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Record Count: 20
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header (Title, Principal Investigator, Institution, City, ST, Award Code, or
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DESCRIPTION (provided by applicant): Malignant melanoma is on the rise in industrialized nations. Indeed, the incidence of mortality related to melanoma has increased by 34% in the United States from 1973-1992. However, there are few effective treatments developed for melanoma. We propose that the aryl hydrocarbon receptor (AhR) pathway plays a role in melanoma progression through the activation of matrix remodeling enzymes. We have chosen to use 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as the agent to activate the AhR- pathway. TCDD and related polycyclic and halogenated aromatic hydrocarbons (PAH/HAH) are ubiquitous environmental contaminants that are the unintentional by-products of industrial combustion. TCDD is ideal for examination of the AhR pathway in melanoma for three reasons: (1.) skin is a target tissue for TCDD-activation of the AhR pathway; (2.) and TCDD is not metabolized; and (3) TCDD is non-mutagenic, and therefore the effects we observe should be directly related to activation of the AhR pathway. We hypothesize that TCDD-activation of the AhR/Arnt pathway stimulates melanoma progression by altering expression of the genes involved in matrix remodeling, specifically the matrix metalloproteinases (MMPs). MMP activity is necessary for cell migration through matrix barriers, and expression of these enzymes correlates with aggressive and invasive tumors. Our preliminary data in melanoma cells demonstrate that both non-invasive and invasive melanoma lines are responsive to TCDD, and invasive melanoma cells express MMPs in response to TCDD exposure. Further, we also show increased invasiveness of melanoma cells when treated with TCDD. This suggests that TCDD directly increases melanoma invasion by activating matrix degradation. Therefore, the specific aims for this proposal are: (1.) Elucidate the molecular mechanism mediating TCDD-induced expression of MMPs in melanoma cell lines. (2.) Elucidate the role of the AhR in TCDD-induced changes in MMP expression in melanoma. (3.) Demonstrate the role of the AhR pathway in melanoma migration and invasion using an in vitro invasion assay. (4.) Using a three-dimensional skin model system, determine the role of cell-cell interaction on AhR-activation of MMP expression.
DESCRIPTION (provided by applicant): The goal of this research project, Environmental Health Literacy for Low Literate Groups, is to explore and determine concepts that characterize health literacy related to environmental risk and to identify appropriate environmental health risk visual and written concepts for individuals with low literacy skills. An innovative method to investigate emerging concepts will be employed using an adapted Mental Models approach. Using open-ended interviews of 20 environmental experts and 20 risk communication experts, the project team will create a model of concepts that constitute environmental health literacy. Using these frameworks as a basis, six focus groups with low literate members will be conducted in three communities, in partnership with local community organizations. Focus group recruitment will include an assessment of literacy level. The purpose of the focus groups is to explore perceptions and definitions of identified environmental literacy concepts and assess comprehension of currently used messages and images in environmental risk communiques. Pro-type messages and images will be developed and pretested with three additional focus groups with low literacy members. Results will provide understanding of essential concepts for environmental risk literacy, and provide useful methods and messages for conveying messages to low literacy groups. These groups often are more at risk for environmental exposure than groups with higher literacy levels. The testing of an innovative approach to developing risk messages and methods is an additional benefit of this study. The University of Medicine and Dentistry of New Jersey- School of Public Health (UMDNJ-SPH), including the Resource Center of the Public Education and Risk Communication (PERC) Division, Environmental and Occupational Health Science Institute (EOHSI) will direct this two year research project.
Crisp Terms/Key Words: focus group, educational resource design /development, behavioral /social science research tag, clinical research, educational psychology, academic achievement, psychological model, model design /development, interview, human subject, environmental health, educationally disadvantaged, health education
The goal of this renewal application for the NIEHS Center at EOHSI in Piscataway, NJ is to provide support and continuity to our mission of improving environmental and public health through research, education, outreach and communication. The EHS Center serves New Jersey, the most densely populated and perhaps the most heavily polluted state in the nation. The grant proposal consists of 4 Research Cores, 6 Facility Cores, a COEP and a Pilot Project Program. The Cores are as follows: I. Environment-Gene Interactions, II. Environmental Effects on Signal Transduction, III. Neural and Developmental Toxicology, IV. Exposure Analysis and Health Effects and Community Outreach and Education Program (COEP). Facility Cores are: Analytical Cytometry/Image Analysis, Biostatistics, Chemical Analysis, Molecular Genetics, Molecular Pathology and Proteomics.
