and p53 are essential for mediating TBTCL-induced germ cell apoptosis. Moreover, TBTCL exposure can inhibit germ cell proliferation, which is also mediated by the conserved checkpoint pathway. We thereby propose that TBT exhibits its effects on the germline by inducing DNA damage and impaired maintenance of genomic integrity. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Principles for developing animal models of military PTSD

PubMed Central

Daskalakis, Nikolaos P.; Yehuda, Rachel

2014-01-01

The extent to which animal studies can be relevant to military posttraumatic stress disorder (PTSD) continues to be a matter of discussion. Some features of the clinical syndrome are more easily modeled than others. In the animal literature, a great deal of attention is focused on modeling the characteristics of military exposures and their impact on measurable behaviors and biological parameters. There are many issues to consider regarding the ecological validity of predator, social defeat or immobilization stress to combat-related experience. In contrast, less attention has been paid to individual variation following these exposures. Such variation is critical to understand how individual differences in the response to military trauma exposure may result to PTSD or resilience. It is important to consider potential differences in biological findings when comparing extremely exposed to non-exposed animals, versus those that result from examining individual differences. Animal models of military PTSD are also critical in advancing efforts in clinical treatment. In an ideal translational approach to study deployment related outcomes, information from humans and animals, blood and brain, should be carefully considered in tandem, possibly even computed simultaneously, to identify molecules, pathways and networks that are likely to be the key drivers of military PTSD symptoms. With the use novel biological methodologies (e.g., optogenetics) in the animal models, critical genes and pathways can be tuned up or down (rather than over-expressed or ablated completely) in discrete brain regions. Such techniques together with pre-and post-deployment human imaging will accelerate the identification of novel pharmacological and non-pharmacological intervention strategies. PMID:25206946

Sulfanegen sodium treatment in a rabbit model of sub-lethal cyanide toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brenner, Matthew, E-mail: mbrenner@uci.ed; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Irvine, CA 92868; Kim, Jae G.

2010-11-01

The aim of this study is to investigate the ability of intramuscular and intravenous sulfanegen sodium treatment to reverse cyanide effects in a rabbit model as a potential treatment for mass casualty resulting from cyanide exposure. Cyanide poisoning is a serious chemical threat from accidental or intentional exposures. Current cyanide exposure treatments, including direct binding agents, methemoglobin donors, and sulfur donors, have several limitations. Non-rhodanese mediated sulfur transferase pathways, including 3-mercaptopyruvate sulfurtransferase (3-MPST) catalyze the transfer of sulfur from 3-MP to cyanide, forming pyruvate and less toxic thiocyanate. We developed a water-soluble 3-MP prodrug, 3-mercaptopyruvatedithiane (sulfanegen sodium), with the potentialmore » to provide a continuous supply of substrate for CN detoxification. In addition to developing a mass casualty cyanide reversal agent, methods are needed to rapidly and reliably diagnose and monitor cyanide poisoning and reversal. We use non-invasive technology, diffuse optical spectroscopy (DOS) and continuous wave near infrared spectroscopy (CWNIRS) to monitor physiologic changes associated with cyanide exposure and reversal. A total of 35 animals were studied. Sulfanegen sodium was shown to reverse the effects of cyanide exposure on oxyhemoglobin and deoxyhemoglobin rapidly, significantly faster than control animals when administered by intravenous or intramuscular routes. RBC cyanide levels also returned to normal faster following both intramuscular and intravenous sulfanegen sodium treatment than controls. These studies demonstrate the clinical potential for the novel approach of supplying substrate for non-rhodanese mediated sulfur transferase pathways for cyanide detoxification. DOS and CWNIRS demonstrated their usefulness in optimizing the dose of sulfanegen sodium treatment.« less

Contamination and radiation exposure in central Europe after the Chernobyl accident

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bayer, A.; Mueck, K.; Loosli, H.H.

1996-06-01

Ten years ago, on 26 April 1986, as a consequence of an accident in Unit 4 of the Chernobyl-NPP, a large quantity of radioactive material was released into the atmosphere for some days. This material was spread over wide areas of Europe. Due to variable weather conditions the activity concentrations in air varied considerably in different regions. Also as a consequence of large variations in precipitation intensity-particularly in the regions of Southeastern Germany, Austria and Southern Switzerland-up to 100 kBq m{sup -2} {sup 137}Cs were deposited on the soil. Due to fallout, washout, and/or rainout, a range of foodstuffs weremore » contaminated, and foodstuffs directly exposed to the fallout [vegetables and green fodder (grass)] showed the highest contamination levels. Consequently, milk also showed a significantly increased activity concentration, in particular of {sup 131}I. In the following years contamination in all kinds of foodstuffs decreased, but elevated contamination levels in special pathways like venison and mushrooms are still observed to date. This contamination resulted in additional exposure, mainly due to external radiation from ground and from consumption of contaminated food. The radiation exposure in the most contaminated areas was calculated on the basis of model assumptions and was found to be about 1 mSv during the first year after the accident. Using this model, the ingestion pathway was overestimated by at least a factor of two. This additional exposure decreased and is now less than 1 % on average; in the most contaminated areas, this is a few percent of the average natural radiation exposure.« less

Ethnic Diversity, Inter-group Attitudes and Countervailing Pathways of Positive and Negative Inter-group Contact: An Analysis Across Workplaces and Neighbourhoods.

PubMed

Laurence, James; Schmid, Katharina; Hewstone, Miles

2018-01-01

This study advances the current literature investigating the relationship between contextual out-group exposure, inter-group attitudes and the role of inter-group contact. Firstly, it introduces the concept of contact-valence into this relationship; that is, whether contact is experienced positively or negatively. Secondly, it presents a comparative analysis of how processes of out-group exposure and frequency of (valenced) contact affect prejudice across both neighbourhoods and workplaces. Applying path analysis modelling to a nationally-representative sample of white British individuals in England, we demonstrate, across both contexts, that increasing out-group exposure is associated with higher rates of both positively- and negatively-valenced contact. This results in exposure exhibiting both positive and negative indirect associations with prejudice via more frequent inter-group mixing. These countervailing contact-pathways help explain how out-group exposure is associated with inter-group attitudes. In neighbourhoods, increasing numbers of individuals experiencing positive-contact suppress an otherwise negative effect of neighbourhood diversity (driven partly by increasing numbers of individuals reporting negative contact). Across workplaces the effect differs such that increasing numbers of individuals experiencing negative-contact suppress an otherwise positive effect of workplace diversity (driven largely by increasing numbers of individuals experiencing positive contact).

Evaluation of in vitro vs. in vivo methods for assessment of dermal absorption of organic flame retardants: a review.

PubMed

Abdallah, Mohamed Abou-Elwafa; Pawar, Gopal; Harrad, Stuart

2015-01-01

There is a growing interest to study human dermal exposure to a large number of chemicals, whether in the indoor or outdoor environment. Such studies are essential to predict the systemic exposure to xenobiotic chemicals for risk assessment purposes and to comply with various regulatory guidelines. However, very little is currently known about human dermal exposure to persistent organic pollutants. While recent pharmacokinetic studies have highlighted the importance of dermal contact as a pathway of human exposure to brominated flame retardants, risk assessment studies had to apply assumed values for percutaneous penetration of various flame retardants (FRs) due to complete absence of specific experimental data on their human dermal bioavailability. Therefore, this article discusses the current state-of-knowledge on the significance of dermal contact as a pathway of human exposure to FRs. The available literature on in vivo and in vitro methods for assessment of dermal absorption of FRs in human and laboratory animals is critically reviewed. Finally, a novel approach for studying human dermal absorption of FRs using in vitro three-dimensional (3D) human skin equivalent models is presented and the challenges facing future dermal absorption studies on FRs are highlighted. Copyright © 2014 Elsevier Ltd. All rights reserved.

Role of oxidative stress in cardiovascular disease outcomes following exposure to ambient air pollution.

PubMed

Kelly, Frank J; Fussell, Julia C

2017-09-01

Exposure to ambient air pollution is associated with adverse cardiovascular outcomes. These are manifested through several, likely overlapping, pathways including at the functional level, endothelial dysfunction, atherosclerosis, pro-coagulation and alterations in autonomic nervous system balance and blood pressure. At numerous points within each of these pathways, there is potential for cellular oxidative imbalances to occur. The current review examines epidemiological, occupational and controlled exposure studies and research employing healthy and diseased animal models, isolated organs and cell cultures in assessing the importance of the pro-oxidant potential of air pollution in the development of cardiovascular disease outcomes. The collective body of data provides evidence that oxidative stress (OS) is not only central to eliciting specific cardiac endpoints, but is also implicated in modulating the risk of succumbing to cardiovascular disease, sensitivity to ischemia/reperfusion injury and the onset and progression of metabolic disease following ambient pollution exposure. To add to this large research effort conducted to date, further work is required to provide greater insight into areas such as (a) whether an oxidative imbalance triggers and/or worsens the effect and/or is representative of the consequence of disease progression, (b) OS pathways and cardiac outcomes caused by individual pollutants within air pollution mixtures, or as a consequence of inter-pollutant interactions and (c) potential protection provided by nutritional supplements and/or pharmacological agents with antioxidant properties, in susceptible populations residing in polluted urban cities. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Critical radionuclide/critical pathway analysis for the U.S. Department of Energy's Savannah River Site.

PubMed

Jannik, G T

1999-06-01

Many different radionuclides have been released to the environment from the Savannah River Site (SRS) during the facility's operational history. However, as shown by this analysis, only a small number of the released radionuclides have been significant contributors to potential doses and risks to off-site people. This article documents the radiological critical contaminant/critical pathway analysis performed for SRS. If site missions and operations remain constant over the next 30 years, only tritium oxide releases are projected to exceed a maximally exposed individual (MEI) risk of 1.0E-06 for either the airborne or liquid pathways. The critical exposure pathways associated with site airborne releases are inhalation and vegetation consumption, whereas the critical exposure pathways associated with liquid releases are drinking water and fish consumption. For the SRS-specific, nontypical exposure pathways (i.e., recreational fishing and deer and hog hunting), cesium-137 is the critical radionuclide.

Joint inhibition of TOR and JNK pathways interacts to extend the lifespan of Brachionus manjavacas (Rotifera)

PubMed Central

Snell, Terry W.; Johnston, Rachel K.; Rabeneck, Brett; Zipperer, Cody; Teat, Stephanie

2014-01-01

The TOR kinase pathway is central in modulating aging in a variety of animal models. The target of rapamycin (TOR) integrates a complex network of signals from growth conditions, nutrient availability, energy status, and physiological stresses and matches an organism’s growth rate to the resource environment. Important problems remaining are to identify the pathways that interact with TOR and characterize them as additive or synergistic. One of the most versatile stress sensors in metazoans is the Jun-N-terminal Kinase (JNK) signalling pathway. JNK is an evolutionarily conserved stress-activated protein kinase that is induced by a range of stressors, including UV irradiation, reactive oxygen species, DNA damage, heat, and bacterial antigens. JNK is thought to interact with the TOR pathway, but its effects on TOR are poorly understood. We used the rotifer Brachionus manjavacas as a model animal to probe the regulation of TOR and JNK pathways and explore their interaction. The effect of various chemical inhibitors was examined in life table and stressor challenge experiments. A survey of 12 inhibitors revealed two, rapamycin and JNK inhibitor, that significantly extended lifespan of B. manjavacas. At 1 μM concentration, exposure to rapamycin or JNK inhibitor extended mean rotifer lifespan by 35% and maximum lifespan by 37%. Exposure to both rapamycin and JNK inhibitor simultaneously extended mean rotifer lifespan 65% more than either alone. Exposure to a combination of rapamycin and JNK inhibitors conveyed greater protection to starvation, UV and osmotic stress than either inhibitor alone. RNAi knockdown of TOR and JNK gene expression was investigated for its ability to extend rotifer lifespan. RNAi knockdown of the TOR gene resulted in 29% extension of mean lifespan compared to control and knockdown of the JNK gene resulted in 51% mean lifespan extension. In addition to lifespan, we quantified mitochondria activity using the fluorescent marker Mitotracker and lysosome activity using Lysotracker. Treatment of rotifers with JNK inhibitor enhanced mitochondria activity nearly 3-fold, whereas rapamycin treatment had no significant effect. Treatment of rotifers with rapamycin or JNK inhibitor reduced lysosome activity in 1, 3 and 8 day old animals, but treatment with both inhibitors did not produce any additive effect. We conclude that inhibition of TOR and JNK pathways significantly extends the lifespan of B. manjavacas. These pathways interact so that inhibition of both simultaneously acts additively to extend rotifer lifespan more than inhibition of either alone. PMID:24486130

Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

PubMed Central

Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan

2015-01-01

Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression. PMID:26114099

Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression.

PubMed

Chang, Chia-Yu; Guo, How-Ran; Tsai, Wan-Chen; Yang, Kai-Lin; Lin, Li-Chuan; Cheng, Tain-Junn; Chuu, Jiunn-Jye

2015-01-01

Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

Metabolic Profiling as Well as Stable Isotope Assisted Metabolic and Proteomic Analysis of RAW 264.7 Macrophages Exposed to Ship Engine Aerosol Emissions: Different Effects of Heavy Fuel Oil and Refined Diesel Fuel

PubMed Central

Sapcariu, Sean C.; Kanashova, Tamara; Dilger, Marco; Diabaté, Silvia; Oeder, Sebastian; Passig, Johannes; Radischat, Christian; Buters, Jeroen; Sippula, Olli; Streibel, Thorsten; Paur, Hanns-Rudolf; Schlager, Christoph; Mülhopt, Sonja; Stengel, Benjamin; Rabe, Rom; Harndorf, Horst; Krebs, Tobias; Karg, Erwin; Gröger, Thomas; Weiss, Carsten; Dittmar, Gunnar; Hiller, Karsten; Zimmermann, Ralf

2016-01-01

Exposure to air pollution resulting from fossil fuel combustion has been linked to multiple short-term and long term health effects. In a previous study, exposure of lung epithelial cells to engine exhaust from heavy fuel oil (HFO) and diesel fuel (DF), two of the main fuels used in marine engines, led to an increased regulation of several pathways associated with adverse cellular effects, including pro-inflammatory pathways. In addition, DF exhaust exposure was shown to have a wider response on multiple cellular regulatory levels compared to HFO emissions, suggesting a potentially higher toxicity of DF emissions over HFO. In order to further understand these effects, as well as to validate these findings in another cell line, we investigated macrophages under the same conditions as a more inflammation-relevant model. An air-liquid interface aerosol exposure system was used to provide a more biologically relevant exposure system compared to submerged experiments, with cells exposed to either the complete aerosol (particle and gas phase), or the gas phase only (with particles filtered out). Data from cytotoxicity assays were integrated with metabolomics and proteomics analyses, including stable isotope-assisted metabolomics, in order to uncover pathways affected by combustion aerosol exposure in macrophages. Through this approach, we determined differing phenotypic effects associated with the different components of aerosol. The particle phase of diluted combustion aerosols was found to induce increased cell death in macrophages, while the gas phase was found more to affect the metabolic profile. In particular, a higher cytotoxicity of DF aerosol emission was observed in relation to the HFO aerosol. Furthermore, macrophage exposure to the gas phase of HFO leads to an induction of a pro-inflammatory metabolic and proteomic phenotype. These results validate the effects found in lung epithelial cells, confirming the role of inflammation and cellular stress in the response to combustion aerosols. PMID:27348622

Risk to pollinators from the use of chlorpyrifos in the United States.

PubMed

Cutler, G Christopher; Purdy, John; Giesy, John P; Solomon, Keith R

2014-01-01

CPY is an organophosphorus insecticide that is widely used in North American agriculture. It is non-systemic, comes in several sprayable and granular formulations,and is used on a number of high-acreage crops on which pollinators can forage,including tree fruits, alfalfa, corn, sunflower, and almonds. Bees (Apoidea) are the most important pollinators of agricultural crops in North America and were the main pollinators of interest in this risk assessment.The conceptual model identified a number of potential exposure pathways for pollinators, some more significant than others. CPY is classified as being highly toxic to honey bees by direct contact exposure. However, label precautions and good agricultural practices prohibit application of CPY when bees are flying and/or when flowering crops or weeds are present in the treatment area. Therefore, the risk of CPY to pollinators through direct contact exposure should be small. The main hazards for primary exposure for honey bees are dietary and contact exposure from flowers that were sprayed during application and remain available to bees after application. The main pathways for potential secondary exposure to CPY is through pollen and nectar brought to the hive by forager bees and the sublethal body burden of CPY carried on forager bees. Foraging for other materials, including water or propolis, does not appear to be an important exposure route. Since adult forager honey bees are most exposed, their protection from exposure via pollen, honey, and contact with plant surfaces is expected to be protective of other life stages and castes of honey bees.Tier- I approaches to estimate oral exposure to CPY through pollen and nectar/honey, the principle food sources for honey bees, suggested that CPY poses a risk to honey bees through consumption of pollen and nectar. However, a Tier-2 assessment of concentrations reported in pollen and honey from monitoring work in North America indicated there is little risk of acute toxicity from CPY through consumption of these food sources.Several models were also used to estimate upper-limit exposure of honey bees to CPY through consumption of water from puddles or dew. All models suggest that the risk of CPY is below the LOC for this pathway. Laboratory experiments with field-treated foliage, and semi-field and field tests with honey bees, bumble bees,and alfalfa leaf cutting bees indicate that exposure to foliage, pollen and/or nectar is hazardous to bees up to 3 d after application of CPY to a crop. Pollinators exposed to foliage, pollen or nectar after this time should be minimally affected.Several data gaps and areas of uncertainty were identified, which apply to CPYand other foliar insecticides. These primarily concern the lack of exposure and toxicological data on non-Apis pollinators. Overall, the rarity of reported bee kill incidents involving CPY indicates that compliance with the label precautions and good agricultural practice with the product is the norm in North American agriculture.Overall, we concluded that, provided label directions and good agricultural practices are followed, the use of CPY in agriculture in North America does not present an unacceptable risk to honeybees.

Nonradiological chemical pathway analysis and identification of chemicals of concern for environmental monitoring at the Hanford Site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blanton, M.L.; Cooper, A.T.; Castleton, K.J.

1995-11-01

Pacific Northwest`s Surface Environmental Surveillance Project (SESP) is an ongoing effort tot design, review, and conducted monitoring on and off the Hanford site. Chemicals of concern that were selected are listed. Using modeled exposure pathways, the offsite cancer incidence and hazard quotient were calculated and a retrospective pathway analysis performed to estimate what onsite concentrations would be required in the soil for each chemical of concern and other detected chemicals that would be required to obtain an estimated offsite human-health risk of 1.0E-06 cancer incidence or 1.0 hazard quotient. This analysis indicates that current nonradiological chemical contamination occurring on themore » site does not pose a significant offsite human-health risk; the highest cancer incidence to the offsite maximally exposed individual was from arsenic (1.76E-10); the highest hazard quotient was chromium(VI) (1.48E-04). The most sensitive pathways of exposure were surfacewater and aquatic food consumption. Combined total offsite excess cancer incidence was 2.09E-10 and estimated hazard quotient was 2.40E-04. Of the 17 identified chemicals of concern, the SESP does not currently (routinely) monitor arsenic, benzo(a)pyrene, bis(2- ethylhexyl)phthalate (BEHP), and chrysene. Only 3 of the chemicals of concern (arsenic, BEHP, chloroform) could actually occur in onsite soil at concern high enough to cause a 1.0E-06 excess cancer incidence or a 1.0 hazard index for a given offsite exposure pathway. During the retrospective analysis, 20 other chemicals were also evaluated; only vinyl chloride and thallium could reach targeted offsite risk values.« less

Activation of VEGF/Flk-1-ERK Pathway Induced Blood-Brain Barrier Injury After Microwave Exposure.

PubMed

Wang, Li-Feng; Li, Xiang; Gao, Ya-Bing; Wang, Shui-Ming; Zhao, Li; Dong, Ji; Yao, Bin-Wei; Xu, Xin-Ping; Chang, Gong-Min; Zhou, Hong-Mei; Hu, Xiang-Jun; Peng, Rui-Yun

2015-08-01

Microwaves have been suggested to induce neuronal injury and increase permeability of the blood-brain barrier (BBB), but the mechanism remains unknown. The role of the vascular endothelial growth factor (VEGF)/Flk-1-Raf/MAPK kinase (MEK)/extracellular-regulated protein kinase (ERK) pathway in structural and functional injury of the blood-brain barrier (BBB) following microwave exposure was examined. An in vitro BBB model composed of the ECV304 cell line and primary rat cerebral astrocytes was exposed to microwave radiation (50 mW/cm(2), 5 min). The structure was observed by scanning electron microscopy (SEM) and the permeability was assessed by measuring transendothelial electrical resistance (TEER) and horseradish peroxidase (HRP) transmission. Activity and expression of VEGF/Flk-1-ERK pathway components and occludin also were examined. Our results showed that microwave radiation caused intercellular tight junctions to broaden and fracture with decreased TEER values and increased HRP permeability. After microwave exposure, activation of the VEGF/Flk-1-ERK pathway and Tyr phosphorylation of occludin were observed, along with down-regulated expression and interaction of occludin with zonula occludens-1 (ZO-1). After Flk-1 (SU5416) and MEK1/2 (U0126) inhibitors were used, the structure and function of the BBB were recovered. The increase in expression of ERK signal transduction molecules was muted, while the expression and the activity of occludin were accelerated, as well as the interactions of occludin with p-ERK and ZO-1 following microwave radiation. Thus, microwave radiation may induce BBB damage by activating the VEGF/Flk-1-ERK pathway, enhancing Tyr phosphorylation of occludin, while partially inhibiting expression and interaction of occludin with ZO-1.

Transcriptome changes induced in vitro by alcohol-containing mouthwashes in normal and dysplastic oral keratinocytes.

PubMed

Fox, Simon A; Currie, Sean S; Dalley, Andrew J; Farah, Camile S

2018-05-01

The role of alcohol-containing mouthwash as a risk factor for the development of oral cancer is a subject of conflicting epidemiological evidence in the literature despite alcohol being a recognised carcinogen. The aim of this study was to use in vitro models to investigate mechanistic and global gene expression effects of exposure to alcohol-containing mouthwash. Two brands of alcohol-containing mouthwash and their alcohol-free counterparts were used to treat two oral cell lines derived from normal (OKF6-TERT) and dysplastic (DOK) tissues. Genotoxicity was determined by Comet assay. RNA-seq was performed using the Ion Torrent platform. Bioinformatics analysis used R/Bioconductor packages with differential expression using DEseq2. Pathway enrichment analysis used EnrichR with the WikiPathways and Kegg databases. Both cell lines displayed dose-dependent DNA damage in response to acute exposure to ethanol and alcohol-containing mouthwashes as well as alcohol-free mouthwashes reconstituted with ethanol as shown by Comet assay. The transcriptomic effects of alcohol-containing mouthwash exposure were more complex with significant differential gene expression ranging from >2000 genes in dysplastic (DOK) cells to <100 genes in normal (OKF6-TERT) cells. Pathway enrichment analysis in DOK cells revealed alcohol-containing mouthwashes showed common features between the two brands used including DNA damage response as well as cancer-associated pathways. In OKF6-TERT cells, the most significantly enriched pathways involved inflammatory signalling. Alcohol-containing mouthwashes are genotoxic in vitro to normal and dysplastic oral keratinocytes and induce widespread changes in gene expression. Dysplastic cells are more susceptible to the transcriptomic effects of mouthwash. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Probabilistic Modeling of Childhood Multimedia Lead Exposures: Examining the Soil Ingestion Pathway

EPA Science Inventory

BACKGROUND: Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)’s National Drinking Water Advis...

Neurodevelopment and Thyroid Hormone Synthesis Inhibition in the Rat: Quantitative Understanding Within the Adverse Outcome Pathway Framework

EPA Science Inventory

Adequate levels of thyroid hormones (TH) are needed for proper brain development, deficiencies may lead to adverse neurological outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures an...

NCCT ToxCast Program for Nanomaterial Prioritization: High-Throughput Screening, Consideration of Exposure, and Bioactivity Profiling/Modeling

EPA Science Inventory

Find relationships between bioactivities and NM characteristics or testing conditions. Recommend a dose metric for NMs in vitro studies. Establish associations to in vivo toxicity or pathways identified from testing of conventional chemicals with ToxCast HTS methods. May be abl...

TOR and ageing: a complex pathway for a complex process

PubMed Central

McCormick, Mark A.; Tsai, Shih-yin; Kennedy, Brian K.

2011-01-01

Studies in invertebrate model organisms have led to a wealth of knowledge concerning the ageing process. But which of these discoveries will apply to ageing in humans? Recently, an assessment of the degree of conservation of ageing pathways between two of the leading invertebrate model organisms, Saccharomyces cerevisiae and Caenorhabditis elegans, was completed. The results (i) quantitatively indicated that pathways were conserved between evolutionarily disparate invertebrate species and (ii) emphasized the importance of the TOR kinase pathway in ageing. With recent findings that deletion of the mTOR substrate S6K1 or exposure of mice to the mTOR inhibitor rapamycin result in lifespan extension, mTOR signalling has become a major focus of ageing research. Here, we address downstream targets of mTOR signalling and their possible links to ageing. We also briefly cover other ageing genes identified by comparing worms and yeast, addressing the likelihood that their mammalian counterparts will affect longevity. PMID:21115526

Waveband specific transcriptional control of select genetic pathways in vertebrate skin (Xiphophorus maculatus).

PubMed

Walter, Ronald B; Boswell, Mikki; Chang, Jordan; Boswell, William T; Lu, Yuan; Navarro, Kaela; Walter, Sean M; Walter, Dylan J; Salinas, Raquel; Savage, Markita

2018-05-10

Evolution occurred exclusively under the full spectrum of sunlight. Conscription of narrow regions of the solar spectrum by specific photoreceptors suggests a common strategy for regulation of genetic pathways. Fluorescent light (FL) does not possess the complexity of the solar spectrum and has only been in service for about 60 years. If vertebrates evolved specific genetic responses regulated by light wavelengths representing the entire solar spectrum, there may be genetic consequences to reducing the spectral complexity of light. We utilized RNA-Seq to assess changes in the transcriptional profiles of Xiphophorus maculatus skin after exposure to FL ("cool white"), or narrow wavelength regions of light between 350 and 600 nm (i.e., 50 nm or 10 nm regions, herein termed "wavebands"). Exposure to each 50 nm waveband identified sets of genes representing discrete pathways that showed waveband specific transcriptional modulation. For example, 350-400 or 450-500 nm waveband exposures resulted in opposite regulation of gene sets marking necrosis and apoptosis (i.e., 350-400 nm; necrosis suppression, apoptosis activation, while 450-500 nm; apoptosis suppression, necrosis activation). Further investigation of specific transcriptional modulation employing successive 10 nm waveband exposures between 500 and 550 nm showed; (a) greater numbers of genes may be transcriptionally modulated after 10 nm exposures, than observed for 50 nm or FL exposures, (b) the 10 nm wavebands induced gene sets showing greater functional specificity than 50 nm or FL exposures, and (c) the genetic effects of FL are primarily due to 30 nm between 500 and 530 nm. Interestingly, many genetic pathways exhibited completely opposite transcriptional effects after different waveband exposures. For example, the epidermal growth factor (EGF) pathway exhibits transcriptional suppression after FL exposure, becomes highly active after 450-500 nm waveband exposure, and again, exhibits strong transcriptional suppression after exposure to the 520-530 nm waveband. Collectively, these results suggest one may manipulate transcription of specific genetic pathways in skin by exposure of the intact animal to specific wavebands of light. In addition, we identify genes transcriptionally modulated in a predictable manner by specific waveband exposures. Such genes, and their regulatory elements, may represent valuable tools for genetic engineering and gene therapy protocols.

Coupled near-field and far-field exposure assessment framework for chemicals in consumer products.

PubMed

Fantke, Peter; Ernstoff, Alexi S; Huang, Lei; Csiszar, Susan A; Jolliet, Olivier

2016-09-01

Humans can be exposed to chemicals in consumer products through product use and environmental emissions over the product life cycle. Exposure pathways are often complex, where chemicals can transfer directly from products to humans during use or exchange between various indoor and outdoor compartments until sub-fractions reach humans. To consistently evaluate exposure pathways along product life cycles, a flexible mass balance-based assessment framework is presented structuring multimedia chemical transfers in a matrix of direct inter-compartmental transfer fractions. By matrix inversion, we quantify cumulative multimedia transfer fractions and exposure pathway-specific product intake fractions defined as chemical mass taken in by humans per unit mass of chemical in a product. Combining product intake fractions with chemical mass in the product yields intake estimates for use in life cycle impact assessment and chemical alternatives assessment, or daily intake doses for use in risk-based assessment and high-throughput screening. Two illustrative examples of chemicals used in personal care products and flooring materials demonstrate how this matrix-based framework offers a consistent and efficient way to rapidly compare exposure pathways for adult and child users and for the general population. This framework constitutes a user-friendly approach to develop, compare and interpret multiple human exposure scenarios in a coupled system of near-field ('user' environment), far-field and human intake compartments, and helps understand the contribution of individual pathways to overall human exposure in various product application contexts to inform decisions in different science-policy fields for which exposure quantification is relevant. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Uptake Kinetics and Trophic Transfer of Tungsten from Cabbage to a Herbivorous Animal Model

DOE PAGES

Lindsay, James H.; Kennedy, Alan J.; Seiter-Moser, Jennifer M.; ...

2017-10-20

This paper builds on previous studies on military-relevant tungsten (W) to more thoroughly explore environmental pathways and bioaccumulation kinetics during direct soil exposure versus trophic transfer and elucidate its relative accumulation and speciation in different snail organs. The modeled steady-state concentration and bioaccumulation factor (BAF) of W from soil into cabbage were 302 mg/kg and 0.55, respectively. Steady-state concentrations (34 mg/kg) and BAF values (0.05) obtained for the snail directly exposed to contaminated soil were lower than trophic transfer by consumption of W-contaminated cabbage (tissue concentration of 86 mg/kg; BAF of 0.36). Thus, consumption of contaminated food is the mostmore » important pathway for W mobility in this food chain. The highest concentrations of W compartmentalization were in the snail’s hepatopancreas based on wet chemistry and synchrotron-based investigations. Chemical speciation via inductively couple plasma mass spectrometry showed a higher degree of polytungstate partitioning in the hepatopancreas relative to the rest of the body. Based on synchrotron analysis, W was incorporated into the shell matrix during exposure, particularly during the regeneration of damaged shell. Finally, this offers the potential for application of the shell as a longer-term biomonitoring and forensics tool for historic exposure.« less

Uptake Kinetics and Trophic Transfer of Tungsten from Cabbage to a Herbivorous Animal Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindsay, James H.; Kennedy, Alan J.; Seiter-Moser, Jennifer M.

This paper builds on previous studies on military-relevant tungsten (W) to more thoroughly explore environmental pathways and bioaccumulation kinetics during direct soil exposure versus trophic transfer and elucidate its relative accumulation and speciation in different snail organs. The modeled steady-state concentration and bioaccumulation factor (BAF) of W from soil into cabbage were 302 mg/kg and 0.55, respectively. Steady-state concentrations (34 mg/kg) and BAF values (0.05) obtained for the snail directly exposed to contaminated soil were lower than trophic transfer by consumption of W-contaminated cabbage (tissue concentration of 86 mg/kg; BAF of 0.36). Thus, consumption of contaminated food is the mostmore » important pathway for W mobility in this food chain. The highest concentrations of W compartmentalization were in the snail’s hepatopancreas based on wet chemistry and synchrotron-based investigations. Chemical speciation via inductively couple plasma mass spectrometry showed a higher degree of polytungstate partitioning in the hepatopancreas relative to the rest of the body. Based on synchrotron analysis, W was incorporated into the shell matrix during exposure, particularly during the regeneration of damaged shell. Finally, this offers the potential for application of the shell as a longer-term biomonitoring and forensics tool for historic exposure.« less

Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

NASA Astrophysics Data System (ADS)

Margiotta-Casaluci, Luigi; Owen, Stewart F.; Huerta, Belinda; Rodríguez-Mozaz, Sara; Kugathas, Subramanian; Barceló, Damià; Rand-Weaver, Mariann; Sumpter, John P.

2016-02-01

The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-species uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

Occupational exposure due to naturally occurring radionuclide material in granite quarry industry.

PubMed

Ademola, J A

2012-02-01

The potential occupational exposure in granite quarry industry due to the presence of naturally occurring radioactive material (NORM) has been investigated. The activity concentrations of (40)K, (226)Ra and (232)Th were determined using gamma-ray spectroscopy method. The annual effective dose of workers through different exposure pathways was determined by model calculations. The total annual effective dose varied from 21.48 to 33.69 μSv y(-1). Inhalation dose contributes the highest to the total effective dose. The results obtained were much lower than the intervention exemption levels (1.0 mSv y(-1)) given in the International Commission on Radiological Protection Publication 82.

The theory of "truth": how counterindustry campaigns affect smoking behavior among teens.

PubMed

Hershey, James C; Niederdeppe, Jeff; Evans, W Douglas; Nonnemaker, James; Blahut, Steven; Holden, Debra; Messeri, Peter; Haviland, M Lyndon

2005-01-01

This study used structural equation modeling to test a theory-based model of the pathways by which exposure to the "truth" counterindustry media campaign influenced beliefs, attitudes, and smoking behavior in national random-digit-dial telephone surveys of 16,000 12- to 17-year-olds before, 8 months after, and 15 months after campaign launch. Consistent with concepts from the theory of reasoned action, youth in markets with higher levels of campaign exposure had more negative beliefs about tobacco industry practices and more negative attitudes toward the tobacco industry. Models also provided support for a social inoculation effect, because negative industry attitudes were associated with lower receptivity to protobacco advertising and with less progression along a continuum of smoking intentions and behavior.

Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood-brain barrier primary triple coculture model.

PubMed

Xu, Liming; Dan, Mo; Shao, Anliang; Cheng, Xiang; Zhang, Cuiping; Yokel, Robert A; Takemura, Taro; Hanagata, Nobutaka; Niwa, Masami; Watanabe, Daisuke

2015-01-01

Silver nanoparticles (Ag-NPs) can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood-brain barrier (BBB) and the underlying mechanism(s) of action on the BBB and the brain are not well understood. To investigate Ag-NP suspension (Ag-NPS)-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM). Global gene expression of astrocytes was measured using a DNA microarray. A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200 Ω·cm(2). After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the tight junction (TJ) protein ZO-1 was decreased. Discontinuous TJs were also observed between microvascular endothelial cells. After Ag-NPS exposure, severe mitochondrial shrinkage, vacuolations, endoplasmic reticulum expansion, and Ag-NPs were observed in astrocytes by TEM. Global gene expression analysis showed that three genes were upregulated and 20 genes were downregulated in astrocytes treated with Ag-NPS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the 23 genes were associated with metabolic processes, biosynthetic processes, response to stimuli, cell death, the MAPK pathway, and so on. No GO term and KEGG pathways were changed in the released-ion or polystyrene-NP groups. Ag-NPS inhibited the antioxidant defense of the astrocytes by increasing thioredoxin interacting protein, which inhibits the Trx system, and decreasing Nr4a1 and Dusp1. Meanwhile, Ag-NPS induced inflammation and apoptosis through modulation of the MAPK pathway or B-cell lymphoma-2 expression or mTOR activity in astrocytes. These results draw our attention to the importance of Ag-NP-induced toxicity on the neurovascular unit and provide a better understanding of its toxicological mechanisms on astrocytes.

Physiologically based pharmacokinetic model for ethyl tertiary‐butyl ether and tertiary‐butyl alcohol in rats: Contribution of binding to α2u–globulin in male rats and high‐exposure nonlinear kinetics to toxicity and cancer outcomes

PubMed Central

Ring, Caroline; Banton, Marcy I.; Leavens, Teresa L.

2016-01-01

Abstract In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary‐butyl ether (ETBE), caused liver tumors in male rats, while tertiary‐butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary‐butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat‐specific protein α2u–globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0–∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male‐rat‐specific mode of action for TBA‐induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0–∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd PMID:27885692

Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether and tertiary-butyl alcohol in rats: Contribution of binding to α2u-globulin in male rats and high-exposure nonlinear kinetics to toxicity and cancer outcomes.

PubMed

Borghoff, Susan J; Ring, Caroline; Banton, Marcy I; Leavens, Teresa L

2017-05-01

In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary-butyl ether (ETBE), caused liver tumors in male rats, while tertiary-butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary-butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat-specific protein α2u-globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC 0-∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male-rat-specific mode of action for TBA-induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC 0-∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd.

Effect of Cumulating Exposure to Abacavir on the Risk of Cardiovascular Disease Events in Patients From the Swiss HIV Cohort Study.

PubMed

Young, Jim; Xiao, Yongling; Moodie, Erica E M; Abrahamowicz, Michal; Klein, Marina B; Bernasconi, Enos; Schmid, Patrick; Calmy, Alexandra; Cavassini, Matthias; Cusini, Alexia; Weber, Rainer; Bucher, Heiner C

2015-08-01

Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channeling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates. We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD. A total of 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient-years). In a conventional Cox model, recent--but not cumulative--exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past 4 years increased the risk of a CVD event (hazard ratio = 2.06; 95% confidence interval: 1.43 to 2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6-36 months caused the greatest increase in risk. Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.

A MODEL TO EVALUATE PAST EXPOSURE TO 2,3,7,8 ...

EPA Pesticide Factsheets

Data from several studies suggest that concentrations of dioxins rose in the environment from the 1930s to about the 1960s/70s and have been declining over the last decade or two. The most direct evidence of this trend comes from lake core sediments, which can be used to estimate past atmospheric depositions of dioxins. The primary source of human exposure to dioxins is through the food supply. The pathway relating atmospheric depositions to concentrations in food is quite complex, and accordingly, it is not known to what extent the trend in human exposure mirrors the trend in atmospheric depositions. This paper describes an attempt to statistically reconstruct the pattern of past human exposure to the most toxic dioxin congener, 2,3,7,8-TCDD (abbreviated TCDD), through use of a simple pharmacokinetic (PK) model which included a time-varying TCDD exposure dose. This PK model was fit to TCDD body burden data (i.e., TCDD concentrations in lipid) from five U.S. studies dating from 1972 to 1987 and covering a wide age range. A Bayesian statistical approach was used to fit TCDD exposure; model parameters other than exposure were all previously known or estimated from other data sources. The primary results of the analysis are as follows: 1.) use of a time-varying exposure dose provided a far better fit to the TCDD body burden data than did using a dose that was constant over time; this is strong evidence that exposure to TCDD has, in fact, varied during the

Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally.

PubMed

Barrett, Catherine E; Hennessey, Thomas M; Gordon, Katelyn M; Ryan, Steve J; McNair, Morgan L; Ressler, Kerry J; Rainnie, Donald G

2017-01-01

The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes.

Conditioning protects C. elegans from lethal effects of enteropathogenic E. coli through activation of genes that regulate lifespan and innate immunity

PubMed Central

Anyanful, Akwasi; Easley, Kirk A.; Benian, Guy M.; Kalman, Daniel

2010-01-01

SUMMARY Caenorhabditis elegans exhibit avoidance behavior when presented with diverse bacterial pathogens. We hypothesized that exposure to pathogens might not only cause worms to move away but also simultaneously activate pathways that promote resistance to the pathogen. We show that brief exposure to the virulent or avirulent strains of the bacterial pathogen enteropathogenic E. coli (EPEC) “conditions” or “immunizes” C. elegans to survive a subsequent exposure that would otherwise prove lethal. Conditioning requires dopaminergic neurons. Conditioning also requires the p38 MAP Kinase pathway, which regulates innate immunity, and the insulin/IGFR pathway, which regulates lifespan. Our findings suggest that the molecular pathways that regulate innate immunity and lifespan and provide protection may, in nature, be regulated or “conditioned” by exposure to pathogens, and perhaps allow survival in noxious environments. PMID:19454349

Modeling the Intra- and Extracellular Cytokine Signaling Pathway under Heat Stroke in the Liver

PubMed Central

Rodriguez-Fernandez, Maria; Grosman, Benyamin; Yuraszeck, Theresa M.; Helwig, Bryan G.; Leon, Lisa R.; Doyle III, Francis J.

2013-01-01

Heat stroke (HS) is a life-threatening illness induced by prolonged exposure to a hot environment that causes central nervous system abnormalities and severe hyperthermia. Current data suggest that the pathophysiological responses to heat stroke may not only be due to the immediate effects of heat exposure per se but also the result of a systemic inflammatory response syndrome (SIRS). The observation that pro- (e.g., IL-1) and anti-inflammatory (e.g., IL-10) cytokines are elevated concomitantly during recovery suggests a complex network of interactions involved in the manifestation of heat-induced SIRS. In this study, we measured a set of circulating cytokine/soluble cytokine receptor proteins and liver cytokine and receptor mRNA accumulation in wild-type and tumor necrosis factor (TNF) receptor knockout mice to assess the effect of neutralization of TNF signaling on the SIRS following HS. Using a systems approach, we developed a computational model describing dynamic changes (intra- and extracellular events) in the cytokine signaling pathways in response to HS that was fitted to novel genomic (liver mRNA accumulation) and proteomic (circulating cytokines and receptors) data using global optimization. The model allows integration of relevant biological knowledge and formulation of new hypotheses regarding the molecular mechanisms behind the complex etiology of HS that may serve as future therapeutic targets. Moreover, using our unique modeling framework, we explored cytokine signaling pathways with three in silico experiments (e.g. by simulating different heat insult scenarios and responses in cytokine knockout strains in silico). PMID:24039931

Modelling the bioaccumulation of persistent organic pollutants in agricultural food chains for regulatory exposure assessment.

PubMed

Takaki, Koki; Wade, Andrew J; Collins, Chris D

2017-02-01

New models for estimating bioaccumulation of persistent organic pollutants in the agricultural food chain were developed using recent improvements to plant uptake and cattle transfer models. One model named AgriSim was based on K OW regressions of bioaccumulation in plants and cattle, while the other was a steady-state mechanistic model, AgriCom. The two developed models and European Union System for the Evaluation of Substances (EUSES), as a benchmark, were applied to four reported food chain (soil/air-grass-cow-milk) scenarios to evaluate the performance of each model simulation against the observed data. The four scenarios considered were as follows: (1) polluted soil and air, (2) polluted soil, (3) highly polluted soil surface and polluted subsurface and (4) polluted soil and air at different mountain elevations. AgriCom reproduced observed milk bioaccumulation well for all four scenarios, as did AgriSim for scenarios 1 and 2, but EUSES only did this for scenario 1. The main causes of the deviation for EUSES and AgriSim were the lack of the soil-air-plant pathway and the ambient air-plant pathway, respectively. Based on the results, it is recommended that soil-air-plant and ambient air-plant pathway should be calculated separately and the K OW regression of transfer factor to milk used in EUSES be avoided. AgriCom satisfied the recommendations that led to the low residual errors between the simulated and the observed bioaccumulation in agricultural food chain for the four scenarios considered. It is therefore recommended that this model should be incorporated into regulatory exposure assessment tools. The model uncertainty of the three models should be noted since the simulated concentration in milk from 5th to 95th percentile of the uncertainty analysis often varied over two orders of magnitude. Using a measured value of soil organic carbon content was effective to reduce this uncertainty by one order of magnitude.

Prenatal Exposure to Arsenic and Cadmium Impacts Infectious Disease-Related Genes within the Glucocorticoid Receptor Signal Transduction Pathway

PubMed Central

Rager, Julia E.; Yosim, Andrew; Fry, Rebecca C.

2014-01-01

There is increasing evidence that environmental agents mediate susceptibility to infectious disease. Studies support the impact of prenatal/early life exposure to the environmental metals inorganic arsenic (iAs) and cadmium (Cd) on increased risk for susceptibility to infection. The specific biological mechanisms that underlie such exposure-mediated effects remain understudied. This research aimed to identify key genes/signal transduction pathways that associate prenatal exposure to these toxic metals with changes in infectious disease susceptibility using a Comparative Genomic Enrichment Method (CGEM). Using CGEM an infectious disease gene (IDG) database was developed comprising 1085 genes with known roles in viral, bacterial, and parasitic disease pathways. Subsequently, datasets collected from human pregnancy cohorts exposed to iAs or Cd were examined in relationship to the IDGs, specifically focusing on data representing epigenetic modifications (5-methyl cytosine), genomic perturbations (mRNA expression), and proteomic shifts (protein expression). A set of 82 infection and exposure-related genes was identified and found to be enriched for their role in the glucocorticoid receptor signal transduction pathway. Given their common identification across numerous human cohorts and their known toxicological role in disease, the identified genes within the glucocorticoid signal transduction pathway may underlie altered infectious disease susceptibility associated with prenatal exposures to the toxic metals iAs and Cd in humans. PMID:25479081

Application of the IEUBK model for linking Children's blood lead with environmental exposure in a mining site, south China.

PubMed

Zhang, Xin-Ying; Carpenter, David O; Song, Yong-Jin; Chen, Ping; Qin, Yaoming; Wei, Ni-Yu; Lin, Shan-Chun

2017-12-01

This study consisted of a site- and age-specific investigation linking children's blood lead level (BLL) to environmental exposures in a historic mining site in south China. A total of 151 children, aged 3-7 years, were included in this study. The geometric mean (GM) BLL was 8.22 μg/dl, indicating an elevated BLL. The Integrated Exposure Uptake Bio-Kinetic (IEUBK) model has proven useful at many sites for study of routes of exposure. Application of the IEUBK model to these children indicated that the GM difference between observed and predicted BLL levels was only 1.07 μg/dl. It was found that the key environmental exposure pathway was soil/dust intake, which contributed 86.3% to the total risk. Younger children had higher BLL than did older children. Therefore, of the various low risk-high benefit solutions, interventions for the children living near the site should be focused on the dust removal and soil remediation. Implementation of the China Eco-village Construction Plan and China New Rural Reconstruction Movement of the government may be a better solution. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lung Macrophages “Digest” Carbon Nanotubes Using a Superoxide/Peroxynitrite Oxidative Pathway

PubMed Central

2015-01-01

In contrast to short-lived neutrophils, macrophages display persistent presence in the lung of animals after pulmonary exposure to carbon nanotubes. While effective in the clearance of bacterial pathogens and injured host cells, the ability of macrophages to “digest” carbonaceous nanoparticles has not been documented. Here, we used chemical, biochemical, and cell and animal models and demonstrated oxidative biodegradation of oxidatively functionalized single-walled carbon nanotubes via superoxide/NO* → peroxynitrite-driven oxidative pathways of activated macrophages facilitating clearance of nanoparticles from the lung. PMID:24871084

Molecular Indicators of Stress-Induced Neuroinflammation in a Mouse Model Simulating Features of Post-Traumatic Stress Disorder (Open Access)

DTIC Science & Technology

2017-05-23

OPEN ORIGINAL ARTICLE Molecular indicators of stress-induced neuroinflammation in a mouse model simulating features of post -traumatic stress disorder... post -traumatic stress disorder (PTSD). The model involved exposure of an intruder (male C57BL/6) mouse to a resident aggressor (male SJL) mouse for 5...revealed that neurogenesis and synaptic plasticity pathways were activated during the early responses but were inhibited after the later post -trauma

Building-associated neurological damage modeled in human cells: a mechanism of neurotoxic effects by exposure to mycotoxins in the indoor environment.

PubMed

Karunasena, Enusha; Larrañaga, Michael D; Simoni, Jan S; Douglas, David R; Straus, David C

2010-12-01

Damage to human neurological system cells resulting from exposure to mycotoxins confirms a previously controversial public health threat for occupants of water-damaged buildings. Leading scientific organizations disagree about the ability of inhaled mycotoxins in the indoor environment to cause adverse human health effects. Damage to the neurological system can result from exposure to trichothecene mycotoxins in the indoor environment. This study demonstrates that neurological system cell damage can occur from satratoxin H exposure to neurological cells at exposure levels that can be found in water-damaged buildings contaminated with fungal growth. The constant activation of inflammatory and apoptotic pathways at low levels of exposure in human brain capillary endothelial cells, astrocytes, and neural progenitor cells may amplify devastation to neurological tissues and lead to neurological system cell damage from indirect events triggered by the presence of trichothecenes.

Genome-wide gene–environment interaction analysis for asbestos exposure in lung cancer susceptibility

PubMed Central

Wei, Qingyi Wei

2012-01-01

Asbestos exposure is a known risk factor for lung cancer. Although recent genome-wide association studies (GWASs) have identified some novel loci for lung cancer risk, few addressed genome-wide gene–environment interactions. To determine gene–asbestos interactions in lung cancer risk, we conducted genome-wide gene–environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using our published Texas lung cancer GWAS dataset. This dataset included 317 498 SNPs from 1154 lung cancer cases and 1137 cancer-free controls. The initial SNP-level P-values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models with adjustment for age, sex, smoking status and pack-years. The P-value for the most significant SNP rs13383928 was 2.17×10–6, which did not reach the genome-wide statistical significance. Using a versatile gene-based test approach, we found that the top significant gene was C7orf54, located on 7q32.1 (P = 8.90×10–5). Interestingly, most of the other significant genes were located on 11q13. When we used an improved gene-set-enrichment analysis approach, we found that the Fas signaling pathway and the antigen processing and presentation pathway were most significant (nominal P < 0.001; false discovery rate < 0.05) among 250 pathways containing 17 572 genes. We believe that our analysis is a pilot study that first describes the gene–asbestos interaction in lung cancer risk at levels of SNPs, genes and pathways. Our findings suggest that immune function regulation-related pathways may be mechanistically involved in asbestos-associated lung cancer risk. Abbreviations:CIconfidence intervalEenvironmentFDRfalse discovery rateGgeneGSEAgene-set-enrichment analysisGWASgenome-wide association studiesi-GSEAimproved gene-set-enrichment analysis approachORodds ratioSNPsingle nucleotide polymorphism PMID:22637743

Chronic Arsenic Exposure and Angiogenesis in Human Bronchial Epithelial Cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway

PubMed Central

He, Jun; Wang, Min; Jiang, Yue; Chen, Qiudan; Xu, Shaohua; Xu, Qing; Jiang, Bing-Hua

2014-01-01

Background: Environmental and occupational exposure to arsenic is a major public health concern. Although it has been identified as a human carcinogen, the molecular mechanism underlying the arsenic-induced carcinogenesis is not well understood. Objectives: We aimed to determine the role and mechanisms of miRNAs in arsenic-induced tumor angiogenesis and tumor growth. Methods: We utilized an in vitro model in which human lung epithelial BEAS-2B cells were transformed through long-term exposure to arsenic. A human xenograft tumor model was established to assess tumor angiogenesis and tumor growth in vivo. Tube formation assay and chorioallantoic membranes assay were used to assess tumor angiogenesis. Results: We found that miR-199a-5p expression levels were more than 100-fold lower in arsenic-transformed cells than parental cells. Re-expression of miR-199a-5p impaired arsenic-induced angiogenesis and tumor growth through its direct targets HIF-1α and COX-2. We further showed that arsenic induced COX-2 expression through HIF-1 regulation at the transcriptional level. In addition, we demonstrated that reactive oxygen species are an upstream event of miR-199a-5p/ HIF-1α/COX-2 pathway in arsenic-induced carcinogenesis. Conclusion: The findings establish critical roles of miR-199a-5p and its downstream targets HIF-1/COX-2 in arsenic-induced tumor growth and angiogenesis. Citation: He J, Wang M, Jiang Y, Chen Q, Xu S, Xu Q, Jiang BH, Liu LZ. 2014. Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway. Environ Health Perspect 122:255–261; http://dx.doi.org/10.1289/ehp.1307545 PMID:24413338

Integrating Aggregate Exposure Pathway (AEP) and Adverse ...

EPA Pesticide Factsheets

High throughput toxicity testing (HTT) holds the promise of providing data for tens of thousands of chemicals that currently have no data due to the cost and time required for animal testing. Interpretation of these results require information linking the perturbations seen in vitro with adverse outcomes in vivo and requires knowledge of how estimated exposure to the chemicals compare to the in vitro concentrations that show an effect. This abstract discusses how Adverse Outcome Pathways (AOPs) can be used to link HTT with adverse outcomes of regulatory significance and how Aggregate Exposure Pathways (AEPs) can connect concentrations of environment stressors at a source with an expected target site concentration designed to provide exposure estimates that are comparable to concentrations identified in HTT. Presentation at the ICCA-LRI and JRC Workshop: Fit-For-Purpose Exposure Assessment For Risk-Based Decision Making

Genetically modified crops and aquatic ecosystems: considerations for environmental risk assessment and non-target organism testing.

PubMed

Carstens, Keri; Anderson, Jennifer; Bachman, Pamela; De Schrijver, Adinda; Dively, Galen; Federici, Brian; Hamer, Mick; Gielkens, Marco; Jensen, Peter; Lamp, William; Rauschen, Stefan; Ridley, Geoff; Romeis, Jörg; Waggoner, Annabel

2012-08-01

Environmental risk assessments (ERA) support regulatory decisions for the commercial cultivation of genetically modified (GM) crops. The ERA for terrestrial agroecosystems is well-developed, whereas guidance for ERA of GM crops in aquatic ecosystems is not as well-defined. The purpose of this document is to demonstrate how comprehensive problem formulation can be used to develop a conceptual model and to identify potential exposure pathways, using Bacillus thuringiensis (Bt) maize as a case study. Within problem formulation, the insecticidal trait, the crop, the receiving environment, and protection goals were characterized, and a conceptual model was developed to identify routes through which aquatic organisms may be exposed to insecticidal proteins in maize tissue. Following a tiered approach for exposure assessment, worst-case exposures were estimated using standardized models, and factors mitigating exposure were described. Based on exposure estimates, shredders were identified as the functional group most likely to be exposed to insecticidal proteins. However, even using worst-case assumptions, the exposure of shredders to Bt maize was low and studies supporting the current risk assessments were deemed adequate. Determining if early tier toxicity studies are necessary to inform the risk assessment for a specific GM crop should be done on a case by case basis, and should be guided by thorough problem formulation and exposure assessment. The processes used to develop the Bt maize case study are intended to serve as a model for performing risk assessments on future traits and crops.

Linking Family Economic Hardship to Early Childhood Health: An Investigation of Mediating Pathways.

PubMed

Hsu, Hui-Chin; Wickrama, Kandauda A S

2015-12-01

The underlying mechanisms through which family economic adversity influences child health are less understood. Taking a process-oriented approach, this study examined maternal mental health and investment in children, child health insurance, and child healthcare as mediators linking family economic hardship (FEH) to child health. A structural equation modeling was applied to test the hypothesized mediating model. After adjustment for sociodemographic risk factors, results revealed: (1) a significant direct path linking FEH to poor child health (effect size = .372), and (2) six significant mediating pathways (total effect size = .089). In two mediating pathways, exposures to FEH undermined mothers' mental health: in the first pathway poor maternal mental health led to decreased parental investment, which, in turn, contributed to poor child health, whereas in the second pathway the adverse effect of poor maternal mental health was cascaded through child unmet healthcare need, which resulted in poor child health. One pathway involved child insurance status, where the effect of FEH increased the likelihood to be uninsured, which led to unmet healthcare need, and, in turn, to poor health. Three pathways involved preventive care: in one pathway FEH contributed to poor preventive care, which led to unmet healthcare need and then to poor health; in the other two pathways where poor preventive care respectively gave rise to decreased investment in children or poor maternal mental health, which further contributed to poor child health. Results suggest that the association between FEH and children's health is mediated by multiple pathways.

Global metabolomic profiling reveals an association of metal fume exposure and plasma unsaturated fatty acids.

PubMed

Wei, Yongyue; Wang, Zhaoxi; Chang, Chiung-yu; Fan, Tianteng; Su, Li; Chen, Feng; Christiani, David C

2013-01-01

Welding-associated air pollutants negatively affect the health of exposed workers; however, their molecular mechanisms in causing disease remain largely unclear. Few studies have systematically investigated the systemic toxic effects of welding fumes on humans. To explore the effects of welding fumes on the plasma metabolome, and to identify biomarkers for risk assessment of welding fume exposure. The two-stage, self-controlled exploratory study included 11 boilermakers from a 2011 discovery panel and 8 boilermakers from a 2012 validation panel. Plasma samples were collected pre- and post-welding fume exposure and analyzed by chromatography/mass spectrometry. Eicosapentaenoic or docosapentaenoic acid metabolic changes post-welding were significantly associated with particulate (PM2.5) exposure (p<0.05). The combined analysis by linear mixed-effects model showed that exposure was associated with a statistically significant decline in metabolite change of eicosapentaenoic acid [β(95% CI) = -0.013(-0.022 ≈ -0.004); p = 0.005], docosapentaenoic acid n3 [β(95% CI) = -0.010(-0.018 ≈ -0.002); p = 0.017], and docosapentaenoic acid n6 [β(95% CI) = -0.007(-0.013 ≈ -0.001); p = 0.021]. Pathway analysis identified an association of the unsaturated fatty acid pathway with exposure (p Study-2011 = 0.025; p Study-2012 = 0.021; p Combined = 0.009). The functional network built by these fatty acids and their interactive genes contained significant enrichment of genes associated with various diseases, including neoplasms, cardiovascular diseases, and lipid metabolism disorders. High-dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. This alteration in fatty acids is a potential biological mediator and biomarker for exposure-related health disorders.

Human Stem Cell-Derived Cardiomyocytes: An Alternative Model to Evaluate Environmental Chemical Cardiac Safety and Development of Predictive Adverse Outcome Pathways

EPA Science Inventory

Biomonitoring over the last 14 years has shown human exposure to environmental chemicals has increased ~10-fold (1). In addition, mortality and morbidity related cardiovascular disease continues to be the leading national and global public health issue (2, 3). The association bet...

Perceptions of Threat: Understanding Pathways between Stress and Health in Adolescents

ERIC Educational Resources Information Center

Chen, Edith; Hanson, Margaret D.

2005-01-01

Stress has been related to both lower socioeconomic status and poorer health. This research tests a model which suggests that teenagers from varying socioeconomic backgrounds differ not only in terms of exposure to negative life events, but also in their interpretation of life situations. Study participants were 100 high school students (roughly…

Mental health service use among high school students exposed to interpersonal violence

PubMed Central

Johnson, Renee M.; Dunn, Erin C.; Lindsey, Michael; Xuan, Ziming; Zaslavsky, Alan M.

2013-01-01

BACKGROUND Violence-exposed youth rarely receive mental health services, even though exposure increases risk for academic and psychosocial problems. This study examines the association between violence exposure and mental health service contact. The four forms of violence exposure were peer, family, sexual, and witnessing. METHODS Data are from 1,534 Boston public high school students who participated in a 2008 self-report survey of violence exposure and its correlates. Multivariate logistic regressions estimated associations between each form of violence with service contact, then examined whether associations persisted when controlling for suicidality and self-injurious behaviors. RESULTS In unadjusted models, violence-exposed students more often reported service contact than their peers. However, in multivariate models, only exposure to family (OR=1.69, CI=1.23–2.31) and sexual violence (OR=2.34, CI=1.29–4.20) were associated with service contact. Associations attenuated when controlling for suicidality and self-injurious behaviors, indicating they were largely explained by self-harm. Sexual violence alone remained associated with mental health service contact in fully adjusted models, but only for girls (OR=3.32, CI=1.30–8.45), suggesting gender-specific pathways. CONCLUSIONS Associations between adolescent violence exposure and mental health service contact vary by form of exposure. Outreach to a broader set of exposed youth may reduce the impact of violence and its consequences for vulnerable students. PMID:25099429

Perseverative Cognitions and Stress Exposure: Comparing Relationships With Psychological Health Across a Diverse Adult Sample.

PubMed

Zawadzki, Matthew J; Sliwinski, Martin J; Smyth, Joshua M

2018-03-29

Both exposure to stress and perseverative cognitions (PCs)-repetitive cognitive representations of real or imagined stressors-are linked with poor psychological health. Yet, stress exposure and PCs are correlated, thus potentially obscuring any unique effects. The purpose of this paper is to concurrently test associations between stress exposure and PCs and psychological health to examine the independent relationship of each with psychological health. Moreover, we examined whether these relationships are similar across sex, age, and race. An adult community sample (n = 302) completed a measure of stress exposure, three PCs scales, and questionnaires assessing self-reported psychological health, including emotional well-being, vitality, social functioning, role limitations due to personal problems, subjective well-being, depressive symptoms, and poor sleep quality. Structural equation modeling was used to test a model in which both stress exposure and PCs predict psychological health. PCs consistently predicted all the psychological health outcomes, but stress was largely unrelated to the outcomes despite bivariate correlations suggesting a relationship. A follow-up model identified indirect effects of stress exposure on psychological health via PCs. Results were fairly consistent regardless of one's sex, age, or race. PCs robustly predicted all of the psychological health outcomes, intimating PCs as a common pathway to poor psychological health. Results have implications for stress interventions, including the need to address PCs after experiencing stress.

Animal models of chronic obstructive pulmonary disease.

PubMed

Pérez-Rial, Sandra; Girón-Martínez, Álvaro; Peces-Barba, Germán

2015-03-01

Animal models of disease have always been welcomed by the scientific community because they provide an approach to the investigation of certain aspects of the disease in question. Animal models of COPD cannot reproduce the heterogeneity of the disease and usually only manage to represent the disease in its milder stages. Moreover, airflow obstruction, the variable that determines patient diagnosis, not always taken into account in the models. For this reason, models have focused on the development of emphysema, easily detectable by lung morphometry, and have disregarded other components of the disease, such as airway injury or associated vascular changes. Continuous, long-term exposure to cigarette smoke is considered the main risk factor for this disease, justifying the fact that the cigarette smoke exposure model is the most widely used. Some variations on this basic model, related to exposure time, the association of other inducers or inhibitors, exacerbations or the use of transgenic animals to facilitate the identification of pathogenic pathways have been developed. Some variations or heterogeneity of this disease, then, can be reproduced and models can be designed for resolving researchers' questions on disease identification or treatment responses. Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.

Inactivation of GABAA receptor is related to heat shock stress response in organism model Caenorhabditis elegans.

PubMed

Camargo, Gabriela; Elizalde, Alejandro; Trujillo, Xochitl; Montoya-Pérez, Rocío; Mendoza-Magaña, María Luisa; Hernandez-Chavez, Abel; Hernandez, Leonardo

2016-09-01

The mechanisms underlying oxidative stress (OS) resistance are not completely clear. Caenorhabditis elegans (C. elegans) is a good organism model to study OS because it displays stress responses similar to those in mammals. Among these mechanisms, the insulin/IGF-1 signaling (IIS) pathway is thought to affect GABAergic neurotransmission. The aim of this study was to determine the influence of heat shock stress (HS) on GABAergic activity in C. elegans. For this purpose, we tested the effect of exposure to picrotoxin (PTX), gamma-aminobutyric acid (GABA), hydrogen peroxide, and HS on the occurrence of a shrinking response (SR) after nose touch stimulus in N2 (WT) worms. Moreover, the effect of HS on the expression of UNC-49 (GABAA receptor ortholog) in the EG1653 strain and the effect of GABA and PTX exposure on HSP-16.2 expression in the TJ375 strain were analyzed. PTX 1 mM- or H2O2 0.7 mM-exposed worms displayed a SR in about 80 % of trials. GABA exposure did not cause a SR. HS prompted the occurrence of a SR as did PTX 1 mM or H2O2 0.7 mM exposure. In addition, HS increased UNC-49 expression, and PTX augmented HSP-16.2 expression. Thus, the results of the present study suggest that oxidative stress, through either H2O2 exposure or application of heat shock, inactivates the GABAergic system, which subsequently would affect the oxidative stress response, perhaps by enhancing the activity of transcription factors DAF-16 and HSF-1, both regulated by the IIS pathway and related to hsp-16.2 expression.

Movie Exposure to Alcohol Cues and Adolescent Alcohol Problems: A Longitudinal Analysis in a National Sample

PubMed Central

Wills, Thomas A.; Sargent, James D.; Gibbons, Frederick X.; Gerrard, Meg; Stoolmiller, Mike

2009-01-01

The authors tested a theoretical model of how exposure to alcohol cues in movies predicts level of alcohol use (ever use plus ever and recent binge drinking) and alcohol-related problems. A national sample of younger adolescents was interviewed by telephone with 4 repeated assessments spaced at 8-month intervals. A structural equation modeling analysis performed for ever-drinkers at Time 3 (N = 961) indicated that, controlling for a number of covariates, movie alcohol exposure at Time 1 was related to increases in peer alcohol use and adolescent alcohol use at Time 2. Movie exposure had indirect effects to alcohol use and problems at Times 3 and 4 through these pathways, with direct effects to problems from Time 1 rebelliousness and Time 2 movie exposure also found. Prospective risk-promoting effects were also found for alcohol expectancies, peer alcohol use, and availability of alcohol in the home; protective effects were found for mother’s responsiveness and for adolescent’s school performance and self-control. Theoretical and practical implications are discussed. PMID:19290687

Movie exposure to alcohol cues and adolescent alcohol problems: a longitudinal analysis in a national sample.

PubMed

Wills, Thomas A; Sargent, James D; Gibbons, Frederick X; Gerrard, Meg; Stoolmiller, Mike

2009-03-01

The authors tested a theoretical model of how exposure to alcohol cues in movies predicts level of alcohol use (ever use plus ever and recent binge drinking) and alcohol-related problems. A national sample of younger adolescents was interviewed by telephone with 4 repeated assessments spaced at 8-month intervals. A structural equation modeling analysis performed for ever-drinkers at Time 3 (N = 961) indicated that, controlling for a number of covariates, movie alcohol exposure at Time 1 was related to increases in peer alcohol use and adolescent alcohol use at Time 2. Movie exposure had indirect effects to alcohol use and problems at Times 3 and 4 through these pathways, with direct effects to problems from Time 1 rebelliousness and Time 2 movie exposure also found. Prospective risk-promoting effects were also found for alcohol expectancies, peer alcohol use, and availability of alcohol in the home; protective effects were found for mother's responsiveness and for adolescent's school performance and self-control. Theoretical and practical implications are discussed. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simões, Maylla Ronacher, E-mail: yllars@hotmail.com; Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz; Aguado, Andrea

Chronic exposure to low lead concentration produces hypertension; however, the underlying mechanisms remain unclear. We analyzed the role of oxidative stress, cyclooxygenase-2-dependent pathways and MAPK in the vascular alterations induced by chronic lead exposure. Aortas from lead-treated Wistar rats (1st dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g, intramuscular, 30 days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20 μg/dL) were used. Lead blood levels of treated rats attained 21.7 ± 2.38 μg/dL. Lead exposure increased systolic blood pressure and aortic ring contractile response to phenylephrine, reduced acetylcholine-induced relaxation and didmore » not affect sodium nitroprusside relaxation. Endothelium removal and L-NAME left-shifted the response to phenylephrine more in untreated than in lead-treated rats. Apocynin and indomethacin decreased more the response to phenylephrine in treated than in untreated rats. Aortic protein expression of gp91(phox), Cu/Zn-SOD, Mn-SOD and COX-2 increased after lead exposure. In cultured VSMCs lead 1) increased superoxide anion production, NADPH oxidase activity and gene and/or protein levels of NOX-1, NOX-4, Mn-SOD, EC-SOD and COX-2 and 2) activated ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized superoxide anion production, NADPH oxidase activity and mRNA levels of NOX-1, NOX-4 and COX-2. Blockade of the ERK1/2 and p38 signaling pathways abolished lead-induced NOX-1, NOX-4 and COX-2 expression. Results show that lead activation of the MAPK signaling pathways activates inflammatory proteins such as NADPH oxidase and COX-2, suggesting a reciprocal interplay and contribution to vascular dysfunction as an underlying mechanisms for lead-induced hypertension. - Highlights: • Lead-exposure increases oxidative stress, COX-2 expression and vascular reactivity. • Lead exposure activates MAPK signaling pathway. • ROS and COX-2 activation by MAPK in lead exposure • Relationship between vascular ROS and COX-2 products in lead exposure.« less

Biological Networks for Predicting Chemical Hepatocarcinogenicity Using Gene Expression Data from Treated Mice and Relevance across Human and Rat Species

PubMed Central

Thomas, Reuben; Thomas, Russell S.; Auerbach, Scott S.; Portier, Christopher J.

2013-01-01

Background Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. Objectives To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. Methods Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. Results Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. Conclusions Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species. PMID:23737943

Biological networks for predicting chemical hepatocarcinogenicity using gene expression data from treated mice and relevance across human and rat species.

PubMed

Thomas, Reuben; Thomas, Russell S; Auerbach, Scott S; Portier, Christopher J

2013-01-01

Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species.

Mechanism of the synergistic effect of amiodarone and fluconazole in Candida albicans.

PubMed

Gamarra, Soledad; Rocha, Elousa Maria F; Zhang, Yong-Qiang; Park, Steven; Rao, Rajini; Perlin, David S

2010-05-01

The antiarrhythmic drug amiodarone has been found to have fungicidal activity. In Saccharomyces cerevisiae, its antifungal activity is mediated by calcium overload stress, which leads to a rapid nuclear accumulation of the calcineurin-regulated transcription factor CRZ1. In addition, low doses of amiodarone have been reported to be synergistic with fluconazole in fluconazole-resistant Candida albicans. To establish its mechanism of toxicity in C. albicans, we used expression profiling of key pathway genes to examine cellular responses to amiodarone alone and in combination with fluconazole. Gene expression profiling of 59 genes was done in five C. albicans strains (three fluconazole-susceptible strains and two fluconazole-resistant strains) after amiodarone and/or fluconazole exposure. Of the 59 genes, 27 analyzed showed a significant change (>2-fold) in expression levels after amiodarone exposure. The up- or downregulated genes included genes involved in Ca(2+) homeostasis, cell wall synthesis, vacuolar/lysosomal transport, diverse pathway regulation, stress response, and pseudohyphal morphogenesis. As expected, fluconazole induces an increase in ergosterol pathway genes expression levels. The combination treatment significantly dampened the transcriptional response to either drug, suggesting that synergism was due to an inhibition of compensatory response pathways. This dampening resulted in a decrease in total ergosterol levels and decreased pseudohyphal formation, a finding consistent with decreased virulence in a murine candidiasis model.

Quantitative Assessment of Current Risks to Harlequin Ducks in Prince William Sound, Alaska, from the Exxon Valdez Oil Spill

PubMed Central

Harwell, Mark A.; Gentile, John H.; Parker, Keith R.; Murphy, Stephen M.; Day, Robert H.; Bence, A. Edward; Neff, Jerry M.; Wiens, John A.

2012-01-01

Harlequin Ducks (Histrionicus histrionicus) were adversely affected by the Exxon Valdez oil spill (EVOS) in Prince William Sound (PWS), Alaska, and some have suggested effects continue two decades later. We present an ecological risk assessment evaluating quantitatively whether PWS seaducks continue to be at-risk from polycyclic aromatic hydrocarbons (PAHs) in residual Exxon Valdez oil. Potential pathways for PAH exposures are identified for initially oiled and never-oiled reference sites. Some potential pathways are implausible (e.g., a seaduck excavating subsurface oil residues), whereas other pathways warrant quantification. We used data on PAH concentrations in PWS prey species, sediments, and seawater collected during 2001–2008 to develop a stochastic individual-based model projecting assimilated doses to seaducks. We simulated exposures to 500,000 individuals in each of eight age/gender classes, capturing the variability within a population of seaducks living in PWS. Doses to the maximum-exposed individuals are ∼400–4,000 times lower than chronic toxicity reference values established using USEPA protocols for seaducks. These exposures are so low that no individual-level effects are plausible, even within a simulated population that is orders-of-magnitude larger than exists in PWS. We conclude that toxicological risks to PWS seaducks from residual Exxon Valdez oil two decades later are essentially non-existent. PMID:23723680

DEVELOPMENT OF NATIONAL BIOACCUMULATION FACTORS

EPA Science Inventory

The 2000 Human Health Methodology incorporates a number of specific advancements made over the past two decades, one of which is in the assessment of chemical exposure to humans through the food chain pathway. For certain chemicals, the food chain exposure pathway is more importa...

ESTIMATION OF CHILDREN'S EXPOSURES VIA POORLY CHARACTERIZED PATHWAYS USING CTEPP DATA

EPA Science Inventory

This work involved providing better exposure estimates for poorly characterized pathways (dermal and indirect ingestion) for young children in the CTEPP study. The chemicals used in this analysis were chlorpyrifos and its degradation product 3,5,6-trichloro-2-pyridinol.

Exposure to mass media and interpersonal counseling has additive effects on exclusive breastfeeding and its psychosocial determinants among Vietnamese mothers

PubMed Central

Kim, Sunny S.; Nguyen, Tuan T.; Hajeebhoy, Nemat; Tran, Lan M.; Alayon, Silvia; Ruel, Marie T.; Rawat, Rahul; Frongillo, Edward A.; Menon, Purnima

2016-01-01

Abstract The pathways through which behavior change interventions impact breastfeeding practices have not been well studied. This study aimed to examine: (1) the effects of exposure to mass media and interpersonal counseling on exclusive breastfeeding (EBF) and hypothesized psychosocial determinants (i.e. knowledge, intention, beliefs, social norms, and self‐efficacy); and (2) the pathways through which exposure to mass media and interpersonal counseling are associated with EBF. We used survey data from mothers with children < 2 year (n = 2045) from the 2013 process evaluation of Alive & Thrive's program in Viet Nam. Multiple linear regression analyses and structural equation modeling were used to estimate effects. Exposure to mass media only, interpersonal counseling only, both or neither was 51%, 5%, 19% and 25%, respectively. Exposure to both mass media and interpersonal counseling had additive effects on EBF as well as on related psychosocial factors, compared with no exposure. For example, EBF prevalence was 26.1 percentage points (pp) higher in the group that received interpersonal counseling only, 3.9 pp higher in the mass media group and 31.8 pp higher in the group that received both interventions. As hypothesized, more than 90% of the total effect of the two interventions on EBF was explained by the psychosocial factors measured. Our findings suggest that combining different behavior change interventions leads to greater changes in psychosocial factors, which in turn positively affects breastfeeding behaviors. PMID:27334544

A framework for the use of single-chemical transcriptomics data in predicting the hazards associated with complex mixtures of polycyclic aromatic hydrocarbons.

PubMed

Labib, Sarah; Williams, Andrew; Kuo, Byron; Yauk, Carole L; White, Paul A; Halappanavar, Sabina

2017-07-01

The assumption of additivity applied in the risk assessment of environmental mixtures containing carcinogenic polycyclic aromatic hydrocarbons (PAHs) was investigated using transcriptomics. MutaTMMouse were gavaged for 28 days with three doses of eight individual PAHs, two defined mixtures of PAHs, or coal tar, an environmentally ubiquitous complex mixture of PAHs. Microarrays were used to identify differentially expressed genes (DEGs) in lung tissue collected 3 days post-exposure. Cancer-related pathways perturbed by the individual or mixtures of PAHs were identified, and dose-response modeling of the DEGs was conducted to calculate gene/pathway benchmark doses (BMDs). Individual PAH-induced pathway perturbations (the median gene expression changes for all genes in a pathway relative to controls) and pathway BMDs were applied to models of additivity [i.e., concentration addition (CA), generalized concentration addition (GCA), and independent action (IA)] to generate predicted pathway-specific dose-response curves for each PAH mixture. The predicted and observed pathway dose-response curves were compared to assess the sensitivity of different additivity models. Transcriptomics-based additivity calculation showed that IA accurately predicted the pathway perturbations induced by all mixtures of PAHs. CA did not support the additivity assumption for the defined mixtures; however, GCA improved the CA predictions. Moreover, pathway BMDs derived for coal tar were comparable to BMDs derived from previously published coal tar-induced mouse lung tumor incidence data. These results suggest that in the absence of tumor incidence data, individual chemical-induced transcriptomics changes associated with cancer can be used to investigate the assumption of additivity and to predict the carcinogenic potential of a mixture.

Problematic Substance Use in Urban Adolescents: Role of Intrauterine Exposures to Cocaine and Marijuana and Post-Natal Environment

PubMed Central

Frank, Deborah A.; Kuranz, Seth; Appugliese, Danielle; Cabral, Howard; Chen, Clara; Crooks, Denise; Heeren, Timothy; Liebschutz, Jane; Richardson, Mark; Rose-Jacobs, Ruth

2014-01-01

Background Linkages between intrauterine exposures to cocaine and marijuana and adolescents’ problematic substance use have not been fully delineated. Methods Prospective longitudinal study with assessors unaware of intrauterine exposure history followed 157 urban participants from birth until late adolescence. Level of intrauterine exposures was identified by mother's report and infant’s meconium. Problematic substance use, identified by the Voice Diagnostic Interview Schedule for Children (V-DISC) or the Audio Computer Assisted Self-Interview (ACASI) and urine assay, was a composite encompassing DSM-IV indication of tolerance, abuse, and dependence on alcohol, marijuana, and tobacco and any use of cocaine, glue, or opiates. Results Twenty percent (32/157) of the sample experienced problematic substance use by age 18 years, of whom the majority (22/157) acknowledged abuse, tolerance or dependence on marijuana with or without other substances. Structural equation models examining direct and indirect pathways linking a Cox survival model for early substance initiation to a logistic regression models found effects of post-natal factors including childhood exposure to violence and household substance use, early youth substance initiation, and ongoing youth violence exposure contributing to adolescent problematic substance use. Conclusion We did not identify direct relationships between intrauterine cocaine or marijuana exposure and problematic substance use, but did find potentially modifiable post-natal risk factors also noted to be associated with problematic substance use in the general population including earlier substance initiation, exposure to violence and to household substance use. PMID:24999059

Exposure assessment of environmental organic chemicals at contaminated sites: a multicompartment modelling approach.

PubMed

Matthies, M

2003-04-11

For the prevention of future damages from chemicals at large contaminated sites, all transfer pathways leading to the exposure of man and vulnerable ecosystems have to be taken into account. For organic contaminants, the uptake into vegetation is the major entry route for the transfer into the food chains. Lipophilic substances are taken up by roots but are not translocated with the transpiration stream. Atmospheric background concentrations have a significant impact on foliage contamination due to the effective gaseous and particle deposition. Vegetables can also be contaminated after irrigation with contaminated water supplied by groundwater wells. By means of a multicompartment model, the various uptake processes into roots and foliage as well as the transformation and translocation processes are described and the concentration pattern resulting from daily irrigation with methyl-t-butyl ether in the edible parts is simulated. The results demonstrate the advantage of a dynamic multicompartment model over the static environmental quality standard approach in terms of derivation of possible exposure reduction measures for organic chemicals.

Issue Paper on Metal Exposure Assessment

EPA Pesticide Factsheets

This paper explores the best approaches for characterizing exposure pathways and routes, estimating the most relevant exposure concentrations, linking exposure to dose, and coping with natural or background concentrations.

In Vitro Studies and Preliminary Mathematical Model for Jet Fuel and Noise Induced Auditory Impairment

DTIC Science & Technology

2015-06-01

K.C. and Hu, B.H. 2006. The role of oxidative stress in noise-induced hearing loss. Ear Hear 27(1): 1-19. Hillerdal, M. 1987. Cochlear blood flow ...Larsen, H.C., Angelborg, C. and Slepecky, N. 1984. Determination of the regional cochlear blood flow in the rat cochlea using non-radioactive...24-Hour JP-8 Exposure using a Cochlear Cell Model and Cellular Pathway Modulation

A systems toxicology approach identifies Lyn as a key signaling phosphoprotein modulated by mercury in a B lymphocyte cell model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Caruso, Joseph A.; Stemmer, Paul M.; Dombkowski, Alan

2014-04-01

Network and protein–protein interaction analyses of proteins undergoing Hg{sup 2+}-induced phosphorylation and dephosphorylation in Hg{sup 2+}-intoxicated mouse WEHI-231 B cells identified Lyn as the most interconnected node. Lyn is a Src family protein tyrosine kinase known to be intimately involved in the B cell receptor (BCR) signaling pathway. Under normal signaling conditions the tyrosine kinase activity of Lyn is controlled by phosphorylation, primarily of two well known canonical regulatory tyrosine sites, Y-397 and Y-508. However, Lyn has several tyrosine residues that have not yet been determined to play a major role under normal signaling conditions, but are potentially important sitesmore » for phosphorylation following mercury exposure. In order to determine how Hg{sup 2+} exposure modulates the phosphorylation of additional residues in Lyn, a targeted MS assay was developed. Initial mass spectrometric surveys of purified Lyn identified 7 phosphorylated tyrosine residues. A quantitative assay was developed from these results using the multiple reaction monitoring (MRM) strategy. WEHI-231 cells were treated with Hg{sup 2+}, pervanadate (a phosphatase inhibitor), or anti-Ig antibody (to stimulate the BCR). Results from these studies showed that the phosphoproteomic profile of Lyn after exposure of the WEHI-231 cells to a low concentration of Hg{sup 2+} closely resembled that of anti-Ig antibody stimulation, whereas exposure to higher concentrations of Hg{sup 2+} led to increases in the phosphorylation of Y-193/Y-194, Y-501 and Y-508 residues. These data indicate that mercury can disrupt a key regulatory signal transduction pathway in B cells and point to phospho-Lyn as a potential biomarker for mercury exposure. - Highlights: • Inorganic mercury (Hg{sup 2+}) induces changes in the WEHI-231 B cell phosphoproteome. • The B cell receptor (BCR) signaling pathway was the pathway most affected by Hg{sup 2+}. • The Src family phosphoprotein kinase Lyn was the most interconnected node. • Lyn is likely central to the immunotoxic potential of Hg{sup 2+}. • Lyn phosphorylation profiles may be biomarkers for Hg{sup 2+} intoxication of B cells.« less

Organophosphate pesticides exposure among farmworkers: pathways and risk of adverse health effects.

PubMed

Suratman, Suratman; Edwards, John William; Babina, Kateryna

2015-01-01

Organophosphate (OP) compounds are the most widely used pesticides with more than 100 OP compounds in use around the world. The high-intensity use of OP pesticides contributes to morbidity and mortality in farmworkers and their families through acute or chronic pesticides-related illnesses. Many factors contributing to adverse health effects have been investigated by researchers to determine pathways of OP-pesticide exposure among farmers in developed and developing countries. Factors like wind/agricultural pesticide drift, mixing and spraying pesticides, use of personal protective equipment (PPE), knowledge, perceptions, washing hands, taking a shower, wearing contaminated clothes, eating, drinking, smoking, and hot weather are common in both groups of countries. Factors including low socioeconomic status areas, workplace conditions, duration of exposure, pesticide safety training, frequency of applying pesticides, spraying against the wind, and reuse of pesticide containers for storage are specific contributors in developing countries, whereas housing conditions, social contextual factors, and mechanical equipment were specific pathways in developed countries. This paper compares existing research in environmental and behavioural exposure modifying factors and biological monitoring between developing and developed countries. The main objective of this review is to explore the current depth of understanding of exposure pathways and factors increasing the risk of exposure potentially leading to adverse health effects specific to each group of countries.

Genome-Wide Identification of Molecular Pathways and Biomarkers in Response to Arsenic Exposure in Zebrafish Liver

PubMed Central

Xu, Hongyan; Lam, Siew Hong; Shen, Yuan; Gong, Zhiyuan

2013-01-01

Inorganic arsenic is a worldwide metalloid pollutant in environment. Although extensive studies on arsenic-induced toxicity have been conducted using in vivo and in vitro models, the exact molecular mechanism of arsenate toxicity remains elusive. Here, the RNA-SAGE (serial analysis of gene expression) sequencing technology was used to analyse hepatic response to arsenic exposure at the transcriptome level. Based on more than 12 million SAGE tags mapped to zebrafish genes, 1,444 differentially expressed genes (750 up-regulated and 694 down-regulated) were identified from a relatively abundant transcripts (>10 TPM [transcripts per million]) based on minimal two-fold change. By gene ontology analyses, these differentially expressed genes were significantly enriched in several major biological processes including oxidation reduction, translation, iron ion transport, cell redox, homeostasis, etc. Accordingly, the main pathways disturbed include metabolic pathways, proteasome, oxidative phosphorylation, cancer, etc. Ingenity Pathway Analysis further revealed a network with four important upstream factors or hub genes, including Jun, Kras, APoE and Nr2f2. The network indicated apparent molecular events involved in oxidative stress, carcinogenesis, and metabolism. In order to identify potential biomarker genes for arsenic exposure, 27 out of 29 up-regulated transcripts were validated by RT-qPCR analysis in pooled RNA samples. Among these, 14 transcripts were further confirmed for up-regulation by a lower dosage of arsenic in majority of individual zebrafish. Finally, at least four of these genes, frh3 (ferrintin H3), mgst1 (microsomal glutathione S-transferase-like), cmbl (carboxymethylenebutenolidase homolog) and slc40a1 (solute carrier family 40 [iron-regulated transporter], member 1) could be confirmed in individual medaka fish similarly treated by arsenic; thus, these four genes might be robust arsenic biomarkers across species. Thus, our work represents the first comprehensive investigation of molecular mechanism of asenic toxicity and genome-wide search for potential biomarkers for arsenic exposure. PMID:23922661

Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pistollato, Francesca; Louisse, Jochem; Scelfo, Bibiana

2014-10-15

According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro.more » Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2{sup +} neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations. - Highlights: • HESCs derived neuronal cells serve as benchmark for iPSC based neuronal toxicity test development. • Comparisons between hESCs and hiPSCs demonstrated variability of the epigenetic state • CREB pathway modulation have been explored in relation to the neurotoxicant exposure KG-501 • hiPSC might be promising tools to translate theoretical AoPs into toxicological in vitro tests.« less

Multiplatform serum metabolic phenotyping combined with pathway mapping to identify biochemical differences in smokers.

PubMed

Kaluarachchi, Manuja R; Boulangé, Claire L; Garcia-Perez, Isabel; Lindon, John C; Minet, Emmanuel F

2016-10-01

Determining perturbed biochemical functions associated with tobacco smoking should be helpful for establishing causal relationships between exposure and adverse events. A multiplatform comparison of serum of smokers (n = 55) and never-smokers (n = 57) using nuclear magnetic resonance spectroscopy, UPLC-MS and statistical modeling revealed clustering of the classes, distinguished by metabolic biomarkers. The identified metabolites were subjected to metabolic pathway enrichment, modeling adverse biological events using available databases. Perturbation of metabolites involved in chronic obstructive pulmonary disease, cardiovascular diseases and cancer were identified and discussed. Combining multiplatform metabolic phenotyping with knowledge-based mapping gives mechanistic insights into disease development, which can be applied to next-generation tobacco and nicotine products for comparative risk assessment.

Early Adolescent Alcohol Use in Context: How Neighborhoods, Parents and Peers Impact Youth

PubMed Central

Trucco, Elisa M.; Colder, Craig R.; Wieczorek, William F.; Lengua, Liliana J.; Hawk, Larry W.

2014-01-01

Developmental-ecological models are useful for integrating risk factors across multiple contexts and conceptualizing mediational pathways for adolescent alcohol use; yet, these comprehensive models are rarely tested. This study used a developmental-ecological framework to investigate the influence of neighborhood, family, and peer contexts on alcohol use in early adolescence (N = 387). Results from a multi-informant longitudinal cross-lagged mediation path model suggested that high levels of neighborhood disadvantage were associated with high levels of alcohol use two years later via an indirect pathway that included exposure to delinquent peers and adolescent delinquency. Results also indicated that adolescent involvement with delinquent peers and alcohol use led to decrements in parenting, rather than being consequences of poor parenting. Overall, the study supported hypothesized relationships among key microsystems thought to influence adolescent alcohol use, and thus findings underscore the utility of developmental-ecological models of alcohol use. PMID:24621660

Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer

PubMed Central

Roy, Deodutta; Morgan, Marisa; Yoo, Changwon; Deoraj, Alok; Roy, Sandhya; Yadav, Vijay Kumar; Garoub, Mohannad; Assaggaf, Hamza; Doke, Mayur

2015-01-01

We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK) signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors. PMID:26512648

The NRF2-KEAP1 Pathway Is an Early Responsive Gene Network in Arsenic Exposed Lymphoblastoid Cells

PubMed Central

Córdova, Emilio J.; Martínez-Hernández, Angélica; Uribe-Figueroa, Laura; Centeno, Federico; Morales-Marín, Mirna; Koneru, Harsha; Coleman, Matthew A.; Orozco, Lorena

2014-01-01

Inorganic arsenic (iAs), a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 µM), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs. PMID:24516582

Methyl jasmonate and yeast elicitor induce differential transcriptional and metabolic re-programming in cell suspension cultures of the model legume Medicago truncatula.

PubMed

Suzuki, Hideyuki; Reddy, M S Srinivasa; Naoumkina, Marina; Aziz, Naveed; May, Gregory D; Huhman, David V; Sumner, Lloyd W; Blount, Jack W; Mendes, Pedro; Dixon, Richard A

2005-03-01

Exposure of cell suspension cultures of Medicago truncatula Gaerth. to methyl jasmonate (MeJA) resulted in up to 50-fold induction of transcripts encoding the key triterpene biosynthetic enzyme beta-amyrin synthase (betaAS; EC 5.4.99.-). Transcripts reached maximum levels at 24 h post-elicitation with 0.5 mM MeJA. The entry point enzymes into the phenylpropanoid and flavonoid pathways, L: -phenylalanine ammonia-lyase (PAL; EC 4.3.1.5) and chalcone synthase (CHS; EC 2.3.1.74), respectively, were not induced by MeJA. In contrast, exposure of cells to yeast elicitor (YE) resulted in up to 45- and 14-fold induction of PAL and CHS transcripts, respectively, at only 2 h post-elicitation. betaAS transcripts were weakly induced at 12 h after exposure to YE. Over 30 different triterpene saponins were identified in the cultures, many of which were strongly induced by MeJA, but not by YE. In contrast, cinnamic acids, benzoic acids and isoflavone-derived compounds accumulated following exposure of cultures to YE, but few changes in phenylpropanoid levels were observed in response to MeJA. DNA microarray analysis confirmed the strong differential transcriptional re-programming of the cell cultures for multiple genes in the phenylpropanoid and triterpene pathways in response to MeJA and YE, and indicated different responses of individual members of gene families. This work establishes Medicago cell cultures as an excellent model for future genomics approaches to understand the regulation of legume secondary metabolism.

Considerations for Using Genetic and Epigenetic Information in Occupational Health Risk Assessment and Standard Setting

PubMed Central

Schulte, P. A.; Whittaker, C.; Curran, C. P.

2015-01-01

Risk assessment forms the basis for both occupational health decision-making and the development of occupational exposure limits (OELs). Although genetic and epigenetic data have not been widely used in risk assessment and ultimately, standard setting, it is possible to envision such uses. A growing body of literature demonstrates that genetic and epigenetic factors condition biological responses to occupational and environmental hazards or serve as targets of them. This presentation addresses the considerations for using genetic and epigenetic information in risk assessments, provides guidance on using this information within the classic risk assessment paradigm, and describes a framework to organize thinking about such uses. The framework is a 4 × 4 matrix involving the risk assessment functions (hazard identification, dose-response modeling, exposure assessment, and risk characterization) on one axis and inherited and acquired genetic and epigenetic data on the other axis. The cells in the matrix identify how genetic and epigenetic data can be used for each risk assessment function. Generally, genetic and epigenetic data might be used as endpoints in hazard identification, as indicators of exposure, as effect modifiers in exposure assessment and dose-response modeling, as descriptors of mode of action, and to characterize toxicity pathways. Vast amounts of genetic and epigenetic data may be generated by high-throughput technologies. These data can be useful for assessing variability and reducing uncertainty in extrapolations, and they may serve as the foundation upon which identification of biological perturbations would lead to a new paradigm of toxicity pathway-based risk assessments. PMID:26583908

Assessment of the risk of African swine fever introduction into Finland using NORA-a rapid tool for semiquantitative assessment of the risk.

PubMed

Kyyrö, J; Sahlström, L; Lyytikäinen, T

2017-12-01

The NORA rapid risk assessment tool was developed for situations where there is a change in the disease status of easily transmissible animal diseases in neighbouring countries or in countries with significant interactions with Finland. The goal was to develop a tool that is quick to use and will provide consistent results to support risk management decisions. The model contains 63 questions that define the potential for entry and exposure by nine different pathways. The magnitude of the consequences is defined by 23 statements. The weight of different pathways is defined according to the properties of the assessed disease. The model was built as an Excel spreadsheet and is intended for use by animal health control administrators. As an outcome, the model gives the possible pathways of disease entry into the country, an overall approximation for the probability of entry and the subsequent exposure, an overall estimate for the consequences and a combined overall risk estimate (probability multiplied by magnitude of consequences). Model validity was assessed by expert panels. Outside Africa, African swine fever is currently established in Russia and Sardinia. In addition, there have been cases in both wild boar and domestic pigs in Latvia, Lithuania, Poland and Estonia. Finland has frequent contacts with Russia and Estonia, especially through passengers. The risk of African swine fever (ASF) introduction into Finland was tested with NORA for the situation in December 2015, when ASF was endemic in many parts of Russia, Africa and Sardinia and was present in Baltic countries and in Poland. African swine fever was assessed to have a high probability of entry into Finland, with high consequences and therefore a high overall risk. © 2017 Blackwell Verlag GmbH.

Exploring consumer exposure pathways and patterns of use for chemicals in the environment through the Chemical/Product Categories Database

EPA Pesticide Factsheets

Exploring consumer exposure pathways and patterns of use for chemicals in the environment through the Chemical/Product Categories Database (CPCat) (Presented by: Kathie Dionisio, Sc.D., NERL, US EPA, Research Triangle Park, NC (1/23/2014).

A conceptual framework to advance exposure science research and complement the Adverse Outcome Pathway framework

EPA Science Inventory

A tremendous amount of data on environmental stressors has been accumulated in exposure science, epidemiology, and toxicology, yet most of these data reside in different silos. The Adverse Outcome Pathway (AOP) framework was developed as an organizing principle for toxicological ...

Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/beta-catenin signaling in the thymus resulting in altered thymocyte development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hanson, Miranda L.; Brundage, Kathleen M.; Schafer, Rosana

2010-01-15

Cadmium (Cd) is both an environmental pollutant and a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/beta-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/beta-catenin pathways. Pregnant C57Bl/6more » mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways were assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4{sup +} cells and a subpopulation of double-negative cells (DN; CD4{sup -}CD8{sup -}), DN4 (CD44{sup -}CD25{sup -}). Shh and Wnt/beta-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/beta-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.« less

Gene networks and toxicity pathways induced by acute cadmium exposure in adult largemouth bass (Micropterus salmoides).

PubMed

Mehinto, Alvine C; Prucha, Melinda S; Colli-Dula, Reyna C; Kroll, Kevin J; Lavelle, Candice M; Barber, David S; Vulpe, Christopher D; Denslow, Nancy D

2014-07-01

Cadmium is a heavy metal that can accumulate to toxic levels in the environment leading to detrimental effects in animals and humans including kidney, liver and lung injuries. Using a transcriptomics approach, genes and cellular pathways affected by a low dose of cadmium were investigated. Adult largemouth bass were intraperitoneally injected with 20μg/kg of cadmium chloride (mean exposure level - 2.6μg of cadmium per fish) and microarray analyses were conducted in the liver and testis 48h after injection. Transcriptomic profiles identified in response to cadmium exposure were tissue-specific with the most differential expression changes found in the liver tissues, which also contained much higher levels of cadmium than the testis. Acute exposure to a low dose of cadmium induced oxidative stress response and oxidative damage pathways in the liver. The mRNA levels of antioxidants such as catalase increased and numerous transcripts related to DNA damage and DNA repair were significantly altered. Hepatic mRNA levels of metallothionein, a molecular marker of metal exposure, did not increase significantly after 48h exposure. Carbohydrate metabolic pathways were also disrupted with hepatic transcripts such as UDP-glucose, pyrophosphorylase 2, and sorbitol dehydrogenase highly induced. Both tissues exhibited a disruption of steroid signaling pathways. In the testis, estrogen receptor beta and transcripts linked to cholesterol metabolism were suppressed. On the contrary, genes involved in cholesterol metabolism were highly increased in the liver including genes encoding for the rate limiting steroidogenic acute regulatory protein and the catalytic enzyme 7-dehydrocholesterol reductase. Integration of the transcriptomic data using functional enrichment analyses revealed a number of enriched gene networks associated with previously reported adverse outcomes of cadmium exposure such as liver toxicity and impaired reproduction. Copyright © 2014 Elsevier B.V. All rights reserved.

Inorganic Arsenic–Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell–Conditioned Media Model

PubMed Central

Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

2015-01-01

Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal–epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs). Results: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure. Conclusions: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications. Citation: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL, Figueiredo ML. 2016. Inorganic arsenic–related changes in the stromal tumor microenvironment in a prostate cancer cell–conditioned media model. Environ Health Perspect 124:1009–1015; http://dx.doi.org/10.1289/ehp.1510090 PMID:26588813

In Utero Fine Particle Air Pollution and Placental Expression of Genes in the Brain-Derived Neurotrophic Factor Signaling Pathway: An ENVIRONAGE Birth Cohort Study.

PubMed

Saenen, Nelly D; Plusquin, Michelle; Bijnens, Esmée; Janssen, Bram G; Gyselaers, Wilfried; Cox, Bianca; Fierens, Frans; Molenberghs, Geert; Penders, Joris; Vrijens, Karen; De Boever, Patrick; Nawrot, Tim S

2015-08-01

Developmental processes in the placenta and the fetal brain are shaped by the same biological signals. Recent evidence suggests that adaptive responses of the placenta to the maternal environment may influence central nervous system development. We studied the association between in utero exposure to fine particle air pollution with a diameter ≤ 2.5 μm (PM2.5) and placental expression of genes implicated in neural development. Expression of 10 target genes in the brain-derived neurotrophic factor (BDNF) signaling pathway were quantified in placental tissue of 90 mother-infant pairs from the ENVIRONAGE birth cohort using quantitative real-time polymerase chain reaction. Trimester-specific PM2.5 exposure levels were estimated for each mother's home address using a spatiotemporal model. Mixed-effects models were used to evaluate the association between the target genes and PM2.5 exposure measured in different time windows of pregnancy. A 5-μg/m3 increase in residential PM2.5 exposure during the first trimester of pregnancy was associated with a 15.9% decrease [95% confidence interval (CI): -28.7, -3.2%, p = 0.015] in expression of placental BDNF at birth. The corresponding estimate for synapsin 1 (SYN1) was a 24.3% decrease (95% CI: -42.8, -5.8%, p = 0.011). Placental expression of BDNF and SYN1, two genes implicated in normal neurodevelopmental trajectories, decreased with increasing in utero exposure to PM2.5. Future studies are needed to confirm our findings and evaluate the potential relevance of associations between PM2.5 and placental expression of BDNF and SYN1 on neurodevelopment. We provide the first molecular epidemiological evidence concerning associations between in utero fine particle air pollution exposure and the expression of genes that may influence neurodevelopmental processes.

The Genetic Basis for Variation in Sensitivity to Lead Toxicity in Drosophila melanogaster

PubMed Central

Zhou, Shanshan; Morozova, Tatiana V.; Hussain, Yasmeen N.; Luoma, Sarah E.; McCoy, Lenovia; Yamamoto, Akihiko; Mackay, Trudy F.C.; Anholt, Robert R.H.

2016-01-01

Background: Lead toxicity presents a worldwide health problem, especially due to its adverse effects on cognitive development in children. However, identifying genes that give rise to individual variation in susceptibility to lead toxicity is challenging in human populations. Objectives: Our goal was to use Drosophila melanogaster to identify evolutionarily conserved candidate genes associated with individual variation in susceptibility to lead exposure. Methods: To identify candidate genes associated with variation in susceptibility to lead toxicity, we measured effects of lead exposure on development time, viability and adult activity in the Drosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association analyses to identify candidate genes. We used mutants to assess functional causality of candidate genes and constructed a genetic network associated with variation in sensitivity to lead exposure, on which we could superimpose human orthologs. Results: We found substantial heritabilities for all three traits and identified candidate genes associated with variation in susceptibility to lead exposure for each phenotype. The genetic architectures that determine variation in sensitivity to lead exposure are highly polygenic. Gene ontology and network analyses showed enrichment of genes associated with early development and function of the nervous system. Conclusions: Drosophila melanogaster presents an advantageous model to study the genetic underpinnings of variation in susceptibility to lead toxicity. Evolutionary conservation of cellular pathways that respond to toxic exposure allows predictions regarding orthologous genes and pathways across phyla. Thus, studies in the D. melanogaster model system can identify candidate susceptibility genes to guide subsequent studies in human populations. Citation: Zhou S, Morozova TV, Hussain YN, Luoma SE, McCoy L, Yamamoto A, Mackay TF, Anholt RR. 2016. The genetic basis for variation in sensitivity to lead toxicity in Drosophila melanogaster. Environ Health Perspect 124:1062–1070; http://dx.doi.org/10.1289/ehp.1510513 PMID:26859824

Pathways from assaultive violence to post-traumatic stress, depression, and generalized anxiety symptoms through stressful life events: longitudinal mediation models.

PubMed

Lowe, S R; Joshi, S; Galea, S; Aiello, A E; Uddin, M; Koenen, K C; Cerdá, M

2017-10-01

Assaultive violence events are associated with increased risk for adverse psychiatric outcomes, including post-traumatic stress (PTS), depression, and generalized anxiety. Prior research has indicated that economic, legal, and social stressors that could follow assaultive events may explain the increased risk for adverse psychiatric outcomes, yet longitudinal studies have not adequately examined this pathway. In the current study, we aimed to address this limitation. Participants (N = 1360) were part of a longitudinal population-based study of adults living in Detroit. At three waves, participants indicated their exposure to assaultive violence and economic, legal, and social stressors, and completed inventories of PTS, depression, and generalized anxiety. Longitudinal mediation models were used to test the hypothesized pathway from assaultive violence to each psychiatric outcome. The hypothesized models evidenced good fit with the data and, in each, the paths from Wave 1 (W1) assaultive violence to W2 stressors, and from W2 stressors to W3 symptoms were significant (range of Standardized Estimates: 0.09-0.15, all p < 0.01). Additionally, the indirect paths from W1 assaultive violence to W3 symptoms were significant (range of Standardized Estimates: 0.01-0.02, all p < 0.05). The findings illustrate that the economic, legal, and social stressors that could follow assaultive violence increase risk for a range of psychiatric symptoms. Although future research is needed, the results suggest that investment in interventions that prevent and mitigate assaultive violence survivors' exposure to such stressors may be an effective way to prevent mental illness in the aftermath of violent assaults.

A Drosophila model for fetal alcohol syndrome disorders: role for the insulin pathway

PubMed Central

McClure, Kimberly D.; French, Rachael L.; Heberlein, Ulrike

2011-01-01

SUMMARY Prenatal exposure to ethanol in humans results in a wide range of developmental abnormalities, including growth deficiency, developmental delay, reduced brain size, permanent neurobehavioral abnormalities and fetal death. Here we describe the use of Drosophila melanogaster as a model for exploring the effects of ethanol exposure on development and behavior. We show that developmental ethanol exposure causes reduced viability, developmental delay and reduced adult body size. We find that flies reared on ethanol-containing food have smaller brains and imaginal discs, which is due to reduced cell division rather than increased apoptosis. Additionally, we show that, as in mammals, flies reared on ethanol have altered responses to ethanol vapor exposure as adults, including increased locomotor activation, resistance to the sedating effects of the drug and reduced tolerance development upon repeated ethanol exposure. We have found that the developmental and behavioral defects are largely due to the effects of ethanol on insulin signaling; specifically, a reduction in Drosophila insulin-like peptide (Dilp) and insulin receptor expression. Transgenic expression of Dilp proteins in the larval brain suppressed both the developmental and behavioral abnormalities displayed by ethanol-reared adult flies. Our results thus establish Drosophila as a useful model system to uncover the complex etiology of fetal alcohol syndrome. PMID:21303840

Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis.

PubMed

Vit, Jean-Philippe; Rosselli, Filippo

2003-11-27

Ionizing radiations (IR) exposure leads to damage on several cellular targets. How signals from different targets are integrated to determine the cell fate remains a controversial issue. Understanding the pathway(s) responsible(s) for the cell killing effect of the IR exposure is of prime importance in light of using radiations as anticancer agent or as diagnostic tool. In this study, we have established that IR-induced cell damage initiates two independent signaling pathways that lead to a biphasic intracellular ceramide increase. A transitory increase of ceramide is observed within minutes after IR exposure as a consequence of DNA damage-independent acid sphingomyelinase activation. Several hours after irradiation, a second wave of ceramide accumulation is observed depending on the DNA damage-dependent activation of ceramide synthase, which requires a signaling pathway involving ATM. Importantly, we have demonstrated that the late ceramide accumulation is also dependent on the first one and is rate limiting for the apoptotic process induced by IR. In conclusion, our observations suggest that ceramide is a major determinant of the IR-induced apoptotic process at the cross-point of different signal transduction pathways.

Repeated exposure of mouse dermal fibroblasts at a sub-cytotoxic dose of UVB leads to premature senescence: a robust model of cellular photoaging.

PubMed

Zeng, Ji-ping; Bi, Bo; Chen, Liang; Yang, Ping; Guo, Yu; Zhou, Yi-qun; Liu, Tian-yi

2014-01-01

Photoaging skin is due to accumulative effect of UV irradiation that mainly imposes its damage on dermal fibroblasts. To mimic the specific cellular responses invoked by long term effect of UVB, it is preferable to develop a photo-damaged model in vitro based on repeated UVB exposure instead of a single exposure. To develop a photo-damaged model of fibroblasts by repeated UVB exposure allowing for investigation of molecular mechanism underlying premature senescence and testing of potential anti-photoaging compounds. Mouse dermal fibroblasts (MDFs) at early passages (passages 1-3) were exposed to a series of 4 sub-cytotoxic dose of UVB. The senescent phenotypes were detected at 24 or 48h after the last irradiation including cell viability, ROS generation, mitochondrial membrane potential, cell cycle, production and degradation of extracellular matrix. Repeated exposure of UVB resulted in remarkable features of senescence. It effectively avoided the disadvantages of single dose such as induction of cell death rather than senescence, inadequate stress resulting in cellular self-rehabilitation. Our work confirms the possibility of detecting cellular machinery that mediates UVB damage to fibroblasts in vitro by repeated exposure, while the potential molecular mechanisms including cell surface receptors, protein kinase signal transduction pathways, and transcription factors remain to be further evaluated. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

A conceptual framework to support exposure science research ...

EPA Pesticide Factsheets

While knowledge of exposure is fundamental to assessing and mitigating risks, exposure information has been costly and difficult to generate. Driven by major scientific advances in analytical methods, biomonitoring, computational tools, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition that allows it to be more agile, predictive, and data- and knowledge-driven. A necessary element of this evolved paradigm is an organizational and predictive framework for exposure science that furthers the application of systems-based approaches. To enable such systems-based approaches, we proposed the Aggregate Exposure Pathway (AEP) concept to organize data and information emerging from an invigorated and expanding field of exposure science. The AEP framework is a layered structure that describes the elements of an exposure pathway, as well as the relationship between those elements. The basic building blocks of an AEP adopt the naming conventions used for Adverse Outcome Pathways (AOPs): Key Events (KEs) to describe the measurable, obligate steps through the AEP; and Key Event Relationships (KERs) describe the linkages between KEs. Importantly, the AEP offers an intuitive approach to organize exposure information from sources to internal site of action, setting the stage for predicting stressor concentrations at an internal target site. These predicted concentrations can help inform the r

Associations between exposure to stressful life events and alcohol use disorder in a longitudinal birth cohort studied to age 30.

PubMed

Boden, Joseph M; Fergusson, David M; Horwood, L John

2014-09-01

To examine associations between measures of stressful life events exposure and alcohol abuse/dependence (AAD) from ages 18 to 30 using data from a longitudinal birth cohort (n=987 to 1011). Outcome measures included DSM-IV (American Psychiatric Association, 1994) AAD symptoms and AAD, at ages 20-21, 24-25, and 29-30 years. Exposure to a range of stressful life events was measured during the periods 18-21, 21-25, and 25-30 years using items adapted from the social readjustment rating scale (Holmes and Rahe, 1967). Data were analysed using Generalised Estimating Equation models, adjusted for non-observed sources of confounding using conditional fixed effects regression. Further analyses examined: gender×life events exposure interactions, structural equation modelling of possible reciprocal causal pathways linking stressful life events and AAD symptoms, and an alternative conceptualization of the stressful life events measure. After adjustment, those with the highest exposure to stressful life events had rates of AAD symptoms that were 2.24 (p<.0001) times higher, and odds of AAD that were 2.24 times higher(p<.01), than those at the lowest level of exposure. Associations between life events exposure and AAD symptoms were stronger for females than for males (p<.05), with results consistent using a count measure of stressful life events. Structural equation modelling showed that the best-fitting model was one in which life events influenced AAD symptoms. The results suggest that there were persistent linkages between stressful life events and AAD, providing support for a stress-reduction model of alcohol consumption. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

USE OF METAL- AND FLUORESCEIN-TAGGED MATERIALS TO STUDY SETTLED PARTICLES EXPOSURE PATHWAYS

EPA Science Inventory

Through the use of ten size ranges of tagged materials (Antley et. al., 2000a), inductively coupled plasma- mass spectrometry (ICP-MS) and flourometry are being used to study the movement of settled particles in the indoor environment, exposure pathways, and the collection effi...

Endocrine disrupting chemicals in fish: developing exposure indicators and predictive models of effects based on mechanism of action.

PubMed

Ankley, Gerald T; Bencic, David C; Breen, Michael S; Collette, Timothy W; Conolly, Rory B; Denslow, Nancy D; Edwards, Stephen W; Ekman, Drew R; Garcia-Reyero, Natalia; Jensen, Kathleen M; Lazorchak, James M; Martinović, Dalma; Miller, David H; Perkins, Edward J; Orlando, Edward F; Villeneuve, Daniel L; Wang, Rong-Lin; Watanabe, Karen H

2009-05-05

Knowledge of possible toxic mechanisms (or modes) of action (MOA) of chemicals can provide valuable insights as to appropriate methods for assessing exposure and effects, thereby reducing uncertainties related to extrapolation across species, endpoints and chemical structure. However, MOA-based testing seldom has been used for assessing the ecological risk of chemicals. This is in part because past regulatory mandates have focused more on adverse effects of chemicals (reductions in survival, growth or reproduction) than the pathways through which these effects are elicited. A recent departure from this involves endocrine-disrupting chemicals (EDCs), where there is a need to understand both MOA and adverse outcomes. To achieve this understanding, advances in predictive approaches are required whereby mechanistic changes caused by chemicals at the molecular level can be translated into apical responses meaningful to ecological risk assessment. In this paper we provide an overview and illustrative results from a large, integrated project that assesses the effects of EDCs on two small fish models, the fathead minnow (Pimephales promelas) and zebrafish (Danio rerio). For this work a systems-based approach is being used to delineate toxicity pathways for 12 model EDCs with different known or hypothesized toxic MOA. The studies employ a combination of state-of-the-art genomic (transcriptomic, proteomic, metabolomic), bioinformatic and modeling approaches, in conjunction with whole animal testing, to develop response linkages across biological levels of organization. This understanding forms the basis for predictive approaches for species, endpoint and chemical extrapolation. Although our project is focused specifically on EDCs in fish, we believe that the basic conceptual approach has utility for systematically assessing exposure and effects of chemicals with other MOA across a variety of biological systems.

Gene expression changes in a zebrafish model of drug dependency suggest conservation of neuro-adaptation pathways.

PubMed

Kily, Layla J M; Cowe, Yuka C M; Hussain, Osman; Patel, Salma; McElwaine, Suzanne; Cotter, Finbarr E; Brennan, Caroline H

2008-05-01

Addiction is a complex psychiatric disorder considered to be a disease of the brain's natural reward reinforcement system. Repeated stimulation of the 'reward' pathway leads to adaptive changes in gene expression and synaptic organization that reinforce drug taking and underlie long-term changes in behaviour. The primitive nature of reward reinforcement pathways and the near universal ability of abused drugs to target the same system allow drug-associated reward and reinforcement to be studied in non-mammalian species. Zebrafish have proved to be a valuable model system for the study of vertebrate development and disease. Here we demonstrate that adult zebrafish show a dose-dependent acute conditioned place preference (CPP) reinforcement response to ethanol or nicotine. Repeated exposure of adult zebrafish to either nicotine or ethanol leads to a robust CPP response that persists following 3 weeks of abstinence and in the face of adverse stimuli, a behavioural indicator of the establishment of dependence. Microarray analysis using whole brain samples from drug-treated and control zebrafish identified 1362 genes that show a significant change in expression between control and treated individuals. Of these genes, 153 are common to both ethanol- and nicotine-treated animals. These genes include members of pathways and processes implicated in drug dependence in mammalian models, revealing conservation of neuro-adaptation pathways between zebrafish and mammals.

Transcriptome-wide analyses indicate mitochondrial responses to particulate air pollution exposure.

PubMed

Winckelmans, Ellen; Nawrot, Tim S; Tsamou, Maria; Den Hond, Elly; Baeyens, Willy; Kleinjans, Jos; Lefebvre, Wouter; Van Larebeke, Nicolas; Peusens, Martien; Plusquin, Michelle; Reynders, Hans; Schoeters, Greet; Vanpoucke, Charlotte; de Kok, Theo M; Vrijens, Karen

2017-08-18

Due to their lack of repair capacity mitochondria are critical targets for environmental toxicants. We studied genes and pathways reflecting mitochondrial responses to short- and medium-term PM 10 exposure. Whole genome gene expression was measured in peripheral blood of 98 adults (49% women). We performed linear regression analyses stratified by sex and adjusted for individual and temporal characteristics to investigate alterations in gene expression induced by short-term (week before blood sampling) and medium-term (month before blood sampling) PM 10 exposure. Overrepresentation analyses (ConsensusPathDB) were performed to identify enriched mitochondrial associated pathways and gene ontology sets. Thirteen Human MitoCarta genes were measured by means of quantitative real-time polymerase chain reaction (qPCR) along with mitochondrial DNA (mtDNA) content in an independent validation cohort (n = 169, 55.6% women). Overrepresentation analyses revealed significant pathways (p-value <0.05) related to mitochondrial genome maintenance and apoptosis for short-term exposure and to the electron transport chain (ETC) for medium-term exposure in women. For men, medium-term PM 10 exposure was associated with the Tri Carbonic Acid cycle. In an independent study population, we validated several ETC genes, including UQCRH and COX7C (q-value <0.05), and some genes crucial for the maintenance of the mitochondrial genome, including LONP1 (q-value: 0.07) and POLG (q-value: 0.04) in women. In this exploratory study, we identified mitochondrial genes and pathways associated with particulate air pollution indicating upregulation of energy producing pathways as a potential mechanism to compensate for PM-induced mitochondrial damage.

Prenatal low-dose methylmercury exposure impairs neurite outgrowth and synaptic protein expression and suppresses TrkA pathway activity and eEF1A1 expression in the rat cerebellum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujimura, Masatake, E-mail: fujimura@nimd.go.jp; Usuki, Fusako; Cheng, Jinping

Methylmercury (MeHg) is a highly neurotoxic environmental chemical that can cause developmental impairments. Human fetuses and neonates are particularly susceptible to MeHg toxicity; however, the mechanisms governing its effects in the developing brain are unclear. In the present study, we investigated the effects of prenatal and lactational MeHg exposure on the developing cerebellum in rats. We demonstrated that exposure to 5 ppm MeHg decreased postnatal expression of pre- and postsynaptic proteins, suggesting an impairment in synaptic development. MeHg exposure also reduced neurite outgrowth, as shown by a decrease in the expression of the neurite marker neurofilament H. These changes weremore » not observed in rats exposed to 1 ppm MeHg. In order to define the underlying mechanism, we investigated the effects of MeHg exposure on the tropomyosin receptor kinase (Trk) A pathway, which plays important roles in neuronal differentiation and synapse formation. We demonstrated suppression of the TrkA pathway on gestation day 20 in rats exposed to 5 ppm MeHg. In addition, down-regulation of eukaryotic elongation factor 1A1 (eEF1A1) was observed on postnatal day 1. eEF1A1 knockdown in differentiating PC12 cells impaired neurite outgrowth and synaptic protein expression, similar to the results of MeHg exposure in the cerebellum. These results suggest that suppression of the TrkA pathway and subsequent decreases in eEF1A1 expression induced by prenatal exposure to MeHg may lead to reduced neurite outgrowth and synaptic protein expression in the developing cerebellum. - Highlights: • Prenatal exposure to MeHg decreased postnatal expression of synaptic proteins. • MeHg exposure also reduced neurite outgrowth postnatally. • Suppression of the TrkA pathway and eEF1A1 expression was induced by MeHg exposure. • eEF1A1 knockdown impaired neurite outgrowth and synaptic protein expression.« less

Prenatal Alcohol Exposure in Rodents As a Promising Model for the Study of ADHD Molecular Basis

PubMed Central

Rojas-Mayorquín, Argelia E.; Padilla-Velarde, Edgar; Ortuño-Sahagún, Daniel

2016-01-01

A physiological parallelism, or even a causal effect relationship, can be deducted from the analysis of the main characteristics of the “Alcohol Related Neurodevelopmental Disorders” (ARND), derived from prenatal alcohol exposure (PAE), and the behavioral performance in the Attention-deficit/hyperactivity disorder (ADHD). These two clinically distinct disease entities, exhibits many common features. They affect neurological shared pathways, and also related neurotransmitter systems. We briefly review here these parallelisms, with their common and uncommon characteristics, and with an emphasis in the subjacent molecular mechanisms of the behavioral manifestations, that lead us to propose that PAE in rats can be considered as a suitable model for the study of ADHD. PMID:28018163

Application of in Vitro Biotransformation Data and ...

EPA Pesticide Factsheets

The adverse biological effects of toxic substances are dependent upon the exposure concentration and the duration of exposure. Pharmacokinetic models can quantitatively relate the external concentration of a toxicant in the environment to the internal dose of the toxicant in the target tissues of an exposed organism. The exposure concentration of a toxic substance is usually not the same as the concentration of the active form of the toxicant that reaches the target tissues following absorption, distribution, and biotransformation of the parent toxicant. Biotransformation modulates the biological activity of chemicals through bioactivation and detoxication pathways. Many toxicants require biotransformation to exert their adverse biological effects. Considerable species differences in biotransformation and other pharmacokinetic processes can make extrapolation of toxicity data from laboratory animals to humans problematic. Additionally, interindividual differences in biotransformation among human populations with diverse genetics and lifestyles can lead to considerable variability in the bioactivation of toxic chemicals. Compartmental pharmacokinetic models of animals and humans are needed to understand the quantitative relationships between chemical exposure and target tissue dose as well as animal to human differences and interindividual differences in human populations. The data-based compartmental pharmacokinetic models widely used in clinical pharmacology ha

Computational toxicology as implemented by the U.S. EPA: providing high throughput decision support tools for screening and assessing chemical exposure, hazard and risk.

PubMed

Kavlock, Robert; Dix, David

2010-02-01

Computational toxicology is the application of mathematical and computer models to help assess chemical hazards and risks to human health and the environment. Supported by advances in informatics, high-throughput screening (HTS) technologies, and systems biology, the U.S. Environmental Protection Agency EPA is developing robust and flexible computational tools that can be applied to the thousands of chemicals in commerce, and contaminant mixtures found in air, water, and hazardous-waste sites. The Office of Research and Development (ORD) Computational Toxicology Research Program (CTRP) is composed of three main elements. The largest component is the National Center for Computational Toxicology (NCCT), which was established in 2005 to coordinate research on chemical screening and prioritization, informatics, and systems modeling. The second element consists of related activities in the National Health and Environmental Effects Research Laboratory (NHEERL) and the National Exposure Research Laboratory (NERL). The third and final component consists of academic centers working on various aspects of computational toxicology and funded by the U.S. EPA Science to Achieve Results (STAR) program. Together these elements form the key components in the implementation of both the initial strategy, A Framework for a Computational Toxicology Research Program (U.S. EPA, 2003), and the newly released The U.S. Environmental Protection Agency's Strategic Plan for Evaluating the Toxicity of Chemicals (U.S. EPA, 2009a). Key intramural projects of the CTRP include digitizing legacy toxicity testing information toxicity reference database (ToxRefDB), predicting toxicity (ToxCast) and exposure (ExpoCast), and creating virtual liver (v-Liver) and virtual embryo (v-Embryo) systems models. U.S. EPA-funded STAR centers are also providing bioinformatics, computational toxicology data and models, and developmental toxicity data and models. The models and underlying data are being made publicly available through the Aggregated Computational Toxicology Resource (ACToR), the Distributed Structure-Searchable Toxicity (DSSTox) Database Network, and other U.S. EPA websites. While initially focused on improving the hazard identification process, the CTRP is placing increasing emphasis on using high-throughput bioactivity profiling data in systems modeling to support quantitative risk assessments, and in developing complementary higher throughput exposure models. This integrated approach will enable analysis of life-stage susceptibility, and understanding of the exposures, pathways, and key events by which chemicals exert their toxicity in developing systems (e.g., endocrine-related pathways). The CTRP will be a critical component in next-generation risk assessments utilizing quantitative high-throughput data and providing a much higher capacity for assessing chemical toxicity than is currently available.

Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio.

PubMed

Ryu, Do-Yeal; Rahman, Md Saidur; Pang, Myung-Geol

2017-09-06

Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive biological cell model systems in determining BPA health risk are lacking. Here, we determined suitable cell model systems and potential biomarkers for predicting BPA-mediated disease using the bioinformatics tool Pathway Studio. We compiled known BPA-mediated diseases in humans, which were categorized into five major types. Subsequently, we investigated the differentially expressed proteins following BPA exposure in several cell types, and analyzed the efficacy of altered proteins to investigate their associations with BPA-mediated diseases. Our results demonstrated that colon cancer cells (SW480), mammary gland, and Sertoli cells were highly sensitive biological model systems, because of the efficacy of predicting the majority of BPA-mediated diseases. We selected glucose-6-phosphate dehydrogenase (G6PD), cytochrome b-c1 complex subunit 1 (UQCRC1), and voltage-dependent anion-selective channel protein 2 (VDAC2) as highly sensitive biomarkers to predict BPA-mediated diseases. Furthermore, we summarized proteomic studies in spermatozoa following BPA exposure, which have recently been considered as another suitable cell type for predicting BPA-mediated diseases.

Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio

PubMed Central

Ryu, Do-Yeal

2017-01-01

Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive biological cell model systems in determining BPA health risk are lacking. Here, we determined suitable cell model systems and potential biomarkers for predicting BPA-mediated disease using the bioinformatics tool Pathway Studio. We compiled known BPA-mediated diseases in humans, which were categorized into five major types. Subsequently, we investigated the differentially expressed proteins following BPA exposure in several cell types, and analyzed the efficacy of altered proteins to investigate their associations with BPA-mediated diseases. Our results demonstrated that colon cancer cells (SW480), mammary gland, and Sertoli cells were highly sensitive biological model systems, because of the efficacy of predicting the majority of BPA-mediated diseases. We selected glucose-6-phosphate dehydrogenase (G6PD), cytochrome b-c1 complex subunit 1 (UQCRC1), and voltage-dependent anion-selective channel protein 2 (VDAC2) as highly sensitive biomarkers to predict BPA-mediated diseases. Furthermore, we summarized proteomic studies in spermatozoa following BPA exposure, which have recently been considered as another suitable cell type for predicting BPA-mediated diseases. PMID:28878155

Signaling Pathways Involved in 1-Octen-3-ol-Mediated Neurotoxicity in Drosophila melanogaster: Implication in Parkinson’s Disease

PubMed Central

Masurekar, Prakash; Hossain, Muhammad; Richardson, Jason R.; Bennett, Joan W.

2014-01-01

Previously, we have pioneered Drosophila melanogaster as a reductionist model to show that 1-octen-3-ol, a musty-smelling volatile compound emitted by fungi and other organisms, causes loss of dopaminergic neurons and Parkinson’s disease-like symptoms in flies. Using our in vivo Drosophila system, the modulatory roles of important signaling pathways—JNK, Akt and the caspase-3-dependent apoptotic pathway were investigated in the context of 1-octen-3-ol-induced dopamine neurotoxicity. When heterozygous flies carrying mutant alleles for these proteins were exposed to 0.5 ppm of 1-octen-3-ol, they had shorter survival times than wild-type Drosophila. The overexpressed levels of wild-type JNK and Akt, (UAS-bsk and UAS-Akt) with TH-GAL4 and elav-GAL4 drivers improved the survival duration of exposed flies compared with controls. Thus, we found that Akt and JNK both protect against loss of dopamine activity associated with 1-octen-3-ol exposure, indicating the pro-survival role of these signaling pathways. Further, 1-octen-3-ol exposure was associated with activation of caspase 3, a hallmark for apoptosis. PMID:23959949

Global gene expression analysis reveals pathway differences between teratogenic and non-teratogenic exposure concentrations of bisphenol A and 17β-estradiol in embryonic zebrafish

PubMed Central

Saili, Katerine S.; Tilton, Susan C.; Waters, Katrina M.; Tanguay, Robert L.

2013-01-01

Transient developmental exposure to 0.1 μM bisphenol A (BPA) results in larval zebrafish hyperactivity and learning impairments in the adult, while exposure to 80 μM BPA results in teratogenic responses, including craniofacial abnormalities and edema. The mode of action underlying these effects is unclear. We used global gene expression analysis to identify candidate genes and signaling pathways that mediate BPA’s developmental toxicity in zebrafish. Exposure concentrations were selected and anchored to the positive control, 17β-estradiol (E2), based on previously determined behavioral or teratogenic phenotypes. Functional analysis of differentially expressed genes revealed distinct expression profiles at 24 hours post fertilization for 0.1 versus 80 μM BPA and 0.1 versus 15 μM E2 exposure, identification of prothrombin activation as a top canonical pathway impacted by both 0.1 μM BPA and 0.1 μM E2 exposure, and suppressed expression of several genes involved in nervous system development and function following 0.1 μM BPAexposure. PMID:23557687

Impact of Physical Abuse on Internalizing Behavior Across Generations.

PubMed

Esteves, Kyle; Gray, Sarah A O; Theall, Katherine P; Drury, Stacy S

2017-10-01

This study investigated the multigenerational impact of mothers' own exposure to physical maltreatment on internalizing symptoms in her child after accounting for her parenting practices, depression, and the child's own exposure to stressful life events. Children ( n = 101, ages 5-16), predominantly African American, were recruited into this cross sectional study using ethnographic mapping and targeted sampling for high-risk neighborhoods. Mothers reported retrospectively on their own exposure to physical maltreatment in childhood, their parenting practices, as well as current depressive symptoms. Maternal report of her child's exposure to stressful life events and child behavior was also collected. Maternal childhood exposure to physical maltreatment was significantly associated with her child's internalizing symptoms ( p = .004); this effect remained after accounting for child sex, maternal depressive symptoms, harsh parenting practices, and the child's own exposure to stressful life events. Formal tests of mediation through these pathways were non-significant. Findings suggest mothers' experience of childhood maltreatment contributes uniquely to children's internalizing symptoms, potentially through previously uncharacterized pathways. Examination of additional behavioral, psychosocial and biological pathways may help better describe the multi-generational effects of child maltreatment.

Editor's Highlight: Periodic Exposure to Smartphone-Mimic Low-Luminance Blue Light Induces Retina Damage Through Bcl-2/BAX-Dependent Apoptosis.

PubMed

Lin, Cheng-Hui; Wu, Man-Ru; Li, Ching-Hao; Cheng, Hui-Wen; Huang, Shih-Hsuan; Tsai, Chi-Hao; Lin, Fan-Li; Ho, Jau-Der; Kang, Jaw-Jou; Hsiao, George; Cheng, Yu-Wen

2017-05-01

Blue light-induced phototoxicity plays an important role in retinal degeneration and might cause damage as a consequence of smartphone dependency. Here, we investigated the effects of periodic exposure to blue light-emitting diode in a cell model and a rat retinal damage model. Retinal pigment epithelium (RPE) cells were subjected to blue light in vitro and the effects of blue light on activation of key apoptotic pathways were examined by measuring the levels of Bcl-2, Bax, Fas ligand (FasL), Fas-associated protein with death domain (FADD), and caspase-3 protein. Blue light treatment of RPE cells increased Bax, cleaved caspase-3, FasL, and FADD expression, inhibited Bcl-2 and Bcl-xL accumulation, and inhibited Bcl-2/Bax association. A rat model of retinal damage was developed with or without continuous or periodic exposure to blue light for 28 days. In this rat model of retinal damage, periodic blue light exposure caused fundus damage, decreased total retinal thickness, caused atrophy of photoreceptors, and injured neuron transduction in the retina. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A screening level risk assessment of the indirect impacts from the Columbus Waste to Energy facility in Columbus, Ohio

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lorber, M.; Cleverly, D.; Schaum, J.

1996-12-31

Testing for emissions of dioxins from the stack of the Columbus, Ohio Waste to Energy (WTE) municipal solid waste combustion facility in 1992 implied that dioxin emissions could approach 1,000 grams of dioxin toxic equivalents (TEQs) per year. The incinerator has been in operation since the early 1980s. Several varying activities to further evaluate or curtail emissions were conducted by local, state and federal agencies in 1994. Also in that year, US EPA`s Region 5 issued an emergency order under Section 7003 of RCRA requiring the facility to install maximum Achievable Control Technology (MACT). As part of their justification formore » this emergency order, Region 5 used a screening level risk assessment of potential indirect impacts. This paper describes this assessment. The exposure setting is a hypothetical dairy farm where individuals on the farm obtain their beef, milk, and vegetables from home sources. A 70-year exposure scenario is considered, which includes 45 years of facility operation at the pre- and post-MACT emission rates, followed by 25 years of impact due to residual soil concentrations. Soil dermal contact, inhalation, and breast milk exposures were also considered for this assessment. The source term, or dioxin loadings to this setting, were derived from air dispersion modeling of emissions from the Columbus WTE. A key finding of the assessment was that exposures to dioxin in beef and milk dominated the estimated risks, with excess cancer risk form these two pathways estimated at 2.8 {times} 10{sup {minus}4}. A second key finding was that over 90% of a lifetime of impact from these two pathways, and the inhalation and vegetable ingestion pathways, has already occurred due to pre-MACT emissions.« less

Counterbalancing Regulation in Response Memory of a Positively Autoregulated Two-Component System.

PubMed

Gao, Rong; Godfrey, Katherine A; Sufian, Mahir A; Stock, Ann M

2017-09-15

Fluctuations in nutrient availability often result in recurrent exposures to the same stimulus conditions. The ability to memorize the past event and use the "memory" to make adjustments to current behaviors can lead to a more efficient adaptation to the recurring stimulus. A short-term phenotypic memory can be conferred via carryover of the response proteins to facilitate the recurrent response, but the additional accumulation of response proteins can lead to a deviation from response homeostasis. We used the Escherichia coli PhoB/PhoR two-component system (TCS) as a model system to study how cells cope with the recurrence of environmental phosphate (Pi) starvation conditions. We discovered that "memory" of prior Pi starvation can exert distinct effects through two regulatory pathways, the TCS signaling pathway and the stress response pathway. Although carryover of TCS proteins can lead to higher initial levels of transcription factor PhoB and a faster initial response in prestarved cells than in cells not starved, the response enhancement can be overcome by an earlier and greater repression of promoter activity in prestarved cells due to the memory of the stress response. The repression counterbalances the carryover of the response proteins, leading to a homeostatic response whether or not cells are prestimulated. A computational model based on sigma factor competition was developed to understand the memory of stress response and to predict the homeostasis of other PhoB-regulated response proteins. Our insight into the history-dependent PhoBR response may provide a general understanding of how TCSs respond to recurring stimuli and adapt to fluctuating environmental conditions. IMPORTANCE Bacterial cells in their natural environments experience scenarios that are far more complex than are typically replicated in laboratory experiments. The architectures of signaling systems and the integration of multiple adaptive pathways have evolved to deal with such complexity. In this study, we examined the molecular "memory" that is generated by previous exposure to stimulus. Under our experimental conditions, activating effects of autoregulated two-component signaling and inhibitory effects of the stress response counterbalanced the transcriptional output to approach response homeostasis whether or not cells had been preexposed to stimulus. Modeling allows prediction of response behavior in different scenarios and demonstrates both the robustness of the system output and its sensitivity to historical parameters such as timing and levels of exposure to stimuli. Copyright © 2017 American Society for Microbiology.

Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood–brain barrier primary triple coculture model

PubMed Central

Xu, Liming; Dan, Mo; Shao, Anliang; Cheng, Xiang; Zhang, Cuiping; Yokel, Robert A; Takemura, Taro; Hanagata, Nobutaka; Niwa, Masami; Watanabe, Daisuke

2015-01-01

Background Silver nanoparticles (Ag-NPs) can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood–brain barrier (BBB) and the underlying mechanism(s) of action on the BBB and the brain are not well understood. Method To investigate Ag-NP suspension (Ag-NPS)-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM). Global gene expression of astrocytes was measured using a DNA microarray. Results A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200 Ω·cm2. After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the tight junction (TJ) protein ZO-1 was decreased. Discontinuous TJs were also observed between microvascular endothelial cells. After Ag-NPS exposure, severe mitochondrial shrinkage, vacuolations, endoplasmic reticulum expansion, and Ag-NPs were observed in astrocytes by TEM. Global gene expression analysis showed that three genes were upregulated and 20 genes were downregulated in astrocytes treated with Ag-NPS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the 23 genes were associated with metabolic processes, biosynthetic processes, response to stimuli, cell death, the MAPK pathway, and so on. No GO term and KEGG pathways were changed in the released-ion or polystyrene-NP groups. Ag-NPS inhibited the antioxidant defense of the astrocytes by increasing thioredoxin interacting protein, which inhibits the Trx system, and decreasing Nr4a1 and Dusp1. Meanwhile, Ag-NPS induced inflammation and apoptosis through modulation of the MAPK pathway or B-cell lymphoma-2 expression or mTOR activity in astrocytes. Conclusion These results draw our attention to the importance of Ag-NP-induced toxicity on the neurovascular unit and provide a better understanding of its toxicological mechanisms on astrocytes. PMID:26491287

Counterbalancing Regulation in Response Memory of a Positively Autoregulated Two-Component System

PubMed Central

Gao, Rong; Godfrey, Katherine A.; Sufian, Mahir A.

2017-01-01

ABSTRACT Fluctuations in nutrient availability often result in recurrent exposures to the same stimulus conditions. The ability to memorize the past event and use the “memory” to make adjustments to current behaviors can lead to a more efficient adaptation to the recurring stimulus. A short-term phenotypic memory can be conferred via carryover of the response proteins to facilitate the recurrent response, but the additional accumulation of response proteins can lead to a deviation from response homeostasis. We used the Escherichia coli PhoB/PhoR two-component system (TCS) as a model system to study how cells cope with the recurrence of environmental phosphate (Pi) starvation conditions. We discovered that “memory” of prior Pi starvation can exert distinct effects through two regulatory pathways, the TCS signaling pathway and the stress response pathway. Although carryover of TCS proteins can lead to higher initial levels of transcription factor PhoB and a faster initial response in prestarved cells than in cells not starved, the response enhancement can be overcome by an earlier and greater repression of promoter activity in prestarved cells due to the memory of the stress response. The repression counterbalances the carryover of the response proteins, leading to a homeostatic response whether or not cells are prestimulated. A computational model based on sigma factor competition was developed to understand the memory of stress response and to predict the homeostasis of other PhoB-regulated response proteins. Our insight into the history-dependent PhoBR response may provide a general understanding of how TCSs respond to recurring stimuli and adapt to fluctuating environmental conditions. IMPORTANCE Bacterial cells in their natural environments experience scenarios that are far more complex than are typically replicated in laboratory experiments. The architectures of signaling systems and the integration of multiple adaptive pathways have evolved to deal with such complexity. In this study, we examined the molecular “memory” that is generated by previous exposure to stimulus. Under our experimental conditions, activating effects of autoregulated two-component signaling and inhibitory effects of the stress response counterbalanced the transcriptional output to approach response homeostasis whether or not cells had been preexposed to stimulus. Modeling allows prediction of response behavior in different scenarios and demonstrates both the robustness of the system output and its sensitivity to historical parameters such as timing and levels of exposure to stimuli. PMID:28674072

Moderate UV Exposure Enhances Learning and Memory by Promoting a Novel Glutamate Biosynthetic Pathway in the Brain.

PubMed

Zhu, Hongying; Wang, Ning; Yao, Lei; Chen, Qi; Zhang, Ran; Qian, Junchao; Hou, Yiwen; Guo, Weiwei; Fan, Sijia; Liu, Siling; Zhao, Qiaoyun; Du, Feng; Zuo, Xin; Guo, Yujun; Xu, Yan; Li, Jiali; Xue, Tian; Zhong, Kai; Song, Xiaoyuan; Huang, Guangming; Xiong, Wei

2018-06-14

Sunlight exposure is known to affect mood, learning, and cognition. However, the molecular and cellular mechanisms remain elusive. Here, we show that moderate UV exposure elevated blood urocanic acid (UCA), which then crossed the blood-brain barrier. Single-cell mass spectrometry and isotopic labeling revealed a novel intra-neuronal metabolic pathway converting UCA to glutamate (GLU) after UV exposure. This UV-triggered GLU synthesis promoted its packaging into synaptic vesicles and its release at glutamatergic terminals in the motor cortex and hippocampus. Related behaviors, like rotarod learning and object recognition memory, were enhanced after UV exposure. All UV-induced metabolic, electrophysiological, and behavioral effects could be reproduced by the intravenous injection of UCA and diminished by the application of inhibitor or short hairpin RNA (shRNA) against urocanase, an enzyme critical for the conversion of UCA to GLU. These findings reveal a new GLU biosynthetic pathway, which could contribute to some of the sunlight-induced neurobehavioral changes. Copyright © 2018 Elsevier Inc. All rights reserved.

Secondhand Smoke Exposure Reduced the Compensatory Effects of IGF-I Growth Signaling in the Aging Rat Hearts

PubMed Central

Wu, Jia-Ping; Hsieh, Dennis Jine-Yuan; Kuo, Wei-Wen; Han, Chien-Kuo; Pai, Peiying; Yeh, Yu-Lan; Lin, Chien-Chung; Padma, V. Vijaya; Day, Cecilia Hsuan; Huang, Chih-Yang

2015-01-01

Background: Secondhand smoke (SHS) exposure is associated with increased risk of cardiovascular disease. Aging is a physiological process that involves progressive impairment of normal heart functions due to increased vulnerability to damage. This study examines secondhand smoke exposure in aging rats to determine the age-related death-survival balance. Methods: Rats were placed into a SHS exposure chamber and exposed to smog. Old age male Sprague-Dawley rats were exposed to 10 cigarettes for 30 min, day and night, continuing for one week. After 4 weeks the rats underwent morphological and functional studies. Left ventricular sections were stained with hematoxylin-eosin for histopathological examination. TUNEL detected apoptosis cells and protein expression related death and survival pathway were analyzed using western blot. Results: Death receptor-dependent apoptosis upregulation pathways and the mitochondria apoptosis proteins were apparent in young SHS exposure and old age rats. These biological markers were enhanced in aging SHS-exposed rats. The survival pathway was found to exhibit compensation only in young SHS-exposed rats, but not in the aging rats. Further decrease in the activity of this pathway was observed in aging SHS-exposed rats. TUNEL apoptotic positive cells were increased in young SHS-exposed rats, and in aging rats with or without SHS-exposure. Conclusions: Aging reduces IGF-I compensated signaling with accelerated cardiac apoptotic effects from second-hand smoke. PMID:26392808

Exposure to mass media and interpersonal counseling has additive effects on exclusive breastfeeding and its psychosocial determinants among Vietnamese mothers.

PubMed

Nguyen, Phuong H; Kim, Sunny S; Nguyen, Tuan T; Hajeebhoy, Nemat; Tran, Lan M; Alayon, Silvia; Ruel, Marie T; Rawat, Rahul; Frongillo, Edward A; Menon, Purnima

2016-10-01

The pathways through which behavior change interventions impact breastfeeding practices have not been well studied. This study aimed to examine: (1) the effects of exposure to mass media and interpersonal counseling on exclusive breastfeeding (EBF) and hypothesized psychosocial determinants (i.e. knowledge, intention, beliefs, social norms, and self-efficacy); and (2) the pathways through which exposure to mass media and interpersonal counseling are associated with EBF. We used survey data from mothers with children < 2 year (n = 2045) from the 2013 process evaluation of Alive & Thrive's program in Viet Nam. Multiple linear regression analyses and structural equation modeling were used to estimate effects. Exposure to mass media only, interpersonal counseling only, both or neither was 51%, 5%, 19% and 25%, respectively. Exposure to both mass media and interpersonal counseling had additive effects on EBF as well as on related psychosocial factors, compared with no exposure. For example, EBF prevalence was 26.1 percentage points (pp) higher in the group that received interpersonal counseling only, 3.9 pp higher in the mass media group and 31.8 pp higher in the group that received both interventions. As hypothesized, more than 90% of the total effect of the two interventions on EBF was explained by the psychosocial factors measured. Our findings suggest that combining different behavior change interventions leads to greater changes in psychosocial factors, which in turn positively affects breastfeeding behaviors. © 2016 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.

Historical human exposure to perfluoroalkyl acids in the United States and Australia reconstructed from biomonitoring data using population-based pharmacokinetic modelling.

PubMed

Gomis, Melissa I; Vestergren, Robin; MacLeod, Matthew; Mueller, Jochen F; Cousins, Ian T

2017-11-01

Perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS) and perfluorohexanesulfonic acid (PFHxS) are found in the blood of humans and wildlife worldwide. Since the beginning of the 21st century, a downward trend in the human body burden, especially for PFOS and PFOA, has been observed while there is no clear temporal trend in wildlife. The inconsistency between the concentration decline in human serum and in wildlife could be indicative of a historical exposure pathway for humans linked to consumer products that has been reduced or eliminated. In this study, we reconstruct the past human exposure trends in two different regions, USA and Australia, by inferring the historical intake from cross-sectional biomonitoring data of PFOS, PFOA and PFHxS using a population-based pharmacokinetic model. For PFOS in the USA, the reconstructed daily intake peaked at 4.5ng/kg-bw/day between 1988 and 1999 while in Australia it peaked at 4.0ng/kg-bw/day between 1984 and 1996. For PFOA in the USA and Australia, the peak reconstructed daily intake was 1.1ng/kg-bw/day in 1995 and 3.6ng/kg-bw/day in 1992, respectively, and started to decline in 2000 and 1995, respectively. The model could not be satisfactorily fitted to the biomonitoring data for PFHxS within reasonable boundaries for its intrinsic elimination half-life, and thus reconstructing intakes of PFHxS was not possible. Our results indicate that humans experienced similar exposure levels and trends to PFOS and PFOA in the USA and Australia. Our findings support the hypothesis that near-field consumer product exposure pathways were likely dominant prior to the phase-out in industrialized countries. The intrinsic elimination half-life, which represents elimination processes that are common for all humans, and elimination processes unique to women (i.e., menstruation, cord-blood transfer and breastfeeding) were also investigated. The intrinsic elimination half-lives for PFOS and PFOA derived from model fitting for men were 3.8 and 2.4years, respectively, for the USA, and 4.9 and 2years respectively for Australia. Our results show that menstruation is a depuration pathway for PFOA for women, similarly but to a lesser extent compared to previous reports for PFOS. However menstruation, cord-blood transfer and breastfeeding together do not fully explain the apparently more rapid elimination of PFOA and PFOS by women compared to men; the intrinsic elimination half-lives in women were up to 13% lower for PFOS and up to 12% lower for PFOA compared to the corresponding half-lives in men. Copyright © 2017 Elsevier Ltd. All rights reserved.

Integrating Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Estimate Exposure-relevant Responses

EPA Science Inventory

High throughput toxicity testing (HTT) holds the promise of providing data for tens of thousands of chemicals that currently have no data due to the cost and time required for animal testing. Interpretation of these results require information linking the perturbations seen in vi...

Exposure information in environmental health research: Current opportunities and future directions for particulate matter, ozone, and toxic air pollutants

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKone, Thomas E.; Ryan, P. Barry; Ozkaynak, Haluk

2007-02-01

Understanding and quantifying outdoor and indoor sources of human exposure are essential but often not adequately addressed in health-effects studies for air pollution. Air pollution epidemiology, risk assessment, health tracking and accountability assessments are examples of health-effects studies that require but often lack adequate exposure information. Recent advances in exposure modeling along with better information on time-activity and exposure factors data provide us with unique opportunities to improve the assignment of exposures for both future and ongoing studies linking air pollution to health impacts. In September 2006, scientists from the US Environmental Protection Agency (EPA) and the Centers for Diseasemore » Control and Prevention (CDC) along with scientists from the academic community and state health departments convened a symposium on air pollution exposure and health in order to identify, evaluate, and improve current approaches for linking air pollution exposures to disease. This manuscript presents the key issues, challenges and recommendations identified by the exposure working group, who used cases studies of particulate matter, ozone, and toxic air pollutant exposure to evaluate health-effects for air pollution. One of the over-arching lessons of this workshop is that obtaining better exposure information for these different health-effects studies requires both goal-setting for what is needed and mapping out the transition pathway from current capabilities to meeting these goals. Meeting our long-term goals requires definition of incremental steps that provide useful information for the interim and move us toward our long-term goals. Another over-arching theme among the three different pollutants and the different health study approaches is the need for integration among alternate exposure assessment approaches. For example, different groups may advocate exposure indicators, biomonitoring, mapping methods (GIS), modeling, environmental media monitoring, and/or personal exposure modeling. However, emerging research reveals that the greatest progress comes from integration among two or more of these efforts.« less

Mechanism of the Synergistic Effect of Amiodarone and Fluconazole in Candida albicans▿ †

PubMed Central

Gamarra, Soledad; Rocha, Elousa Maria F.; Zhang, Yong-Qiang; Park, Steven; Rao, Rajini; Perlin, David S.

2010-01-01

The antiarrhythmic drug amiodarone has been found to have fungicidal activity. In Saccharomyces cerevisiae, its antifungal activity is mediated by calcium overload stress, which leads to a rapid nuclear accumulation of the calcineurin-regulated transcription factor CRZ1. In addition, low doses of amiodarone have been reported to be synergistic with fluconazole in fluconazole-resistant Candida albicans. To establish its mechanism of toxicity in C. albicans, we used expression profiling of key pathway genes to examine cellular responses to amiodarone alone and in combination with fluconazole. Gene expression profiling of 59 genes was done in five C. albicans strains (three fluconazole-susceptible strains and two fluconazole-resistant strains) after amiodarone and/or fluconazole exposure. Of the 59 genes, 27 analyzed showed a significant change (>2-fold) in expression levels after amiodarone exposure. The up- or downregulated genes included genes involved in Ca2+ homeostasis, cell wall synthesis, vacuolar/lysosomal transport, diverse pathway regulation, stress response, and pseudohyphal morphogenesis. As expected, fluconazole induces an increase in ergosterol pathway genes expression levels. The combination treatment significantly dampened the transcriptional response to either drug, suggesting that synergism was due to an inhibition of compensatory response pathways. This dampening resulted in a decrease in total ergosterol levels and decreased pseudohyphal formation, a finding consistent with decreased virulence in a murine candidiasis model. PMID:20194694

Selective hair cell ablation and noise exposure lead to different patterns of changes in the cochlea and the cochlear nucleus

PubMed Central

Kurioka, Takaomi; Lee, Min Young; Heeringa, Amarins N.; Beyer, Lisa A.; Swiderski, Donald L.; Kanicki, Ariane C.; Kabara, Lisa L.; Dolan, David F.; Shore, Susan E.; Raphael, Yehoash

2016-01-01

In experimental animal models of auditory hair cell (HC) loss, insults such as noise or ototoxic drugs often lead to secondary changes or degeneration in non-sensory cells and neural components, including reduced density of spiral ganglion neurons, demyelination of auditory nerve fibers and altered cell numbers and innervation patterns in the cochlear nucleus. However, it is not clear whether loss of HCs alone leads to secondary degeneration in these neural components of the auditory pathway. To elucidate this issue, we investigated changes of central components after cochlear insults specific to HCs using diphtheria toxin receptor (DTR) mice expressing DTR only in HCs and exhibiting complete HC loss when injected with diphtheria toxin (DT). We showed that DT-induced HC ablation has no significant impacts on the survival of auditory neurons, central synaptic terminals, and myelin, despite complete HC loss and profound deafness. In contrast, noise exposure induced significant changes in synapses, myelin and CN organization even without loss of inner HCs. We observed a decrease of neuronal size in the auditory pathway, including peripheral axons, spiral ganglion neurons, and cochlear nucleus neurons, likely due to loss of input from the cochlea. Taken together, selective HC ablation and noise exposure showed different patterns of pathology in the auditory pathway and the presence of HCs is not essential for the maintenance of central synaptic connectivity and myelination. PMID:27403879

Activation of AKT1/GSK-3β/β-Catenin-TRIM11/Survivin Pathway by Novel GSK-3β Inhibitor Promotes Neuron Cell Survival: Study in Differentiated SH-SY5Y Cells in OGD Model.

PubMed

Darshit, B S; Ramanathan, M

2016-12-01

The objective of this study is to elucidate the effect of a new glycogen synthase kinase-3β (GSK-3β) inhibitor in RA differentiated SH-SY5Y cells in oxygen and glucose deprivation (OGD) model. The pathway involved in GSK-3β signaling during OGD was measured to elucidate the mechanism of action. The differentiation of SH-SY5Y into mature neuronal cells was done with retinoic acid. During differentiation, upregulation of the growth-associated protein 43 (GAP43), neurogenin1 (NGN1), neuronal differentiation 2 (NeuroD2), and tripartite motif containing 11 (TRIM11) genes were observed. Twelve hours of optimal OGD exposure resulted in the alteration of GSK-3β functions of the neuron cells. Of the five molecules selected for this study, molecule G3 showed better effect in the initial phase of the study. Hence, G3 (0.5, 1, and 5 μM) was selected for further study in the OGD model. The standard GSK-3β inhibitor, AR-A014418 (1 μM), was used for comparison. Molecules were pretreated (30 min) and cotreated during OGD exposure. GSK-3β inhibitors showed antiapoptotic activity as evidenced by reduced caspase-3 enzyme activity and increased survivin transcription, as well as improved membrane integrity, evidenced by LDH assay. The inhibitor molecules also up-regulated survival AKT1/GSK-3β/β-catenin pathway and stabilized β-catenin. Inhibition of GSK-3β maintained neuronal survival by upregulating GAP43, Ngn1, and NeuroD2 gene transcription. Further GSK-3β inhibition reduced the TRIM11 gene transcription. In conclusion, both inhibitors have been found to control apoptosis and maintain neuronal functioning and this effect might have been mediated through AKT1/GSK-3β/β-catenin-TRIM11/survivin pathway.

Differential exposure and differential vulnerability as counteracting forces linking the psychosocial work environment to socioeconomic health differences.

PubMed

Vanroelen, C; Levecque, K; Louckx, F

2010-10-01

In this article, the link between (1) psychosocial working conditions (job demands, job autonomy, task variation, social support), (2) self-reported health (persistent fatigue, musculoskeletal complaints, emotional well-being) and (3) socioeconomic position (skill levels, occupational status) is explored. The two theoretical pathways linking the psychosocial work environment to socioeconomic differences in health are explored: differential exposure and differential vulnerability. Previously, the focus has often been on social inequalities in exposure to the stressors. The pathway of differential vulnerability in different socioeconomic positions is often neglected. In a representative cross-sectional sample of 11,099 Flemish (Belgian) wage earners, 16-65 years of age (47.5% women), logit modelling is applied. Higher exposure to psychosocial occupational stressors is associated with a higher prevalence of adverse health outcomes. Lower skill levels and subordinate occupational positions show a higher prevalence of musculoskeletal complaints, but not of persistent fatigue or emotional well-being. High demands, job strain and iso-strain are more common in higher-skilled, supervisory and managerial positions, but have the strongest health-damaging effects in lower socioeconomic positions. Low control is more prevalent in lower-skilled and subordinate positions, while having stronger adverse health effects in higher socioeconomic positions-the same holds for social support, although it has no clear socioeconomic distribution. Differential exposure and differential vulnerability constitute two counteracting forces in constituting the association between the psychosocial work environment and socioeconomic differences in self-reported health complaints among wage earners.

Cigarette smoke exposure reveals a novel role for the MEK/ERK1/2 MAPK pathway in regulation of CFTR

PubMed Central

Xu, Xiaohua; Balsiger, Robert; Tyrrell, Jean; Boyaka, Prosper N.; Tarran, Robert; Cormet-Boyaka, Estelle

2015-01-01

Background CFTR plays a key role in maintenance of lung fluid homeostasis. Cigarette smoke decreases CFTR expression in the lung but neither the mechanisms leading to CFTR loss, nor potential ways to prevent its loss have been identified to date. Methods The molecular mechanisms leading to down-regulation of CFTR by cigarette smoke were determined using pharmacologic inhibitors and silencing RNAs. Results Using human bronchial epithelial cells, here we show that cigarette smoke induces degradation of CFTR that is attenuated by the lysosomal inhibitors, but not proteasome inhibitors. Cigarette smoke can activate multiple signaling pathways in airway epithelial cells, including the MEK/Erk1/2 MAPK pathway regulating cell survival. Interestingly, pharmacological inhibition of the MEK/Erk1/2 MAPK pathway prevented the loss of plasma membrane CFTR upon cigarette smoke exposure. Similarly, decreased expression of Erk1/2 using silencing RNAs prevented the suppression of CFTR protein by cigarette smoke. Conversely, specific inhibitors of the JNK or p38 MAPK pathways had no effect on CFTR decrease after cigarette smoke exposure. In addition, inhibition of the MEK/Erk1/2 MAPK pathway prevented the reduction of the airway surface liquid observed upon cigarette smoke exposure of primary human airway epithelial cells. Finally, addition of the antioxidant NAC inhibited activation of Erk1/2 by cigarette smoke and precluded the cigarette smoke-induced decrease of CFTR. Conclusions These results show that the MEK/Erk1/2 MAPK pathway regulates plasma membrane CFTR in human airway cells. General Significance The MEK/Erk1/2 MAPK pathway should be considered as a target for strategies to maintain/restore CFTR expression in the lung of smokers. PMID:25697727

Bioaccessibility and human health risk assessment of lead in soil from Daye City

NASA Astrophysics Data System (ADS)

Li, Q.; Li, F.; Xiao, M. S.; Cai, Y.; Xiong, L.; Huang, J. B.; Fu, J. T.

2018-01-01

Lead (Pb) in soil from 4 sampling sites of Daye City was studied. Bioaccessibilities of Pb in soil were determined by the method of simplified bioaccessible extraction test (SBET). Since traditional health risk assessment was built on the basis of metal total content, the risk may be overestimated. Modified human health risk assessment model considering bioaccessibility was built in this study. Health risk of adults and children exposure to Pb based on total contents and bioaccessible contents were evaluated. The results showed that bioaccessible content of Pb in soil was much lower than its total content, and the average bioaccessible factor (BF) was only 25.37%. The hazard indexes (HIs) for adults and children calculated by two methods were all lower than 1. It indicated that there were no no-carcinogenic risks of Pb for human in Daye. By comparing with the results, the average bioaccessible HIs for adults and children were lower than the total one, which was due to the lower hazard quotient (HQ). Proportions of non-carcinogenic risk exposure to Pb via different pathways have also changed. Particularly, the most main risk exposure pathway for adults turned from the oral ingestion to the inhalation.

Genistein inhibition of OGD-induced brain neuron death correlates with its modulation of apoptosis, voltage-gated potassium and sodium currents and glutamate signal pathway.

PubMed

Ma, Xue-Ling; Zhang, Feng; Wang, Yu-Xiang; He, Cong-Cong; Tian, Kun; Wang, Hong-Gang; An, Di; Heng, Bin; Liu, Yan-Qiang

2016-07-25

In the present study, we established an in vitro model of hypoxic-ischemia via exposing primary neurons of newborn rats to oxygen-glucose deprivation (OGD) and observing the effects of genistein, a soybean isoflavone, on hypoxic-ischemic neuron viability, apoptosis, voltage-activated potassium (Kv) and sodium (Nav) currents, and glutamate receptor subunits. The results indicated that OGD exposure reduced the viability and increased the apoptosis of brain neurons. Meanwhile, OGD exposure caused changes in the current-voltage curves and current amplitude values of voltage-activated potassium and sodium currents; OGD exposure also decreased GluR2 expression and increased NR2 expression. However, genistein at least partially reversed the effects caused by OGD. The results suggest that hypoxic-ischemia-caused neuronal apoptosis/death is related to an increase in K(+) efflux, a decrease in Na(+) influx, a down-regulation of GluR2, and an up-regulation of NR2. Genistein may exert some neuroprotective effects via the modulation of Kv and Nav currents and the glutamate signal pathway, mediated by GluR2 and NR2. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ambient PM2.5 exposure and expected premature mortality to 2100 in India under climate change scenarios.

PubMed

Chowdhury, Sourangsu; Dey, Sagnik; Smith, Kirk R

2018-01-22

Premature mortality from current ambient fine particulate (PM 2.5 ) exposure in India is large, but the trend under climate change is unclear. Here we estimate ambient PM 2.5 exposure up to 2100 by applying the relative changes in PM 2.5 from baseline period (2001-2005) derived from Coupled Model Inter-comparison Project 5 (CMIP5) models to the satellite-derived baseline PM 2.5 . We then project the mortality burden using socioeconomic and demographic projections in the Shared Socioeconomic Pathway (SSP) scenarios. Ambient PM 2.5 exposure is expected to peak in 2030 under the RCP4.5 and in 2040 under the RCP8.5 scenario. Premature mortality burden is expected to be 2.4-4 and 28.5-38.8% higher under RCP8.5 scenario relative to the RCP4.5 scenario in 2031-2040 and 2091-2100, respectively. Improved health conditions due to economic growth are expected to compensate for the impact of changes in population and age distribution, leading to a reduction in per capita health burden from PM 2.5 for all scenarios except the combination of RCP8.5 exposure and SSP3.

Blue light reduces organ injury from ischemia and reperfusion

PubMed Central

Yuan, Du; Collage, Richard D.; Huang, Hai; Zhang, Xianghong; Kautza, Benjamin C.; Lewis, Anthony J.; Zuckerbraun, Brian S.; Tsung, Allan; Angus, Derek C.; Rosengart, Matthew R.

2016-01-01

Evidence suggests that light and circadian rhythms profoundly influence the physiologic capacity with which an organism responds to stress. However, the ramifications of light spectrum on the course of critical illness remain to be determined. Here, we show that acute exposure to bright blue spectrum light reduces organ injury by comparison with bright red spectrum or ambient white fluorescent light in two murine models of sterile insult: warm liver ischemia/reperfusion (I/R) and unilateral renal I/R. Exposure to bright blue light before I/R reduced hepatocellular injury and necrosis and reduced acute kidney injury and necrosis. In both models, blue light reduced neutrophil influx, as evidenced by reduced myeloperoxidase (MPO) within each organ, and reduced the release of high-mobility group box 1 (HMGB1), a neutrophil chemotactant and key mediator in the pathogenesis of I/R injury. The protective mechanism appeared to involve an optic pathway and was mediated, in part, by a sympathetic (β3 adrenergic) pathway that functioned independent of significant alterations in melatonin or corticosterone concentrations to regulate neutrophil recruitment. These data suggest that modifying the spectrum of light may offer therapeutic utility in sterile forms of cellular injury. PMID:27114521

Integration of the predictions of two models with dose measurements in a case study of children exposed to the emissions of a lead smelter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bonnard, R.; McKone, T.E.

2009-03-01

The predictions of two source-to-dose models are systematically evaluated with observed data collected in a village polluted by a currently operating secondary lead smelter. Both models were built up from several sub-models linked together and run using Monte-Carlo simulation, to calculate the distribution children's blood lead levels attributable to the emissions from the facility. The first model system is composed of the CalTOX model linked to a recoded version of the IEUBK model. This system provides the distribution of the media-specific lead concentrations (air, soil, fruit, vegetables and blood) in the whole area investigated. The second model consists of amore » statistical model to estimate the lead deposition on the ground, a modified version of the model HHRAP and the same recoded version of the IEUBK model. This system provides an estimate of the concentration of exposure of specific individuals living in the study area. The predictions of the first model system were improved in terms of accuracy and precision by performing a sensitivity analysis and using field data to correct the default value provided for the leaf wet density. However, in this case study, the first model system tends to overestimate the exposure due to exposed vegetables. The second model was tested for nine children with contrasting exposure conditions. It managed to capture the blood levels for eight of them. In the last case, the exposure of the child by pathways not considered in the model may explain the failure of the model. The interest of this integrated model is to provide outputs with lower variance than the first model system, but at the moment further tests are necessary to conclude about its accuracy.« less

Molecular Mechanisms of Stress-Responsive Changes in Collagen and Elastin Networks in Skin.

PubMed

Aziz, Jazli; Shezali, Hafiz; Radzi, Zamri; Yahya, Noor Azlin; Abu Kassim, Noor Hayaty; Czernuszka, Jan; Rahman, Mohammad Tariqur

2016-01-01

Collagen and elastin networks make up the majority of the extracellular matrix in many organs, such as the skin. The mechanisms which are involved in the maintenance of homeostatic equilibrium of these networks are numerous, involving the regulation of genetic expression, growth factor secretion, signalling pathways, secondary messaging systems, and ion channel activity. However, many factors are capable of disrupting these pathways, which leads to an imbalance of homeostatic equilibrium. Ultimately, this leads to changes in the physical nature of skin, both functionally and cosmetically. Although various factors have been identified, including carcinogenesis, ultraviolet exposure, and mechanical stretching of skin, it was discovered that many of them affect similar components of regulatory pathways, such as fibroblasts, lysyl oxidase, and fibronectin. Additionally, it was discovered that the various regulatory pathways intersect with each other at various stages instead of working independently of each other. This review paper proposes a model which elucidates how these molecular pathways intersect with one another, and how various internal and external factors can disrupt these pathways, ultimately leading to a disruption in collagen and elastin networks. © 2016 S. Karger AG, Basel.

Transcriptomic analysis in the developing zebrafish embryo after compound exposure: Individual gene expression and pathway regulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hermsen, Sanne A.B., E-mail: Sanne.Hermsen@rivm.nl; Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht; Institute for Risk Assessment Sciences

2013-10-01

The zebrafish embryotoxicity test is a promising alternative assay for developmental toxicity. Classically, morphological assessment of the embryos is applied to evaluate the effects of compound exposure. However, by applying differential gene expression analysis the sensitivity and predictability of the test may be increased. For defining gene expression signatures of developmental toxicity, we explored the possibility of using gene expression signatures of compound exposures based on commonly expressed individual genes as well as based on regulated gene pathways. Four developmental toxic compounds were tested in concentration-response design, caffeine, carbamazepine, retinoic acid and valproic acid, and two non-embryotoxic compounds, D-mannitol andmore » saccharin, were included. With transcriptomic analyses we were able to identify commonly expressed genes, which were mostly development related, after exposure to the embryotoxicants. We also identified gene pathways regulated by the embryotoxicants, suggestive of their modes of action. Furthermore, whereas pathways may be regulated by all compounds, individual gene expression within these pathways can differ for each compound. Overall, the present study suggests that the use of individual gene expression signatures as well as pathway regulation may be useful starting points for defining gene biomarkers for predicting embryotoxicity. - Highlights: • The zebrafish embryotoxicity test in combination with transcriptomics was used. • We explored two approaches of defining gene biomarkers for developmental toxicity. • Four compounds in concentration-response design were tested. • We identified commonly expressed individual genes as well as regulated gene pathways. • Both approaches seem suitable starting points for defining gene biomarkers.« less

Mustard vesicating agent-induced toxicity in the skin tissue and silibinin as a potential countermeasure.

PubMed

Tewari-Singh, Neera; Agarwal, Rajesh

2016-06-01

Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of their exposure, edema and erythema develop into blisters, ulceration, necrosis, desquamation, and pigmentation changes, which persist weeks and even years after exposure. Research advances have generated data that have started to explain the probable mechanism of action of vesicant-induced skin toxicity; however, despite these advances, effective and targeted therapies are still deficient. This review highlights studies on two SM analogs, 2-chloroethyl ethyl sulfide (CEES) and NM, and CEES- and NM-induced skin injury mouse models that have substantially added to the knowledge on the complex pathways involved in mustard vesicating agent-induced skin injury. Furthermore, employing these mouse models, studies under the National Institutes of Health Countermeasures Against Chemical Threats program have identified the flavanone silibinin as a novel therapeutic intervention with the potential to be developed as an effective countermeasure against skin injury following exposure to mustard vesicating agents. © 2016 New York Academy of Sciences.

Mustard vesicating agents–induced toxicity in the skin tissue and silibinin as a potential countermeasure

PubMed Central

Tewari-Singh, Neera; Agarwal, Rajesh

2016-01-01

Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of their exposure, edema and erythema develop into blisters, ulceration, necrosis, desquamation, and pigmentation changes, which persist weeks and even years after exposure. Research advances have generated data that have started to explain the probable mechanism of action of vesicant-induced skin toxicity; however, despite these advances, effective and targeted therapies are still deficient. This review highlights studies on two SM analogs, chloroethyl ethyl sulfide (CEES) and NM, and CEES- and NM-induced skin injury mouse models that have substantially added to the knowledge on the complex pathways involved in mustard vesicating agent–induced skin injury. Furthermore, employing these mouse models, studies under the National Institutes of Health Countermeasures Against Chemical Threats program have identified the flavanone silibinin as a novel therapeutic intervention with the potential to be developed as an effective countermeasure against skin injury following exposure to mustard vesicating agents. PMID:27326543

Migration of Beryllium via Multiple Exposure Pathways among Work Processes in Four Different Facilities

PubMed Central

Armstrong, Jenna L.; Day, Gregory A.; Park, Ji Young; Stefaniak, Aleksandr B.; Stanton, Marcia L.; Deubner, David C.; Kent, Michael S.; Schuler, Christine R.; Virji, M. Abbas

2016-01-01

Inhalation of beryllium is associated with the development of sensitization; however, dermal exposure may also be important. The primary aim of this study was to elucidate relationships among exposure pathways in four different manufacturing and finishing facilities. Secondary aims were to identify jobs with increased levels of beryllium in air, on skin, and on surfaces; identify potential discrepancies in exposure pathways, and determine if these are related to jobs with previously identified risk. Beryllium was measured in air, on cotton gloves, and on work surfaces. Summary statistics were calculated and correlations among all three measurement types were examined at the facility and job level. Exposure ranking strategies were used to identify jobs with higher exposures. The highest air, glove, and surface measurements were observed in beryllium metal production and beryllium oxide ceramics manufacturing jobs that involved hot processes and handling powders. Two finishing and distribution facilities that handle solid alloy products had lower exposures than the primary production facilities, and there were differences observed among jobs. For all facilities combined, strong correlations were found between air-surface (rp ≥ 0.77), glove-surface (rp ≥ 0.76), and air-glove measurements (rp ≥ 0.69). In jobs where higher risk of beryllium sensitization or disease has been reported, exposure levels for all three measurement types were higher than in jobs with lower risk, though they were not the highest. Some jobs with low air concentrations had higher levels of beryllium on glove and surface wipe samples, suggesting a need to further evaluate the causes of the discrepant levels. Although such correlations provide insight on where beryllium is located throughout the workplace, they cannot identify the direction of the pathways between air, surface, or skin. Ranking strategies helped to identify jobs with the highest combined air, glove, and/or surface exposures. All previously identified high-risk jobs had high air concentrations, dermal mass loading, or both, and none had low dermal and air. We have found that both pathways are relevant. PMID:25357184

Computational modeling of the amphibian thyroid axis ...

EPA Pesticide Factsheets

In vitro screening of chemicals for bioactivity together with computational modeling are beginning to replace animal toxicity testing in support of chemical risk assessment. To facilitate this transition, an amphibian thyroid axis model has been developed to describe thyroid homeostasis during Xenopus laevis pro-metamorphosis. The model simulates the dynamic relationships of normal thyroid biology throughout this critical period of amphibian development and includes molecular initiating events (MIEs) for thyroid axis disruption to allow in silico simulations of hormone levels following chemical perturbations. One MIE that has been formally described using the adverse outcome pathway (AOP) framework is thyroperoxidase (TPO) inhibition. The goal of this study was to refine the model parameters and validate model predictions by generating dose-response and time-course biochemical data following exposure to three TPO inhibitors, methimazole, 6-propylthiouracil and 2-mercaptobenzothiazole. Key model variables including gland and blood thyroid hormone (TH) levels were compared to empirical values measured in biological samples at 2, 4, 7 and 10 days following initiation of exposure at Nieuwkoop and Faber (NF) stage 54 (onset of pro-metamorphosis). The secondary objective of these studies was to relate depleted blood TH levels to delayed metamorphosis, the adverse apical outcome. Delayed metamorphosis was evaluated by continuing exposure with a subset of larvae until a

EPA EcoBox Tools by Exposure Pathways

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

A Systems Toxicology Approach Reveals Biological Pathways Dysregulated by Prenatal Arsenic Exposure

PubMed Central

Laine, Jessica E.; Fry, Rebecca C.

2016-01-01

BACKGROUND Prenatal exposure to inorganic arsenic (iAs) is associated with dysregulated gene and protein expression in the fetus, both evident at birth. Potential epigenetic mechanisms that underlie these changes include but are not limited to the methylation of cytosines (CpG). OBJECTIVE The aim of the present study was to compile datasets from studies on prenatal arsenic exposure to identify whether key genes, proteins, or both and their associated biological pathways are perturbed. METHODS We compiled datasets from 12 studies that analyzed the relationship between prenatal iAs exposure and fetal changes to the epigenome (5-methyl cytosine), transcriptome (mRNA expression), and/or proteome (protein expression changes). FINDINGS Across the 12 studies, a set of 845 unique genes was identified and found to enrich for their role in biological pathways, including those signaled by peroxisome proliferator-activated receptor, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, and the glucocorticoid receptor. Tumor necrosis factor was identified as a putative cellular regulator underlying most (n = 277) of the identified iAs-associated genes or proteins. CONCLUSIONS Given their common identification across numerous human cohorts and their known toxicologic role in disease, the identified genes and pathways may underlie altered disease susceptibility associated with prenatal exposure to iAs. PMID:27325076

Exposure to Community Violence and Sexual Behaviors Among African American Youth: Testing Multiple Pathways.

PubMed

Voisin, Dexter R; Hotton, Anna; Neilands, Torsten

2018-01-01

African American youth bear a disproportionate burden of sexually transmitted infections. A growing number of studies document that youth exposure to community violence and sexual behaviors are highly correlated. Despite such growing evidence, only a few studies have empirically tested conceptually driven pathways that may account for such relationships. This study seeks to address that gap by exploring multiple pathways linking exposure to community violence and youth sexual behaviors. Using an existing sample of 563 African American youth attending high school, we examined whether possible links between exposure to community violence and sexual activity, sexual risk behaviors were mediated by aggression, low student-teacher connectedness, and negative peer norms. Major findings indicated indirect relationships between exposures to community violence and both sexual activity and risky sex, mediated by aggression and negative peer norms with no significant differences based on gender or socioeconomic status. Overall findings also indicated a significant indirect effect of aggression to risky sex via negative peer norms and from community violence to risky peer norms via aggression. By illuminating ways that community violence, aggression, peer norms, and sexual behaviors are dynamically interrelated, these findings have significant implications for future research and intervention initiatives aimed at addressing the different pathways.

Human exposure to per- and polyfluoroalkyl substances (PFASs) via house dust in Korea: Implication to exposure pathway.

PubMed

Tian, Zhexi; Kim, Seung-Kyu; Shoeib, Mahiba; Oh, Jeong-Eun; Park, Jong-Eun

2016-05-15

A wide range of per- and polyfluoroalkyl substances (PFASs), including fluorotelomer alcohols (FTOHs), perfluorooctane sulfonamidoethanols (FOSEs), perfluoroalkyl carboxylic acids (PFCAs), and perfluoroalkane sulfonic acids (PFSAs), were measured in fifteen house dust and two nonresidential indoor dust of Korea. Total concentrations of PFASs in house dust ranged from 29.9 to 97.6 ng g(-1), with a dominance of perfluorooctane sulfonic acid (PFOS), followed by 8:2 FTOH, N-Ethyl perfluorooctane sulfonamidoethanol (EtFOSE), perfluoroctanoic acid (PFOA). In a typical exposure scenario, the estimated daily intakes (EDIs) of total PFASs via house dust ingestion were 2.83 ng d(-1) for toddlers and 1.13 ng d(-1) for adults, which were within the range of the mean EDIs reported from several countries. For PFOA and PFOS exposure via house dust ingestion, indirect exposure (via precursors) was a minor contributor, accounting for 5% and 12%, respectively. An aggregated exposure (hereafter, overall-EDIs) of PFOA and PFOS occurring via all pathways, estimated using data compiled from the literature, were 53.6 and 14.8 ng d(-1) for toddlers, and 20.5 and 40.6 ng d(-1) for adults, respectively, in a typical scenario. These overall-EDIs corresponded to 82% (PFOA) and 92% (PFOS) of a pharmacokinetic model-based EDIs estimated from adults' serum data. Direct dietary exposure was a major contributor (>89% of overall-EDI) to PFOS in both toddlers and adults, and PFOA in toddlers. As for PFOA exposure of adults, however direct exposure via tap water drinking (37%) and indirect exposure via inhalation (22%) were as important as direct dietary exposure (41%). House dust-ingested exposure (direct+indirect) was responsible for 5% (PFOS in toddlers) and <1% (PFOS in adults, and PFOA in both toddlers and adults) of the overall-EDIs. In conclusion, house-dust ingestion was a minor contributor in this study, but should not be ignored for toddlers' PFOS exposure due to its significance in the worst-case scenario. Copyright © 2016 Elsevier B.V. All rights reserved.

The regulation of cellular apoptosis by the ROS-triggered PERK/EIF2α/chop pathway plays a vital role in bisphenol A-induced male reproductive toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yin, Li

Bisphenol A (2,2-bis(4-hydroxyphenyl)propane, BPA) is ubiquitous in the environment, wildlife, and humans. Evidence from past studies suggests that BPA is associated with decreased semen quality. However, the molecular basis for the adverse effect of BPA on male reproductive toxicity remains unclear. We evaluated the effect of BPA on mouse spermatocytes GC-2 cells and adult mice, and we explored the potential mechanism of its action. The results showed that BPA inhibited cell proliferation and increased the apoptosis rate. The testes from BPA-treated mice showed fewer spermatogenic cells and sperm in the seminiferous tubules. In addition, BPA caused reactive oxygen species (ROS)more » accumulation. Previous study has verified that mitochondrion was the organelle affected by the BPA-triggered ROS accumulation. We found that BPA induced damage to the endoplasmic reticulum (ER) in addition to mitochondria, and most ER stress-related proteins were activated in cellular and animal models. Knocking down of the PERK/EIF2α/chop pathway, one of the ER stress pathways, partially recovered the BPA-induced cell apoptosis. In addition, an ROS scavenger attenuated the expression of the PERK/EIF2α/chop pathway-related proteins. Taken together, these data suggested that the ROS regulated PERK/EIF2α/chop pathway played a vital role in BPA-induced male reproductive toxicity. - Highlights: • BPA exposure caused the damage of the endoplasmic reticulum. • BPA exposure activated ER stress related proteins in male reproductive system. • ROS regulated PERK/EIF2α/chop pathway played a vital role in BPA-induced toxicity.« less

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

PubMed Central

Klapacz, Joanna; Pottenger, Lynn H.; Engelward, Bevin P.; Heinen, Christopher D.; Johnson, George E.; Clewell, Rebecca A.; Carmichael, Paul L.; Adeleye, Yeyejide; Andersen, Melvin E.

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. PMID:27036068

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.

PubMed

Klapacz, Joanna; Pottenger, Lynn H; Engelward, Bevin P; Heinen, Christopher D; Johnson, George E; Clewell, Rebecca A; Carmichael, Paul L; Adeleye, Yeyejide; Andersen, Melvin E

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. Copyright © 2015 Elsevier B.V. All rights reserved.

Transcriptomic Responses During Early Development Following Arsenic Exposure in Western Clawed Frogs, Silurana tropicalis.

PubMed

Zhang, Jing; Koch, Iris; Gibson, Laura A; Loughery, Jennifer R; Martyniuk, Christopher J; Button, Mark; Caumette, Guilhem; Reimer, Kenneth J; Cullen, William R; Langlois, Valerie S

2015-12-01

Arsenic compounds are widespread environmental contaminants and exposure elicits serious health issues, including early developmental anomalies. Depending on the oxidation state, the intermediates of arsenic metabolism interfere with a range of subcellular events, but the fundamental molecular events that lead to speciation-dependent arsenic toxicity are not fully elucidated. This study therefore assesses the impact of arsenic exposure on early development by measuring speciation and gene expression profiles in the developing Western clawed frog (Silurana tropicalis) larvae following the environmental relevant 0.5 and 1 ppm arsenate exposure. Using HPLC-ICP-MS, arsenate, dimethylarsenic acid, arsenobetaine, arsenocholine, and tetramethylarsonium ion were detected. Microarray and pathway analyses were utilized to characterize the comprehensive transcriptomic responses to arsenic exposure. Clustering analysis of expression data showed distinct gene expression patterns in arsenate treated groups when compared with the control. Pathway enrichment revealed common biological themes enriched in both treatments, including cell signal transduction, cell survival, and developmental pathways. Moreover, the 0.5 ppm exposure led to the enrichment of pathways and biological processes involved in arsenic intake or efflux, as well as histone remodeling. These compensatory responses are hypothesized to be responsible for maintaining an in-body arsenic level comparable to control animals. With no appreciable changes observed in malformation and mortality between control and exposed larvae, this is the first study to suggest that the underlying transcriptomic regulations related to signal transduction, cell survival, developmental pathways, and histone remodeling may contribute to maintaining ongoing development while coping with the potential arsenic toxicity in S. tropicalis during early development. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Acute respiratory changes and pulmonary inflammation involving a pathway of TGF-β1 induction in a rat model of chlorine-induced lung injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wigenstam, Elisabeth; Elfsmark, Linda; Koch, Bo

We investigated acute and delayed respiratory changes after inhalation exposure to chlorine (Cl{sub 2}) with the aim to understand the pathogenesis of the long-term sequelae of Cl{sub 2}-induced lung-injury. In a rat model of nose-only exposure we analyzed changes in airway hyperresponsiveness (AHR), inflammatory responses in airways, expression of pro-inflammatory markers and development of lung fibrosis during a time-course from 5 h up to 90 days after a single inhalation of Cl{sub 2}. A single dose of dexamethasone (10 mg/kg) was administered 1 h following Cl{sub 2}-exposure. A 15-min inhalation of 200 ppm Cl{sub 2} was non-lethal in Sprague-Dawley rats.more » At 24 h post exposure, Cl{sub 2}-exposed rats displayed elevated numbers of leukocytes with an increase of neutrophils and eosinophils in bronchoalveolar lavage (BAL) and edema was shown both in lung tissue and the heart. At 24 h, the inflammasome-associated cytokines IL-1β and IL-18 were detected in BAL. Concomitant with the acute inflammation a significant AHR was detected. At the later time-points, a delayed inflammatory response was observed together with signs of lung fibrosis as indicated by increased pulmonary macrophages, elevated TGF-β expression in BAL and collagen deposition around airways. Dexamethasone reduced the numbers of neutrophils in BAL at 24 h but did not influence the AHR. Inhalation of Cl{sub 2} in rats leads to acute respiratory and cardiac changes as well as pulmonary inflammation involving induction of TGF-β1. The acute inflammatory response was followed by sustained macrophage response and lack of tissue repair. It was also found that pathways apart from the acute inflammatory response contribute to the Cl{sub 2}-induced respiratory dysfunction. - Highlights: • Inhalation of Cl{sub 2} leads to acute lung inflammation and airway hyperreactivity. • Cl{sub 2} activates an inflammasome pathway of TGF-β induction. • Cl{sub 2} leads to a fibrotic respiratory disease. • Treatment with corticosteroids alone is insufficient to counteract acute lung injury.« less

Exposure to Concentrated Ambient PM2.5 Shortens Lifespan and Induces Inflammation-Associated Signaling and Oxidative Stress in Drosophila.

PubMed

Wang, Xiaoke; Chen, Minjie; Zhong, Mianhua; Hu, Ziying; Qiu, Lianglin; Rajagopalan, Sanjay; Fossett, Nancy G; Chen, Lung-Chi; Ying, Zhekang

2017-03-01

Exposure to ambient PM 2.5 is associated with human premature mortality. However, it has not yet been toxicologically replicated, likely due to the lack of suitable animal models. Drosophila is frequently used in longevity research due to many incomparable merits. The present study aims to validate Drosophila models for PM 2.5 toxicity study through characterizing their biological responses to exposure to concentrated ambient PM 2.5 (CAP). The survivorship curve demonstrated that exposure to CAP markedly reduced lifespan of Drosophila. This antilongevity effect of CAP exposure was observed in both male and female Drosophila, and by comparison, the male was more sensitive [50% survivals: 20 and 48 days, CAP- and filtered air (FA)-exposed males, respectively; 21 and 40 days, CAP- and FA-exposed females, respectively]. Similar to its putative pathogenesis in humans, CAP exposure-induced premature mortality in Drosophila was also coincided with activation of pro-inflammatory signaling pathways including Jak, Jnk, and Nf-κb and increased systemic oxidative stress. Furthermore, like in humans and mammals, exposure to CAP significantly increased whole-body and circulating glucose levels and increased mRNA expression of Ilp2 and Ilp5 , indicating that CAP exposure induces dysregulated insulin signaling in Drosophila. Similar to effects on humans exposure to CAP leads to premature mortality likely through induction of inflammation-associated signaling, oxidative stress, and metabolic abnormality in Drosophila, strongly supporting that it can be a useful model organism for PM 2.5 toxicity study. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Prioritization of pesticides based on daily dietary exposure potential as determined from the SHEDS model.

PubMed

Melnyk, Lisa Jo; Wang, Zhaohui; Li, Zhilin; Xue, Jianping

2016-10-01

A major pathway for exposure to many pesticides is through diet. The objectives were to rank pesticides by comparing their calculated daily dietary exposure as determined by EPA's Stochastic Human Exposure and Dose Simulation (SHEDS) to single pesticides for different age groups to acceptable daily intakes (ADI), characterize pesticide trends in exposures over different time periods, and determine commodities contributing to pesticide exposures. SHEDS was applied, using Pesticide Data Program (PDP) (1991-2011) and pesticide usage data on crops from USDA combined with NHANES dietary consumption data, to generate exposure estimates by age group. ADI data collected from EPA, WHO, and other sources were used to rank pesticides based on relativeness of the dietary exposure potential to ADI by age groups. Sensitivity analysis provided trends in pesticide exposures. Within SHEDS, commodities contributing the majority of pesticides with greatest exposure potential were determined. The results indicated that the highest ranking pesticides were methamidophos and diazinon which exceeded 100% of the ADI. Sensitivity analysis indicated that exposure to methamidophos, diazinon, malathion, ethion and formetanate hydrochloride had a marked decrease from 1991-1999 to 2000-2011. Contributions analysis indicated that apples, mushroom, carrots, and lettuce contributed to diazinon exposure. Beans and pepper contributed to methamidophos exposure. Published by Elsevier Ltd.

Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin on vasoconstriction.

PubMed

Yin, Anyue; Yamada, Akihiro; Stam, Wiro B; van Hasselt, Johan G C; van der Graaf, Piet H

2018-06-02

Development of combination therapies has received significant interest in recent years. Previously a two-receptor one-transducer (2R-1T) model was proposed to characterize drug interactions with two receptors that lead to the same phenotypic response through a common transducer pathway. We applied, for the first time, the 2R-1T model to characterize the interaction of noradrenaline and arginine-vasopressin on vasoconstriction, and performed inter-species scaling to humans using this mechanism-based model. Contractile data was obtained from in vitro rat small mesenteric arteries after exposure to single or combined challenges of noradrenaline and arginine-vasopressin with or without pre-treatment with the irreversible α-adrenoceptor antagonist, phenoxybenzamine. Data was analysed using the 2R-1T model to characterize the observed exposure-response relationships and drug-drug interaction. The model was then scaled to humans by accounting for differences in receptor density. With receptor affinities set to literature values, the 2R-1T model satisfactorily characterized the interaction between noradrenaline and arginine-vasopressin in rat small mesenteric arteries (relative standard error ≤ 20%), as well as the effect of phenoxybenzamine. Furthermore, after scaling the model to human vascular tissue, the model also adequately predicted the interaction between both agents on human renal arteries. The 2R-1T model can be of relevance to quantitatively characterize the interaction between two drugs that interact via different receptors and a common transducer pathway. Its mechanistic properties are valuable for scaling the model across species. This approach is therefore of significant value to rationally optimize novel combination treatments. This article is protected by copyright. All rights reserved.

Assessment of Fecal Exposure Pathways in Low-Income Urban Neighborhoods in Accra, Ghana: Rationale, Design, Methods, and Key Findings of the SaniPath Study

PubMed Central

Robb, Katharine; Null, Clair; Teunis, Peter; Yakubu, Habib; Armah, George; Moe, Christine L.

2017-01-01

Abstract. Rapid urbanization has contributed to an urban sanitation crisis in low-income countries. Residents in low-income, urban neighborhoods often have poor sanitation infrastructure and services and may experience frequent exposure to fecal contamination through a range of pathways. There are little data to prioritize strategies to decrease exposure to fecal contamination in these complex and highly contaminated environments, and public health priorities are rarely considered when planning urban sanitation investments. The SaniPath Study addresses this need by characterizing pathways of exposure to fecal contamination. Over a 16 month period, an in-depth, interdisciplinary exposure assessment was conducted in both public and private domains of four neighborhoods in Accra, Ghana. Microbiological analyses of environmental samples and behavioral data collection techniques were used to quantify fecal contamination in the environment and characterize the behaviors of adults and children associated with exposure to fecal contamination. Environmental samples (n = 1,855) were collected and analyzed for fecal indicators and enteric pathogens. A household survey with 800 respondents and over 500 hours of structured observation of young children were conducted. Approximately 25% of environmental samples were collected in conjunction with structured observations (n = 441 samples). The results of the study highlight widespread and often high levels of fecal contamination in both public and private domains and the food supply. The dominant fecal exposure pathway for young children in the household was through consumption of uncooked produce. The SaniPath Study provides critical information on exposure to fecal contamination in low-income, urban environments and ultimately can inform investments and policies to reduce these public health risks. PMID:28722599

Using exposure prediction tools to link exposure and ...

EPA Pesticide Factsheets

A few different exposure prediction tools were evaluated for use in the new in vitro-based safety assessment paradigm using di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. Daily intake of each phthalate was estimated using both high-throughput (HT) prediction models such as the HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors. Reverse dosimetry was performed using a published physiologically based pharmacokinetic (PBPK) model for phthalates and their metabolites to provide a comparison point. Daily intakes of DEHP and DnBP were estimated based on the urinary concentrations of their respective monoesters, mono-2-ethylhexyl phthalate (MEHP) and monobutyl phthalate (MnBP), reported in NHANES (2011–2012). The PBPK-reverse dosimetry estimated daily intakes at the 50th and 95th percentiles were 0.68 and 9.58 μg/kg/d and 0.089 and 0.68 μg/kg/d for DEHP and DnBP, respectively. For DEHP, the estimated median from PBPK-reverse dosimetry was about 3.6-fold higher than the ExpoCast estimate (0.68 and 0.18 μg/kg/d, respectively). For DnBP, the estimated median was similar to that predicted by ExpoCast (0.089 and 0.094 μg/kg/d, respectively). The SHEDS-HT prediction of DnBP intake from consumer product pathways alone was higher at 0.67 μg/kg/d. The PBPK-reve

Subacute developmental exposure of zebrafish to the organophosphate pesticide metabolite, chlorpyrifos-oxon, results in defects in Rohon-Beard sensory neuron development

PubMed Central

Jacobson, Saskia M.; Birkholz, Denise A.; McNamara, Marcy L.; Bharate, Sandip B.; George, Kathleen M.

2010-01-01

Organophosphate pesticides (OPs) are environmental toxicants known to inhibit the catalytic activity of acetylcholinesterase (AChE) resulting in hypercholinergic toxicity symptoms. In developing embryos, OPs have been hypothesized to affect both cholinergic and non-cholinergic pathways. In order to understand the neurological pathways affected by OP exposure during embryogenesis, we developed a subacute model of OP developmental exposure in zebrafish by exposing embryos to a dose of the OP metabolite chlorpyrifos oxon (CPO) that is non-lethal and significantly inhibited AChE enzymatic activity compared to control embryos (43% at 1 day post-fertilization (dpf) and 11% at 2 dpf). Phenotypic analysis of CPO-exposed embryos demonstrated that embryonic growth, as analyzed by gross morphology, was normal in 85% of treated embryos. Muscle fiber formation was similar to control embryos as analyzed by birefringence, and nicotinic acetylcholine receptor (nAChR) cluster formation was quantitatively similar to control embryos as analyzed by α-bungarotoxin staining. These results indicate that partial AChE activity during the early days of zebrafish development is sufficient for general development, muscle fiber, and nAChR development. Rohon-Beard (RB) sensory neurons exhibited aberrant peripheral axon extension and gene expression profiling suggests that several genes responsible for RB neurogenesis are down-regulated. Stability of CPO in egg water at 28.5 °C was determined by HPLC-UV-MS analysis which revealed that the CPO concentration used in our studies hydrolyzes in egg water with a half-life of one day. The result that developmental CPO exposure affected RB neurogenesis without affecting muscle fiber or nAChR cluster formation demonstrates that zebrafish are a strong model system for characterizing subtle neurological pathologies resulting from environmental toxicants. PMID:20701988

Pathways to adolescent sexual risk behaviors: Effects of prenatal cocaine exposure.

PubMed

Min, Meeyoung O; Minnes, Sonia; Lang, Adelaide; Albert, Jeffrey M; Kim, June-Yung; Singer, Lynn T

2016-04-01

To assess the impact of prenatal cocaine exposure (PCE) on adolescent sexual risk behaviors. Externalizing behavior, teen substance use, and early sexual intercourse were examined as pathways mediating the effects of PCE on sexual risk behaviors. Adolescents (N=364; 185 PCE, 179 non-cocaine exposure (NCE); 205 girls, 159 boys), primarily African-American and of low socioeconomic status, were prospectively enrolled in a longitudinal study at birth. Risky sexual behaviors were assessed at ages 15 and 17. Externalizing behavior at 12 years was assessed with the Youth Self-Report. Substance use, via self-report and biologic assays, and early (before age 15) sexual intercourse were assessed at age 15. Path analyses with the weighted least squares estimator with mean and variance adjustments were performed. The final structural equation model-based path model, χ(2)=31.97 (df=27), p=.23, CFI=.99, TLI=.99, RMSEA=.021, WRMR=.695, indicated a direct effect of PCE on sexual risk behavior (β=.16, p=.02). Although PCE was related to greater externalizing behavior (β=.14, p=.009), which in turn, predicted early sexual intercourse (β=.16, p=.03), leading to sexual risk behavior (β=.44, p<.001), bootstrapping indicated a non-significant indirect effect (β=.01, p>.10). Substance use was correlated with early sexual intercourse (r=.60, p<.001) and predicted sexual risk behavior by age 17 (β=.31, p=.01). Prenatal cocaine exposure was related to more engagement in sexual risk behaviors, suggesting the importance of reducing substance use among pregnant women as a means of prevention of offspring substance use and sexual risk behavior. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Genomic Instability and Radiation Risk in Molecular Pathways to Colon Cancer

PubMed Central

Kaiser, Jan Christian; Meckbach, Reinhard; Jacob, Peter

2014-01-01

Colon cancer is caused by multiple genomic alterations which lead to genomic instability (GI). GI appears in molecular pathways of microsatellite instability (MSI) and chromosomal instability (CIN) with clinically observed case shares of about 15–20% and 80–85%. Radiation enhances the colon cancer risk by inducing GI, but little is known about different outcomes for MSI and CIN. Computer-based modelling can facilitate the understanding of the phenomena named above. Comprehensive biological models, which combine the two main molecular pathways to colon cancer, are fitted to incidence data of Japanese a-bomb survivors. The preferred model is selected according to statistical criteria and biological plausibility. Imprints of cell-based processes in the succession from adenoma to carcinoma are identified by the model from age dependences and secular trends of the incidence data. Model parameters show remarkable compliance with mutation rates and growth rates for adenoma, which has been reported over the last fifteen years. Model results suggest that CIN begins during fission of intestinal crypts. Chromosomal aberrations are generated at a markedly elevated rate which favors the accelerated growth of premalignant adenoma. Possibly driven by a trend of Westernization in the Japanese diet, incidence rates for the CIN pathway increased notably in subsequent birth cohorts, whereas rates pertaining to MSI remained constant. An imbalance between number of CIN and MSI cases began to emerge in the 1980s, whereas in previous decades the number of cases was almost equal. The CIN pathway exhibits a strong radio-sensitivity, probably more intensive in men. Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk. Observance of pathway-specific risks improves the determination of the probability of causation for radiation-induced colon cancer in individual patients, if their exposure histories are known. PMID:25356998

Global Metabolomic Profiling Reveals an Association of Metal Fume Exposure and Plasma Unsaturated Fatty Acids

PubMed Central

Chang, Chiung-yu; Fan, Tianteng; Su, Li; Chen, Feng; Christiani, David C.

2013-01-01

Background Welding-associated air pollutants negatively affect the health of exposed workers; however, their molecular mechanisms in causing disease remain largely unclear. Few studies have systematically investigated the systemic toxic effects of welding fumes on humans. Objectives To explore the effects of welding fumes on the plasma metabolome, and to identify biomarkers for risk assessment of welding fume exposure. Methods The two-stage, self-controlled exploratory study included 11 boilermakers from a 2011 discovery panel and 8 boilermakers from a 2012 validation panel. Plasma samples were collected pre- and post-welding fume exposure and analyzed by chromatography/mass spectrometry. Results Eicosapentaenoic or docosapentaenoic acid metabolic changes post-welding were significantly associated with particulate (PM2.5) exposure (p<0.05). The combined analysis by linear mixed-effects model showed that exposure was associated with a statistically significant decline in metabolite change of eicosapentaenoic acid [(95% CI) = −0.013(−0.022∼−0.004); p = 0.005], docosapentaenoic acid n3 [(95% CI) = −0.010(−0.018∼−0.002); p = 0.017], and docosapentaenoic acid n6 [(95% CI) = −0.007(−0.013∼−0.001); p = 0.021]. Pathway analysis identified an association of the unsaturated fatty acid pathway with exposure (p Study−2011 = 0.025; p Study−2012 = 0.021; p Combined = 0.009). The functional network built by these fatty acids and their interactive genes contained significant enrichment of genes associated with various diseases, including neoplasms, cardiovascular diseases, and lipid metabolism disorders. Conclusions High-dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. This alteration in fatty acids is a potential biological mediator and biomarker for exposure-related health disorders. PMID:24143234

Transplacental exposure to environmental carcinogens: Association with childhood cancer risks and the role of modulating factors.

PubMed

Fucic, A; Guszak, V; Mantovani, A

2017-09-01

Biological responses to carcinogens from environmental exposure during adulthood are modulated over years or decades. Conversely, during transplacental exposure, the effects on the human foetus change within weeks, intertwining with developmental mechanisms: even short periods of transplacental exposure may be imprinted in the organism for a lifetime. The pathways leading to childhood and juvenile cancers, such as leukaemias, neuroblastoma/brain tumours, hepatoblastoma, and Willm's tumour involve prenatally-induced genomic, epigenomic and/or non-genomic effects caused by xenobiotics. Pregnant women most often live in complex environmental settings that cause transplacental exposure of the foetus to xenobiotic mixtures. Mother-child biomonitoring should integrate the analysis of chemicals/radiation present in the living and workplace environment with relevant risk modulators related to life style. The interdisciplinary approach for transplacental cancer risk assessment in high-pressure areas should be based on an integrated model for mother-child exposure estimation via profiling the exposure level by water quality analysis, usage of emission grids, and land use maps. Copyright © 2017. Published by Elsevier Inc.

Transcriptome sequencing reveals e-cigarette vapor and mainstream-smoke from tobacco cigarettes activate different gene expression profiles in human bronchial epithelial cells

PubMed Central

Shen, Yifei; Wolkowicz, Michael J.; Kotova, Tatyana; Fan, Lonjiang; Timko, Michael P.

2016-01-01

Electronic cigarettes (e-cigarettes) generate an aerosol vapor (e-vapor) thought to represent a less risky alternative to main stream smoke (MSS) of conventional tobacco cigarettes. RNA-seq analysis was used to examine the transcriptomes of differentiated human bronchial epithelial (HBE) cells exposed to air, MSS from 1R5F tobacco reference cigarettes, and e-vapor with and without added nicotine in an in vitro air-liquid interface model for cellular exposure. Our results indicate that while e-vapor does not elicit many of the cell toxicity responses observed in MSS-exposed HBE cells, e-vapor exposure is not benign, but elicits discrete transcriptomic signatures with and without added nicotine. Among the cellular pathways with the most significantly enriched gene expression following e-vapor exposure are the phospholipid and fatty acid triacylglycerol metabolism pathways. Our data suggest that alterations in cellular glycerophopholipid biosynthesis are an important consequences of e-vapor exposure. Moreover, the presence of nicotine in e-vapor elicits a cellular response distinct from e-vapor alone including alterations of cytochrome P450 function, retinoid metabolism, and nicotine catabolism. These studies establish a baseline for future analysis of e-vapor and e-vapor additives that will better inform the FDA and other governmental bodies in discussions of the risks and future regulation of these products. PMID:27041137

Environmental Exposure to Cadmium: Health Risk Assessment and its Associations with Hypertension and Impaired Kidney Function

NASA Astrophysics Data System (ADS)

Wu, Haiyun; Liao, Qilin; Chillrud, Steven N.; Yang, Qiang; Huang, Lei; Bi, Jun; Yan, Beizhan

2016-07-01

Cadmium (Cd) is a toxic metal. This study was aimed to estimate the potential health risks in a Cd-polluted district in China, and examine the relationship between urinary cadmium(UCd) and hypertension and impaired kidney function at low exposure levels (UCd: GM 1.3 μg/g creatinine). Blood pressure measurement, questionnaires, and collection of urinary samples were conducted from 217 residents. Environmental samples, food, and cigarette samples were collected and detected to estimate the risks posed by Cd and the contribution of inhalation, ingestion, and dermal contact pathways to these risks. A logistic regression model was used in examining associations between exposure and hypertension and impaired kidney function. Results show that this population is at high risk. For non-smokers, incremental lifetime cancer risk (ILCR) and hazard quotient (HQ) are 1.74E-04 and 2.96, and for smokers, they are 1.07E-03 and 52.5, respectively. Among all exposure pathways, smoking and foods cause the major increases in ILCR and HQ. UCd is significantly associated with hypertension (odds ratio (OR) = 1.468 95% confidence interval (CI): 1.104, 1.953; P = 0.008) and impaired kidney function (OR = 1.902, 95% CI: 1.054, 3.432; P = 0.033). The results demonstrate that Cd can potentially lead to adverse health effects.

Application of the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks to advance cumulative risk assessment by integrating human health and ecological endpoints

EPA Science Inventory

Evaluating risk of adverse outcomes from chemical exposure is essential for understanding the impacts of environmental contaminants. While human health outcomes are of primary concern and are often the focus of risk assessments, important non-human species are also exposed to co...

An application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) frameworks to mechanistically integrate data sources across multiple species into cumulative risk assessment (CRA)

EPA Science Inventory

Toxicologists use dose-response data from both in vivo and in vitro experiments to evaluate the effects of chemical contaminants on organisms. Cumulative risk assessments (CRAs) consider the effects of multiple stressors on multiple endpoints, and utilize environmental exposure ...

Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver

EPA Science Inventory

Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver D.B. Johnson, 1 W.O. Ward, 2 V.L. Bass, 2 M.C.J. Schladweiler, 2A.D. Ledbetter, 2 D. Andrews, and U.P. Kodavanti 2 1 Curriculum in Toxicology, UNC School of Medicine, Cha...

A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways, OpenTox USA 2015 Poster

EPA Science Inventory

Adverse outcome pathways (AOP) link known population outcomes to a molecular initiating event (MIE) that can be quantified using high-throughput in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires consideration of exposure and absorption,...

Using exposure prediction tools to link exposure and dosimetry for risk-based decisions: A case study with phthalates.

PubMed

Moreau, Marjory; Leonard, Jeremy; Phillips, Katherine A; Campbell, Jerry; Pendse, Salil N; Nicolas, Chantel; Phillips, Martin; Yoon, Miyoung; Tan, Yu-Mei; Smith, Sherrie; Pudukodu, Harish; Isaacs, Kristin; Clewell, Harvey

2017-10-01

A few different exposure prediction tools were evaluated for use in the new in vitro-based safety assessment paradigm using di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. Daily intake of each phthalate was estimated using both high-throughput (HT) prediction models such as the HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors. Reverse dosimetry was performed using a published physiologically based pharmacokinetic (PBPK) model for phthalates and their metabolites to provide a comparison point. Daily intakes of DEHP and DnBP were estimated based on the urinary concentrations of their respective monoesters, mono-2-ethylhexyl phthalate (MEHP) and monobutyl phthalate (MnBP), reported in NHANES (2011-2012). The PBPK-reverse dosimetry estimated daily intakes at the 50th and 95th percentiles were 0.68 and 9.58 μg/kg/d and 0.089 and 0.68 μg/kg/d for DEHP and DnBP, respectively. For DEHP, the estimated median from PBPK-reverse dosimetry was about 3.6-fold higher than the ExpoCast estimate (0.68 and 0.18 μg/kg/d, respectively). For DnBP, the estimated median was similar to that predicted by ExpoCast (0.089 and 0.094 μg/kg/d, respectively). The SHEDS-HT prediction of DnBP intake from consumer product pathways alone was higher at 0.67 μg/kg/d. The PBPK-reverse dosimetry-estimated median intake of DEHP and DnBP was comparable to values previously reported for US populations. These comparisons provide insights into establishing criteria for selecting appropriate exposure prediction tools for use in an integrated modeling platform to link exposure to health effects. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Developmental Programming, a Pathway to Disease

PubMed Central

Cardoso, Rodolfo C.; Puttabyatappa, Muraly

2016-01-01

Accumulating evidence suggests that insults occurring during the perinatal period alter the developmental trajectory of the fetus/offspring leading to long-term detrimental outcomes that often culminate in adult pathologies. These perinatal insults include maternal/fetal disease states, nutritional deficits/excess, stress, lifestyle choices, exposure to environmental chemicals, and medical interventions. In addition to reviewing the various insults that contribute to developmental programming and the benefits of animal models in addressing underlying mechanisms, this review focuses on the commonalities in disease outcomes stemming from various insults, the convergence of mechanistic pathways via which various insults can lead to common outcomes, and identifies the knowledge gaps in the field and future directions. PMID:26859334

Early Life Stress, Air Pollution, Inflammation, and Disease: An Integrative Review and Immunologic Model of Social-Environmental Adversity and Lifespan Health.

PubMed

Olvera Alvarez, Hector A; Kubzansky, Laura D; Campen, Matthew J; Slavich, George M

2018-06-03

Socially disadvantaged individuals are at greater risk for simultaneously being exposed to adverse social and environmental conditions. Although the mechanisms underlying joint effects remain unclear, one hypothesis is that toxic social and environmental exposures have synergistic effects on inflammatory processes that underlie the development of chronic diseases, including cardiovascular disease, diabetes, depression, and certain types of cancer. In the present review, we examine how exposure to two risk factors that commonly occur with social disadvantage-early life stress and air pollution-affect health. Specifically, we identify neuroimmunologic pathways that could link early life stress, inflammation, air pollution, and poor health, and use this information to propose an integrated, multi-level model that describes how these factors may interact and cause health disparity across individuals based on social disadvantage. This model highlights the importance of interdisciplinary research considering multiple exposures across domains and the potential for synergistic, cross-domain effects on health, and may help identify factors that could potentially be targeted to reduce disease risk and improve lifespan health. Copyright © 2018. Published by Elsevier Ltd.

Predictable "individual differences" in uptake and excretion of gases and lipid soluble vapours simulation study.

PubMed Central

Fiserova-Bergerova, V; Vlach, J; Cassady, J C

1980-01-01

A five-compartment pharmacokinetic model with two excretory pathways, exhalation and metabolism, based on first order kinetics is used to outline the effect of body build, pulmonary ventilation, and lipid content in blood on uptake, distribution, and clearance of low solubility gases and lipid soluble vapours during and after exposure. The model shows the extent that individual differences have on altering uptake and distribution, with consequent changes in blood concentration, rate of excretion, and toxicity, even when variations in these parameters are within physiological ranges. The model is also used to describe the concentration variation of inhaled substances in tissues of subjects exposed to concentrations with permitted excursions. During the same course of exposure, the tissue concentrations of low solubility gases fluctuate much more than tissue concentrations of lipid soluble vapours. The fluctuation is reduced by metabolism of inhaled substance. These conclusions are recommended for consideration whenever evaluating the effect of excursions above the threshold limit values used in the control of industrial exposures (by excursion factors). PMID:7370192

LOW COST, LOW BURDEN, EXPOSURE MONITORING STRATEGIES

EPA Science Inventory

A birth cohort study designed to evaluate the association between exposures to environmental agents and health outcomes presents many challenges for exposure monitoring. Exposure of the child must be measured for multiple chemicals through multiply pathways over an extended peri...

EPA EcoBox Tools by Exposure Pathways - Soil

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

EPA EcoBox Tools by Exposure Pathways - Food Chains

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

EPA EcoBox Tools by Exposure Pathways - References

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

EPA EcoBox Tools by Exposure Pathways - Air

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

ADVANCES IN DIETARY EXPOSURE RESEARCH AT THE UNITED STATES

EPA Science Inventory

The United States Environmental Protection Agency-National Exposure Research Laboratory's (USEPA-NERL)dietary exposure research program investigates the role of diet, including drinking water, as a potential pathway of human exposure to environmental contaminants. A primary progr...

Gene expression profiles following exposure to a developmental neurotoxicant, Aroclor 1254: Pathway analysis for possible mode(s) of action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Royland, Joyce E.; Kodavanti, Prasada Rao S.

2008-09-01

Epidemiological studies indicate that low levels of polychlorinated biphenyl (PCB) exposure can adversely affect neurocognitive development. In animal models, perturbations in calcium signaling, neurotransmitters, and thyroid hormones have been postulated as potential mechanisms for PCB-induced developmental neurotoxicity. In order to understand the role of these proposed mechanisms and to identify other mechanisms in PCB-induced neurotoxicity, we have chosen a global approach utilizing oligonucleotide microarrays to examine gene expression profiles in the brain following developmental exposure to Aroclor 1254 (0 or 6 mg/kg/day from gestation day 6 through postnatal day (PND) 21) in Long-Evans rats. Gene expression levels in the cerebellummore » and hippocampus from PNDs 7 and 14 animals were determined on Affymetrix rat 230A{sub 2}.0 chips. In the cerebellum, 87 transcripts were altered at PND7 compared to 27 transcripts at PND14 by Aroclor 1254 exposure, with only one transcript affected at both ages. In hippocampus, 175 transcripts and 50 transcripts were altered at PND7 and PND14, respectively, by Aroclor 1254 exposure with five genes commonly affected. Functional analysis suggests that pathways related to calcium homeostasis (Gng3, Ryr2, Trdn, Cacna1a), intracellular signaling (Camk2d, Stk17b, Pacsin2, Ryr2, Trio, Fert2, Ptk2b), axonal guidance (Lum, Mxd3, Akap11, Gucy1b3), aryl hydrocarbon receptor signaling (Nfia, Col1a2), and transcripts involved in cell proliferation (Gspt2, Cdkn1c, Ptk2b) and differentiation (Ifitm31, Hpca, Zfp260, Igsf4a, Hes5) leading to the development of nervous system were significantly altered by Aroclor 1254 exposure. Of the two brain regions examined, Aroclor 1254-induced genomic changes were greater in the hippocampus than the cerebellum. The genomic data suggests that PCB-induced neurotoxic effects were due to disruption of normal ontogenetic pattern of nervous system growth and development by altering intracellular signaling pathways but not by endocrine disruption.« less

Topical Rapamycin Suppresses the Angiogenesis Pathways Induced by Pulsed Dye Laser: Molecular Mechanisms of Inhibition of Regeneration and Revascularization of Photocoagulated Cutaneous Blood Vessels

PubMed Central

Tan, Wenbin; Jia, Wangcun; Sun, Victor; Mihm, Martin C.; Nelson, J. Stuart

2014-01-01

Background and Objectives Pulsed dye laser (PDL) is the most effective treatment for port wine stain (PWS) birthmarks. However, regeneration and revascularization of photocoagulated blood vessels may result in poor therapeutic outcome. We have recently shown that rapamycin (RPM), an angiogenesis inhibitor, can reduce the regeneration and revascularization of photocoagulated blood vessels. Herein, we attempt to further elucidate the molecular pathophysiology on the inhibition of the regeneration and revascularization of photocoagulated blood vessels by topical RPM in an animal model. Materials and Methods Two separate skin areas on each hamster were irradiated by PDL. After PDL exposure, topical RPM was applied daily to one of the randomly selected test sites. PDL, PDL + RPM and normal skin test sites were biopsied on day 3 after PDL exposure. The total ribonucleic acid (RNA) and protein were extracted from biopsied skin samples and quantified. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunoblot were subsequently performed to quantify the mRNA and protein levels of hypoxia-inducible factor-1alpha (HIF-1α), vascular endothelial growth factor (VEGF) and ribosomal protein S6 kinase (S6). The phosphorylation levels of S6 and AKT were also evaluated by immunoblot. Results The mRNA and protein levels of HIF-1α, VEGF, and S6 significantly increased after PDL exposure as compared to the normal hamster skin. Topical application of 1% RPM suppressed the PDL-induced increase in mRNA and protein levels of those genes on day 3 post-PDL exposure. The phosphorylation levels of S6 and AKT increased after PDL exposure but the increases were suppressed by the topical application of RPM. Conclusion The increase in expression of HIF-1α, VEGF, and S6 after PDL-exposure suggests that angiogenesis pathways play very active roles in the process of skin blood vessel regeneration and revascularization. Topical application of 1% RPM can suppress the angiogenesis pathways and, therefore, reduce the regeneration and revascularization of photocoagulated blood vessels. PMID:23213008

TOXICITY TESTING IN THE 21ST CENTURY: A VISION AND A STRATEGY

PubMed Central

Krewski, Daniel; Acosta, Daniel; Andersen, Melvin; Anderson, Henry; Bailar, John C.; Boekelheide, Kim; Brent, Robert; Charnley, Gail; Cheung, Vivian G.; Green, Sidney; Kelsey, Karl T.; Kerkvliet, Nancy I.; Li, Abby A.; McCray, Lawrence; Meyer, Otto; Patterson, Reid D.; Pennie, William; Scala, Robert A.; Solomon, Gina M.; Stephens, Martin; Yager, James; Zeise, Lauren

2015-01-01

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology. PMID:20574894

Cardiovascular reactivity as a mechanism linking child trauma to adolescent psychopathology.

PubMed

Heleniak, Charlotte; McLaughlin, Katie A; Ormel, Johan; Riese, Harriette

2016-10-01

Alterations in physiological reactivity to stress are argued to be central mechanisms linking adverse childhood environmental experiences to internalizing and externalizing psychopathology. Childhood trauma exposure may influence physiological reactivity to stress in distinct ways from other forms of childhood adversity. This study applied a novel theoretical model to investigate the impact of childhood trauma on cardiovascular stress reactivity - the biopsychosocial model of challenge and threat. This model suggests that inefficient cardiovascular responses to stress - a threat as opposed to challenge profile - are characterized by blunted cardiac output (CO) reactivity and increased vascular resistance. We examined whether childhood trauma exposure predicted an indicator of the threat profile of cardiovascular reactivity and whether such a pattern was associated with adolescent psychopathology in a population-representative sample of 488 adolescents (M=16.17years old, 49.2% boys) in the TRacking Adolescents' Individual Lives Survey (TRAILS). Exposure to trauma was associated with both internalizing and externalizing symptoms and a pattern of cardiovascular reactivity consistent with the threat profile, including blunted CO reactivity during a social stress task. Blunted CO reactivity, in turn, was positively associated with externalizing, but not internalizing symptoms and mediated the link between trauma and externalizing psychopathology. None of these associations varied by gender. The biopsychosocial model of challenge and threat provides a novel theoretical framework for understanding disruptions in physiological reactivity to stress following childhood trauma exposure, revealing a potential pathway linking such exposure with externalizing problems in adolescents. Copyright © 2016 Elsevier B.V. All rights reserved.

Cardiovascular reactivity as a mechanism linking child trauma to adolescent psychopathology

PubMed Central

Heleniak, Charlotte; McLaughlin, Katie A.; Ormel, Johan; Riese, Harriette

2016-01-01

Alterations in physiological reactivity to stress are argued to be central mechanisms linking adverse childhood environmental experiences to internalizing and externalizing psychopathology. Childhood trauma exposure may influence physiological reactivity to stress in distinct ways from other forms of childhood adversity. This study applied a novel theoretical model to investigate the impact of childhood trauma on cardiovascular stress reactivity – the biopsychosocial model of challenge and threat. This model suggests that inefficient cardiovascular responses to stress – a threat as opposed to challenge profile – are characterized by blunted cardiac output (CO) reactivity and increased vascular resistance. We examined whether childhood trauma exposure predicted an indicator of the threat profile of cardiovascular reactivity and whether such a pattern was associated with adolescent psychopathology in a population-representative sample of 488 adolescents (M = 16.17 years old, 49.2% boys) in the TRacking Adolescents’ Individual Lives Survey (TRAILS). Exposure to trauma was associated with both internalizing and externalizing symptoms and a pattern of cardiovascular reactivity consistent with the threat profile, including blunted CO reactivity during a social stress task. Blunted CO reactivity, in turn, was positively associated with externalizing, but not internalizing symptoms and mediated the link between trauma and externalizing psychopathology. None of these associations varied by gender. The biopsychosocial model of challenge and threat provides a novel theoretical framework for understanding disruptions in physiological reactivity to stress following childhood trauma exposure, revealing a potential pathway linking such exposure with externalizing problems in adolescents. PMID:27568327

Spaceflight and Simulated Microgravity Increases Virulence of the Known Bacterial Pathogen S. Marcescens

NASA Technical Reports Server (NTRS)

Clemens-Grisham, Rachel Andrea; Bhattacharya, Sharmila; Wade, William

2016-01-01

After spaceflight, the number of immune cells is reduced in humans. In other research models, including Drosophila, not only is there a reduction in the number of plasmatocytes, but expression of immune-related genes is also changed after spaceflight. These observations suggest that the immune system is compromised after exposure to microgravity. It has also been reported that there is a change in virulence of some bacterial pathogens after spaceflight. We recently observed that samples of gram-negative S. marcescens retrieved from spaceflight is more virulent than ground controls, as determined by reduced survival and increased bacterial growth in the host. We were able to repeat this finding of increased virulence after exposure to simulated microgravity using the rotating wall vessel, a ground based analog to microgravity. With the ground and spaceflight samples, we looked at involvement of the Toll and Imd pathways in the Drosophila host in fighting infection by ground and spaceflight samples. We observed that Imd-pathway mutants were more susceptible to infection by the ground bacterial samples, which aligns with the known role of this pathway in fighting infections by gram-negative bacteria. When the Imd-pathway mutants were infected with the spaceflight sample, however, they exhibited the same susceptibility as seen with the ground control bacteria. Interestingly, all mutant flies show the same susceptibility to the spaceflight bacterial sample as do wild type flies. This suggests that neither humoral immunity pathway is effectively able to counter the increased pathogenicity of the space-flown S. marcescens bacteria.

DISTRIBUTIONS, ASSOCIATIONS, AND PARTIAL AGGREGATE EXPOSURE OF PESTICIDES AND POLYNUCLEAR AROMATIC HYDROCARBONS IN THE MINNESOTA CHILDREN'S PESTICIDE EXPOSURE STUDY (MNCPES)

EPA Science Inventory

The Minnesota Children's Pesticide Exposure Study (MNCPES) provides exposure, environmental, and biologic data relating to multi-pathway exposures of children for four primary pesticides (chlorpyrifos, malathion, diazinon, and atrazine), 14 secondary pesticides, and 13 polynucl...

The Health Impacts of Energy Policy Pathways in Ulaanbaatar, Mongolia: A Total Exposure Assessment

NASA Astrophysics Data System (ADS)

Hill, L. A.; Damdinsuren, Y.; Olkhanud, P. B.; Smith, K. R.; Turner, J. R.; Edwards, R.; Odsuren, M.; Ochir, C.

2015-12-01

Ulaanbaatar is home to nearly half of Mongolia's 2.8 million residents. The city's rapid growth, frigid winters, valley topography, and reliance on coal-fired stoves have led to some of the worst winter pollution levels in the world. To better understand this issue, we modeled integrated PM2.5exposures and related health impacts for various city-wide heating policies through 2024. This assessment is one of the first to employ a total exposure approach and results of the 2014 Comparative Risk Assessments of the Global Burden of Disease Project (CRA/GBD) in a policy-relevant energy study. Emissions related to heating, traffic, and power generation were considered under Business as Usual, Moderate Improvement, and Max Improvement scenarios. Calibrated outdoor models were combined with indoor models, local infiltration and time activity estimates, and demographic projections to estimate PM2.5exposures in 2014 and 2024. Indoor exposures were assigned by heating type, home type, and smoking status; outdoor exposures were assigned through geocoding. Population average annual exposures were calculated and applied to local disease rates and integrated exposure-response curves (2014 CRA/GBD) to arrive at annual projections of premature deaths and DALYs. We estimate 2014 annual average exposures at 68 μg/m3, dictated almost exclusively by indoor winter exposures. Under current trends, annual exposures increase 10% to 75 μg/m3 in 2024. This is in stark contrast to the moderate and max improvement scenarios, which lead to 2024 annual exposures that are 31%, and 68% lower, respectively. Under the Moderate scenario, 2024 per capita annual DALY and death burdens drop 26% and 22%, respectively, from 2014 levels. Under the Max scenario, 2024 per capita annual DALY and death burdens drop 71% and 66%, respectively, from 2014. SHS becomes a major contributor as emissions from other sectors decrease. Reductions are dominated by cardiovascular and lower respiratory diseases in children.

Causal mediation analysis for longitudinal data with exogenous exposure

PubMed Central

Bind, M.-A. C.; Vanderweele, T. J.; Coull, B. A.; Schwartz, J. D.

2016-01-01

Mediation analysis is a valuable approach to examine pathways in epidemiological research. Prospective cohort studies are often conducted to study biological mechanisms and often collect longitudinal measurements on each participant. Mediation formulae for longitudinal data have been developed. Here, we formalize the natural direct and indirect effects using a causal framework with potential outcomes that allows for an interaction between the exposure and the mediator. To allow different types of longitudinal measures of the mediator and outcome, we assume two generalized mixed-effects models for both the mediator and the outcome. The model for the mediator has subject-specific random intercepts and random exposure slopes for each cluster, and the outcome model has random intercepts and random slopes for the exposure, the mediator, and their interaction. We also expand our approach to settings with multiple mediators and derive the mediated effects, jointly through all mediators. Our method requires the absence of time-varying confounding with respect to the exposure and the mediator. This assumption is achieved in settings with exogenous exposure and mediator, especially when exposure and mediator are not affected by variables measured at earlier time points. We apply the methodology to data from the Normative Aging Study and estimate the direct and indirect effects, via DNA methylation, of air pollution, and temperature on intercellular adhesion molecule 1 (ICAM-1) protein levels. Our results suggest that air pollution and temperature have a direct effect on ICAM-1 protein levels (i.e. not through a change in ICAM-1 DNA methylation) and that temperature has an indirect effect via a change in ICAM-1 DNA methylation. PMID:26272993

In vitro systems toxicology approach to investigate the effects of repeated cigarette smoke exposure on human buccal and gingival organotypic epithelial tissue cultures.

PubMed

Schlage, Walter K; Iskandar, Anita R; Kostadinova, Radina; Xiang, Yang; Sewer, Alain; Majeed, Shoaib; Kuehn, Diana; Frentzel, Stefan; Talikka, Marja; Geertz, Marcel; Mathis, Carole; Ivanov, Nikolai; Hoeng, Julia; Peitsch, Manuel C

2014-10-01

Smoking has been associated with diseases of the lung, pulmonary airways and oral cavity. Cytologic, genomic and transcriptomic changes in oral mucosa correlate with oral pre-neoplasia, cancer and inflammation (e.g. periodontitis). Alteration of smoking-related gene expression changes in oral epithelial cells is similar to that in bronchial and nasal epithelial cells. Using a systems toxicology approach, we have previously assessed the impact of cigarette smoke (CS) seen as perturbations of biological processes in human nasal and bronchial organotypic epithelial culture models. Here, we report our further assessment using in vitro human oral organotypic epithelium models. We exposed the buccal and gingival organotypic epithelial tissue cultures to CS at the air-liquid interface. CS exposure was associated with increased secretion of inflammatory mediators, induction of cytochrome P450s activity and overall weak toxicity in both tissues. Using microarray technology, gene-set analysis and a novel computational modeling approach leveraging causal biological network models, we identified CS impact on xenobiotic metabolism-related pathways accompanied by a more subtle alteration in inflammatory processes. Gene-set analysis further indicated that the CS-induced pathways in the in vitro buccal tissue models resembled those in the in vivo buccal biopsies of smokers from a published dataset. These findings support the translatability of systems responses from in vitro to in vivo and demonstrate the applicability of oral organotypical tissue models for an impact assessment of CS on various tissues exposed during smoking, as well as for impact assessment of reduced-risk products.

In vitro systems toxicology approach to investigate the effects of repeated cigarette smoke exposure on human buccal and gingival organotypic epithelial tissue cultures

PubMed Central

Schlage, Walter K.; Kostadinova, Radina; Xiang, Yang; Sewer, Alain; Majeed, Shoaib; Kuehn, Diana; Frentzel, Stefan; Talikka, Marja; Geertz, Marcel; Mathis, Carole; Ivanov, Nikolai; Hoeng, Julia; Peitsch, Manuel C.

2014-01-01

Smoking has been associated with diseases of the lung, pulmonary airways and oral cavity. Cytologic, genomic and transcriptomic changes in oral mucosa correlate with oral pre-neoplasia, cancer and inflammation (e.g. periodontitis). Alteration of smoking-related gene expression changes in oral epithelial cells is similar to that in bronchial and nasal epithelial cells. Using a systems toxicology approach, we have previously assessed the impact of cigarette smoke (CS) seen as perturbations of biological processes in human nasal and bronchial organotypic epithelial culture models. Here, we report our further assessment using in vitro human oral organotypic epithelium models. We exposed the buccal and gingival organotypic epithelial tissue cultures to CS at the air–liquid interface. CS exposure was associated with increased secretion of inflammatory mediators, induction of cytochrome P450s activity and overall weak toxicity in both tissues. Using microarray technology, gene-set analysis and a novel computational modeling approach leveraging causal biological network models, we identified CS impact on xenobiotic metabolism-related pathways accompanied by a more subtle alteration in inflammatory processes. Gene-set analysis further indicated that the CS-induced pathways in the in vitro buccal tissue models resembled those in the in vivo buccal biopsies of smokers from a published dataset. These findings support the translatability of systems responses from in vitro to in vivo and demonstrate the applicability of oral organotypical tissue models for an impact assessment of CS on various tissues exposed during smoking, as well as for impact assessment of reduced-risk products. PMID:25046638

EPA EcoBox Tools by Exposure Pathways - Water and Sediment

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

New developments in exposure assessment: the impact on the practice of health risk assessment and epidemiological studies.

PubMed

Nieuwenhuijsen, Mark; Paustenbach, Dennis; Duarte-Davidson, Raquel

2006-12-01

The field of exposure assessment has matured significantly over the past 10-15 years. Dozens of studies have measured the concentrations of numerous chemicals in many media to which humans are exposed. Others have catalogued the various exposure pathways and identified typical values which can be used in the exposure calculations for the general population such as amount of water or soil ingested per day or the percent of a chemical than can pass through the skin. In addition, studies of the duration of exposure for many tasks (e.g. showering, jogging, working in the office) have been conducted which allow for more general descriptions of the likely range of exposures. All of this information, as well as the development of new and better models (e.g. air dispersion or groundwater models), allow for better estimates of exposure. In addition to identifying better exposure factors, and better mathematical models for predicting the aerial distribution of chemicals, the conduct of simulation studies and dose-reconstruction studies can offer extraordinary opportunities for filling in data gaps regarding historical exposures which are critical to improving the power of epidemiology studies. The use of probabilistic techniques such as Monte Carlo analysis and Bayesian statistics have revolutionized the practice of exposure assessment and has greatly enhanced the quality of the risk characterization. Lastly, the field of epidemiology is about to undergo a sea change with respect to the exposure component because each year better environmental and exposure models, statistical techniques and new biological monitoring techniques are being introduced. This paper reviews these techniques and discusses where additional research is likely to pay a significant dividend. Exposure assessment techniques are now available which can significantly improve the quality of epidemiology and health risk assessment studies and vastly improve their usefulness. As more quantitative exposure components can now be incorporated into these studies, they can be better used to identify safe levels of exposure using customary risk assessment methodologies. Examples are drawn from both environmental and occupational studies illustrating how these techniques have been used to better understand exposure to specific chemicals. Some thoughts are also presented on what lessons have been learned about conducting exposure assessment for health risk assessments and epidemiological studies.

Tobacco exposure and maternal psychopathology: Impact on toddler problem behavior.

PubMed

Godleski, Stephanie A; Eiden, Rina D; Schuetze, Pamela; Colder, Craig R; Huestis, Marilyn A

Prenatal exposure to tobacco has consistently predicted later problem behavior for children. However, little is known about developmental mechanisms underlying this association. We examined a conceptual model for the association between prenatal tobacco exposure and child problem behavior in toddlerhood via indirect paths through fetal growth, maternal depression, and maternal aggressive disposition in early infancy and via maternal warmth and sensitivity and infant negative affect in later infancy. The sample consisted of 258 mother-child dyads recruited during pregnancy and assessed periodically at 2, 9, and 16months of child age. Pathways via maternal depression and infant negative affect to toddler problem behavior were significant. Further, combined tobacco and marijuana exposure during pregnancy and reduced fetal growth also demonstrated important associations with infant negative affect and subsequent problem behavior. These results highlight the importance of considering the role of maternal negative affect and poor fetal growth as risk factors in the context of prenatal exposure. Copyright © 2016. Published by Elsevier Inc.

In Utero Exposure to Low-Dose Alcohol Induces Reprogramming of Mammary Development and Tumor Risk in MMTV-erbB-2 Transgenic Mice

PubMed Central

Ma, Zhikun; Blackwelder, Amanda J.; Lee, Harry; Zhao, Ming; Yang, Xiaohe

2015-01-01

There is increasing evidence that prenatal exposure to environmental factors may modify breast cancer risk later in life. This study aimed to investigate the effects of in utero exposure to low-dose alcohol on mammary development and tumor risk. Pregnant MMTV-erbB-2 mice were exposed to alcohol (6 g/kg/day) between day 13 and day 19 of gestation, and the female offspring were examined for tumor risk. Whole mount analysis indicated that in utero exposure to low-dose alcohol induced significant increases in ductal extension at 10 weeks of age. Molecular analysis showed that in utero alcohol exposure induced upregulation of ERα signaling and activation of Akt and Erk1/2 in pubertal mammary glands. However, enhanced signaling in the EGFR/erbB-2 pathway appeared to be more prominent in 10-week-old glands than did signaling in the other pathways. Interestingly, tumor development in mice with in utero exposure to low-dose alcohol was slightly delayed compared to control mice, but tumor multiplicity was increased. The results indicate that in utero exposure to low-dose alcohol induces the reprogramming of mammary development by mechanisms that include altered signaling in the estrogen receptor (ER) and erbB-2 pathways. The intriguing tumor development pattern might be related to alcohol dose and exposure conditions, and warrants further investigation. PMID:25853264

Intersection of child abuse and children's exposure to domestic violence.

PubMed

Herrenkohl, Todd I; Sousa, Cynthia; Tajima, Emiko A; Herrenkohl, Roy C; Moylan, Carrie A

2008-04-01

This review addresses research on the overlap in physical child abuse and domestic violence, the prediction of child outcomes, and resilience in children exposed to family violence. The authors explore current findings on the intersection of physical child abuse and domestic violence within the context of other risk factors, including community violence and related family and environmental stressors. Evidence from the studies reviewed suggests considerable overlap, compounding effects, and possible gender differences in outcomes of violence exposure. The data indicate a need to apply a broad conceptualization of risk to the study of family violence and its effects on children. Further testing of competing theoretical models will advance understanding of the pathways through which exposure leads to later problems in youth, as well as protective factors and processes through which resilience unfolds.

PROTEIN PROFILING OF XENOPUS LAEVIS BRAIN CELLS FOLLOWING EXPOSURE TO T4-SYNTHESIS INHIBITORS: POTENTIAL APPLICATION TO THE ASSESSMENT/DIAGNOSIS OF XENOBIOTICS THAT PERTURB THE THYROID PATHWAY

EPA Science Inventory

To address USEPA's need for a cost effective, non-mammalian screening assay for thyroid axis disrupting chemicals, a multi-endpoint strategy combining molecular and in vivo protocols in an amphibian model is being applied at MED-Duluth. To support the molecular phase goals of thi...

JNK pathway activation is controlled by Tao/TAOK3 to modulate ethanol sensitivity.

PubMed

Kapfhamer, David; King, Ian; Zou, Mimi E; Lim, Jana P; Heberlein, Ulrike; Wolf, Fred W

2012-01-01

Neuronal signal transduction by the JNK MAP kinase pathway is altered by a broad array of stimuli including exposure to the widely abused drug ethanol, but the behavioral relevance and the regulation of JNK signaling is unclear. Here we demonstrate that JNK signaling functions downstream of the Sterile20 kinase family gene tao/Taok3 to regulate the behavioral effects of acute ethanol exposure in both the fruit fly Drosophila and mice. In flies tao is required in neurons to promote sensitivity to the locomotor stimulant effects of acute ethanol exposure and to establish specific brain structures. Reduced expression of key JNK pathway genes substantially rescued the structural and behavioral phenotypes of tao mutants. Decreasing and increasing JNK pathway activity resulted in increased and decreased sensitivity to the locomotor stimulant properties of acute ethanol exposure, respectively. Further, JNK expression in a limited pattern of neurons that included brain regions implicated in ethanol responses was sufficient to restore normal behavior. Mice heterozygous for a disrupted allele of the homologous Taok3 gene (Taok3Gt) were resistant to the acute sedative effects of ethanol. JNK activity was constitutively increased in brains of Taok3Gt/+ mice, and acute induction of phospho-JNK in brain tissue by ethanol was occluded in Taok3Gt/+ mice. Finally, acute administration of a JNK inhibitor conferred resistance to the sedative effects of ethanol in wild-type but not Taok3Gt/+ mice. Taken together, these data support a role of a TAO/TAOK3-JNK neuronal signaling pathway in regulating sensitivity to acute ethanol exposure in flies and in mice.

Implementing Toxicity Testing in the 21st Century (TT21C): Making safety decisions using toxicity pathways, and progress in a prototype risk assessment.

PubMed

Adeleye, Yeyejide; Andersen, Melvin; Clewell, Rebecca; Davies, Michael; Dent, Matthew; Edwards, Sue; Fowler, Paul; Malcomber, Sophie; Nicol, Beate; Scott, Andrew; Scott, Sharon; Sun, Bin; Westmoreland, Carl; White, Andrew; Zhang, Qiang; Carmichael, Paul L

2015-06-05

Risk assessment methodologies in toxicology have remained largely unchanged for decades. The default approach uses high dose animal studies, together with human exposure estimates, and conservative assessment (uncertainty) factors or linear extrapolations to determine whether a specific chemical exposure is 'safe' or 'unsafe'. Although some incremental changes have appeared over the years, results from all new approaches are still judged against this process of extrapolating high-dose effects in animals to low-dose exposures in humans. The US National Research Council blueprint for change, entitled Toxicity Testing in the 21st Century: A Vision and Strategy called for a transformation of toxicity testing from a system based on high-dose studies in laboratory animals to one founded primarily on in vitro methods that evaluate changes in normal cellular signalling pathways using human-relevant cells or tissues. More recently, this concept of pathways-based approaches to risk assessment has been expanded by the description of 'Adverse Outcome Pathways' (AOPs). The question, however, has been how to translate this AOP/TT21C vision into the practical tools that will be useful to those expected to make safety decisions. We have sought to provide a practical example of how the TT21C vision can be implemented to facilitate a safety assessment for a commercial chemical without the use of animal testing. To this end, the key elements of the TT21C vision have been broken down to a set of actions that can be brought together to achieve such a safety assessment. Such components of a pathways-based risk assessment have been widely discussed, however to-date, no worked examples of the entire risk assessment process exist. In order to begin to test the process, we have taken the approach of examining a prototype toxicity pathway (DNA damage responses mediated by the p53 network) and constructing a strategy for the development of a pathway based risk assessment for a specific chemical in a case study mode. This contribution represents a 'work-in-progress' and is meant to both highlight concepts that are well-developed and identify aspects of the overall process which require additional development. To guide our understanding of what a pathways-based risk assessment could look like in practice, we chose to work on a case study chemical (quercetin) with a defined human exposure and to bring a multidisciplinary team of chemists, biologists, modellers and risk assessors to work together towards a safety assessment. Our goal was to see if the in vitro dose response for quercetin could be sufficiently understood to construct a TT21C risk assessment without recourse to rodent carcinogenicity study data. The data presented include high throughput pathway biomarkers (p-H2AX, p-ATM, p-ATR, p-Chk2, p53, p-p53, MDM2 and Wip1) and markers of cell-cycle, apoptosis and micronuclei formation, plus gene transcription in HT1080 cells. Eighteen point dose response curves were generated using flow cytometry and imaging to determine the concentrations that resulted in significant perturbation. NOELs and BMDs were compared to the output from biokinetic modelling and the potential for in vitro to in vivo extrapolation explored. A first tier risk assessment was performed comparing the total quercetin concentration in the in vitro systems with the predicted total quercetin concentration in plasma and tissues. The shortcomings of this approach and recommendations for improvement are described. This paper therefore describes the current progress in an ongoing research effort aimed at providing a pathways-based, proof-of-concept in vitro-only safety assessment for a consumer use product. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Tadalafil modulates aromatase activity and androgen receptor expression in a human osteoblastic cell in vitro model.

PubMed

Aversa, A; Fittipaldi, S; Bimonte, V M; Wannenes, F; Papa, V; Francomano, D; Greco, E A; Lenzi, A; Migliaccio, S

2016-02-01

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD). Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression. Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation. Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

A spatially-dynamic preliminary risk assessment of the American peregrine falcon at the Los Alamos National Laboratory (version 1)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gallegos, A.F.; Gonzales, G.J.; Bennett, K.D.

1997-06-01

The Endangered Species Act and the Record of Decision on the Dual Axis Radiographic Hydrodynamic Test Facility at the Los Alamos National Laboratory require protection of the American peregrine falcon. A preliminary risk assessment of the peregrine was performed using a custom FORTRAN model and a geographical information system. Estimated doses to the falcon were compared against toxicity reference values to generate hazard indices. Hazard index results indicated no unacceptable risk to the falcon from the soil ingestion pathway, including a measure of cumulative effects from multiple contaminants that assumes a linear additive toxicity type. Scaling home ranges on themore » basis of maximizing falcon height for viewing prey decreased estimated risk by 69% in a canyons-based home range and increased estimated risk by 40% in a river-based home range. Improving model realism by weighting simulated falcon foraging based on distance from potential nest sites decreased risk by 93% in one exposure unit and by 82% in a second exposure unit. It was demonstrated that choice of toxicity reference values can have a substantial impact on risk estimates. Adding bioaccumulation factors for several organics increased partial hazard quotients by a factor of 110, but increased the mean hazard index by only 0.02 units. Adding a food consumption exposure pathway in the form of biomagnification factors for 15 contaminants of potential ecological concern increased the mean hazard index to 1.16 ({+-} 1.0), which is above the level of acceptability (1.0). Aroclor-1254, dichlorodiphenyltrichlorethane (DDT) and dichlorodiphenylethelyne (DDE) accounted for 81% of the estimated risk that includes soil ingestion and food consumption Contaminant pathways and a biomagnification component. Information on risk by specific geographical location was generated, which can be used to manage contaminated areas, falcon habitat, facility siting, and/or facility operations. 123 refs., 10 figs., 2 tabs.« less

Tracking natural and anthropogenic Pb exposure to its geological source.

PubMed

Evans, Jane; Pashley, Vanessa; Madgwick, Richard; Neil, Samantha; Chenery, Carolyn

2018-01-31

Human Pb exposure comes from two sources: (i) natural uptake through ingestion of soils and typified by populations that predate mining activity and (ii) anthropogenic exposure caused by the exposure to Pb derived from ore deposits. Currently, the measured concentration of Pb within a sample is used to discriminate between these two exposure routes, with the upper limit for natural exposure in skeletal studies given as 0.5 or 0.7 mg/kg in enamel and 0.5/0.7 μg/dL in blood. This threshold approach to categorising Pb exposure does not distinguish between the geological origins of the exposure types. However, Pb isotopes potentially provide a more definitive means of discriminating between sources. Whereas Pb from soil displays a crustal average 238 U/ 204 Pb (μ) value of c 9.7, Pb from ore displays a much wider range of evolution pathways. These characteristics are transferred into tooth enamel, making it possible to characterize human Pb exposure in terms of the primary source of ingested Pb and to relate mining activity to geotectonic domains. We surmise that this ability to discriminate between silicate and sulphide Pb exposure will lead to a better understanding of the evolution of early human mining activity and development of exposure models through the Anthropocene.

Semivolatile Organic Compounds in Homes: Strategies for Efficient and Systematic Exposure Measurement Based on Empirical and Theoretical Factors

PubMed Central

2014-01-01

Residential exposure can dominate total exposure for commercial chemicals of health concern; however, despite the importance of consumer exposures, methods for estimating household exposures remain limited. We collected house dust and indoor air samples in 49 California homes and analyzed for 76 semivolatile organic compounds (SVOCs)—phthalates, polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and pesticides. Sixty chemicals were detected in either dust or air and here we report 58 SVOCs detected in dust for the first time. In dust, phthalates (bis(2-ethylhexyl) phthalate, benzyl butyl phthalate, di-n-butyl phthalate) and flame retardants (PBDE 99, PBDE 47) were detected at the highest concentrations relative to other chemicals at the 95th percentile, while phthalates were highest at the median. Because SVOCs are found in both gas and condensed phases and redistribute from their original source over time, partitioning models can clarify their fate indoors. We use empirical data to validate air-dust partitioning models and use these results, combined with experience in SVOC exposure assessment, to recommend residential exposure measurement strategies. We can predict dust concentrations reasonably well from measured air concentrations (R2 = 0.80). Partitioning models and knowledge of chemical Koa elucidate exposure pathways and suggest priorities for chemical regulation. These findings also inform study design by allowing researchers to select sampling approaches optimized for their chemicals of interest and study goals. While surface wipes are commonly used in epidemiology studies because of ease of implementation, passive air sampling may be more standardized between homes and also relatively simple to deploy. Validation of passive air sampling methods for SVOCs is a priority. PMID:25488487

Gene expression profiles in liver of mouse after chronic exposure to drinking water.

PubMed

Wu, Bing; Zhang, Yan; Zhao, Dayong; Zhang, Xuxiang; Kong, Zhiming; Cheng, Shupei

2009-10-01

cDNA micorarray approach was applied to hepatic transcriptional profile analysis in male mouse (Mus musculus, ICR) to assess the potential health effects of drinking water in Nanjing, China. Mice were treated with continuous exposure to drinking water for 90 days. Hepatic gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 arrays, and pathway analysis was carried out by Molecule Annotation System 2.0 and KEGG pathway database. A total of 836 genes were found to be significantly altered (1.5-fold, P < or = 0.05), including 294 up-regulated genes and 542 down-regulated genes. According to biological pathway analysis, drinking water exposure resulted in aberration of gene expression and biological pathways linked to xenobiotic metabolism, signal transduction, cell cycle and oxidative stress response. Further, deregulation of several genes associated with carcinogenesis or tumor progression including Ccnd1, Egfr, Map2k3, Mcm2, Orc2l and Smad2 was observed. Although transcription changes in identified genes are unlikely to be used as a sole indicator of adverse health effects, the results of this study could enhance our understanding of early toxic effects of drinking water exposure and support future studies on drinking water safety.

Genome-wide gene expression changes associated with exposure of rat liver, heart, and kidney cells to endosulfan.

PubMed

Liu, Ruifeng; Printz, Richard L; Jenkins, Erin C; O'Brien, Tracy P; Te, Jerez A; Shiota, Masakazu; Wallqvist, Anders

2018-04-01

Endosulfan was once the most commonly used pesticide in agriculture and horticulture. It is an environmentally persistent organochlorine compound with the potential to bioaccumulate as it progresses through the food chain. Its acute and chronic toxicity to mammals, including humans, is well known, but the molecular mechanisms of its toxicity are not fully understood. To gain insight to these mechanisms, we examined genome-wide gene expression changes of rat liver, heart, and kidney cells induced by endosulfan exposure. We found that among the cell types examined, kidney and liver cells were the most sensitive and most resilient, respectively, to endosulfan insult. We acquired RNA sequencing information from cells exposed to endosulfan to identify differentially expressed genes, which we further examined to determine the cellular pathways that were affected. In kidney cells, exposure to endosulfan was uniquely associated with altered expression levels of genes constituting the hypoxia-inducible factor-1 (HIF-1) signaling pathway. In heart and liver cells, exposure to endosulfan altered the expression levels of genes for many members of the extracellular matrix (ECM)-receptor interaction pathway. Because both HIF-1 signaling and ECM-receptor interaction pathways directly or indirectly control cell growth, differentiation, proliferation, and apoptosis, our findings suggest that dysregulation of these pathways is responsible for endosulfan-induced cell death. Copyright © 2018 Elsevier Ltd. All rights reserved.

Food contamination as a pathway for lead exposure in children during the 2010-2013 lead poisoning epidemic in Zamfara, Nigeria.

PubMed

Tirima, Simba; Bartrem, Casey; von Lindern, Ian; von Braun, Margrit; Lind, Douglas; Anka, Shehu Mohamed; Abdullahi, Aishat

2018-05-01

In 2010, an estimated 400 to 500 children died of acute lead poisoning associated with artisanal gold mining in Zamfara, Nigeria. Processing of gold ores containing up to 10% lead within residential compounds put residents, especially children, at the highest risk. Principal routes of exposure were incidental ingestion and inhalation of contaminated soil and dusts. Several Nigerian and international health organizations collaborated to reduce lead exposures through environmental remediation and medical treatment. The contribution of contaminated food to total lead exposure was assessed during the environmental health response. Objectives of this investigation were to assess the influence of cultural/dietary habits on lead exposure pathways and estimate the contribution of contaminated food to children's blood lead levels (BLLs). A survey of village dietary practices and staple food lead content was conducted to determine dietary composition, caloric intakes, and lead intake. Potential blood lead increments were estimated using bio-kinetic modeling techniques. Most dietary lead exposure was associated with contamination of staple cereal grains and legumes during post-harvest processing and preparation in contaminated homes. Average post-harvest and processed cereal grain lead levels were 0.32mg/kg and 0.85mg/kg dry weight, respectively. Age-specific food lead intake ranged from 7 to 78μg/day. Lead ingestion and absorption were likely aggravated by the dusty environment, fasting between meals, and nutritional deficiencies. Contamination of staple cereal grains by highly bioavailable pulverized ores could account for as much as 11%-34% of children's BLLs during the epidemic, and were a continuing source after residential soil remediation until stored grain inventories were exhausted. Copyright © 2017. Published by Elsevier B.V.

Early life ethanol exposure causes long-lasting disturbances in rat mesenchymal stem cells via epigenetic modifications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leu, Yu-Wei; Chu, Pei-Yi; Chen, Chien-Min

Highlights: • Ethanol exposure alters proliferation and differentiation of MSCs. • Ethanol exposure suppresses osteogenesis and adipogenesis of MSCs. • H3K27me3-associated genes/pathways are affected in ethanol-exposed MSCs. • Expression of lineage-specific genes is dysregulated in ethanol-exposed MSCs. - Abstract: Fetal alcohol syndrome (FAS) is a birth defect due to maternal alcohol consumption during pregnancy. Because mesenchymal stem cells (MSCs) are the main somatic stem cells in adults and may contribute to tissue homeostasis and repair in adulthood, we investigated whether early life ethanol exposure affects MSCs and contributes to the propensity for disease onset in later life. Using a rodentmore » model of FAS, we found that ethanol exposure (5.25 g/kg/day) from postnatal days 4 to 9 in rat pups (mimic of human third trimester) caused long-term anomalies in bone marrow-derived MSCs. MSCs isolated from ethanol-exposed animals were prone to neural induction but resistant to osteogenic and adipogenic inductions compared to their age-matched controls. The altered differentiation may contribute to the severe trabecular bone loss seen in ethanol-exposed animals at 3 months of age as well as overt growth retardation. Expression of alkaline phosphatase, osteocalcin, aP2, and PPARγ were substantially inhibited, but BDNF was up-regulated in MSCs isolated from ethanol-exposed 3 month-old animals. Several signaling pathways were distorted in ethanol-exposed MSCs via altered trimethylation at histone 3 lysine 27. These results demonstrate that early life ethanol exposure can have long-term impacts in rat MSCs by both genetic and epigenetic mechanisms.« less

Impact of exposure time, particle size and uptake pathway on silver nanoparticle effects on circulating immune cells in mytilus galloprovincialis.

PubMed

Bouallegui, Younes; Ben Younes, Ridha; Turki, Faten; Oueslati, Ridha

2017-12-01

Nanomaterials have increasingly emerged as potential pollutants to aquatic organisms. Nanomaterials are known to be taken up by hemocytes of marine invertebrates including Mytilus galloprovincialis. Indeed, assessments of hemocyte-related parameters are a valuable tool in the determination of potentials for nanoparticle (NP) toxicity. The present study assessed the effects from two size types of silver nanoparticles (AgNP: <50 nm and <100 nm) on the frequency of hemocytes subpopulations as immunomodulation biomarkers exposed in a mollusk host. Studies were performed using exposures prior to and after inhibition of potential NP uptake pathways (i.e. clathrin- and caveolae-mediated endocytosis) and over different durations of exposure (3, 6 and 12 h). Differential hemocyte counts (DHC) revealed significant variations in frequency of different immune cells in mussels exposed for 3 hr to either AgNP size. However, as exposure duration progressed cell levels were subsequently differentially altered depending on particle size (i.e. no significant effects after 3 h with larger AgNP). AgNP effects were also delayed/varied after blockade of either clathrin- or caveolae-mediated endocytosis. The results also noted significant negative correlations between changes in levels hyalinocytes and acidophils or in levels basophils and acidophils as a result of AgNP exposure. From these results, we concluded AgNP effects on mussels were size and duration of exposure dependent. This study highlighted how not only was NP size important, but that differing internalization mechanisms could be key factors impacting on the potential for NP in the environment to induce immunomodulation in a model/test sentinel host like M. galloprovincialis.

Mitochondrial Dysfunction, Disruption of F-Actin Polymerization, and Transcriptomic Alterations in Zebrafish Larvae Exposed to Trichloroethylene.

PubMed

Wirbisky, Sara E; Damayanti, Nur P; Mahapatra, Cecon T; Sepúlveda, Maria S; Irudayaraj, Joseph; Freeman, Jennifer L

2016-02-15

Trichloroethylene (TCE) is primarily used as an industrial degreasing agent and has been in use since the 1940s. TCE is released into the soil, surface, and groundwater. From an environmental and regulatory standpoint, more than half of Superfund hazardous waste sites on the National Priority List are contaminated with TCE. Occupational exposure to TCE occurs primarily via inhalation, while environmental TCE exposure also occurs through ingestion of contaminated drinking water. Current literature links TCE exposure to various adverse health effects including cardiovascular toxicity. Current studies aiming to address developmental cardiovascular toxicity utilized rodent and avian models, with the majority of studies using relatively higher parts per million (mg/L) doses. In this study, to further investigate developmental cardiotoxicity of TCE, zebrafish embryos were treated with 0, 10, 100, or 500 parts per billion (ppb; μg/L) TCE during embryogenesis and/or through early larval stages. After the appropriate exposure period, angiogenesis, F-actin, and mitochondrial function were assessed. A significant dose-response decrease in angiogenesis, F-actin, and mitochondrial function was observed. To further complement this data, a transcriptomic profile of zebrafish larvae was completed to identify gene alterations associated with the 10 ppb TCE exposure. Results from the transcriptomic data revealed that embryonic TCE exposure caused significant changes in genes associated with cardiovascular disease, cancer, and organismal injury and abnormalities with a number of targets in the FAK signaling pathway. Overall, results from our study support TCE as a developmental cardiovascular toxicant, provide molecular targets and pathways for investigation in future studies, and indicate a need for continued priority for environmental regulation.