Crisp Terms/Key Words: clinical research, environmental toxicology, chemical carcinogen, chemical carcinogenesis, environmental health, biomedical facility
DESCRIPTION (provided by applicant): Human exposure to phthalates is ubiquitous. Esters of phthalic acid are widely used as plasticizers for many types of plastic ranging from polyvinyl chloride to food wraps, toys and building products. Recent evidence suggests that environmental phthalate exposure adversely impact pregnancy outcome in humans. The objective of this project is to test the hypothesis that maternal exposure to phthalates early in pregnancy has an adverse effect on pregnancy outcome. The subject population is a cohort of 1500 low income, minority pregnant women from Camden, New Jersey. Maternal excretion of phthalate metabolites in urine and plasma early and late in pregnancy will be measured by isotope ratio gas chromatography mass spectrometry with selective ion monitoring. Outcomes of interest include preterm delivery (<37 weeks) and very preterm (<32 weeks), low birthweight (<2500 g), fetal growth restriction (<10 percentile of standard), gestation duration together with the incidence of birth defects, particularly male urogenital defects including cryptorchidism and hypospadias. All of the necessary samples along with subject data, prospective biological samples and pregnancy outcomes are in hand for the cohort. Preterm delivery, the leading cause of infant morbidity and mortality in the United States, has increased by 30% during the past 2 decades for reasons that are unknown. Risk is highest for low income minorities who may also have increased exposure to environmental pollutants like phthalate. Relevance: It is now generally accepted that chemicals introduced into the environment by human activity have adverse effects on human health. This study will provide information on the effects of maternal phthalate exposure to pregnancy outcome. The findings will have immediate ramifications for public health, for the packaging trade and for the chemical industry.
PUBLIC HEALTH RELEVANCE: Human exposure to phthalates is ubiquitous. Esters of phthalic acid are widely used as plasticizers for many types of plastic used for food wraps, toys and building products. Recent evidence suggests that environmental phthalate exposure adversely impact pregnancy outcome in humans. The objective of this project is to test the hypothesis that maternal exposure to phthalates early in pregnancy has an adverse effect on pregnancy outcome. The findings will have ramifications for public health, for the packaging trade and for the chemical industry.
DESCRIPTION (provided by applicant): As of 1998, more than 80,000 chemicals were registered by the EPA as being in commerce in the United States. Of the nearly 3000 chemicals that were imported or manufactured at a rate of more than one million pounds per year, 43% had no available toxicology data, and only 7% had full information on basic health and environmental effects. Some of these compounds are now classified as endocrine disruptors, and have been associated with mammary and other tumors, as well as decreases in fertility in human and animal populations. Despite these findings, only a small fraction of the close to 100,000 chemicals listed in the NIH TOXNET database have been fully characterized for endocrine disruptive effects, primarily due to the complexity of the assays required for accurate classification. Thus a critical goal is to develop quick and reliable methods to identify and characterize unknown compounds, so that risks and appropriate regulations can be determined. This proposal seeks to aid in this goal through the development of a bacterial biosensor for the rapid and reliable detection of endocrine disrupting effects in isolated chemicals and complex mixtures. This sensor relies on an engineered, four-domain fusion protein, which includes the ligand-binding domain of a given nuclear hormone receptor linked to a reporter enzyme through a small stabilization domain. When expressed in an appropriate Escherichia coli host strain, this protein generates a hormone-sensitive phenotype, which can be used to detect ligands that interact with the included nuclear hormone receptor domain. This system has been shown to be capable of detecting a wide variety of estrogenic compounds, including phytoestrogens, xenoestrogens, and estrogenic steroids, and it can reliably differentiate agonistic from antagonistic behaviors. Further, the modular design of the sensor has facilitated the construction of additional sensors for thyroid hormone-like compounds, and even insect-hormone like compounds. In our proposed work, we will develop this sensor into a fully validated and functional first-line tool for use in identifying potential endocrine disruptors. Specific aims include its formal validation for estrogenic compound identification, along with the generation and validation of additional sensors through ligand-binding domain swapping. Enhancement of the system readout is also suggested to facilitate future applications based on high-throughput technologies. It is anticipated that this system will ultimately hold significant utility as part of a multi-tiered program for their systematic discovery and classification of endocrine disrupting compounds. PUBLIC HEALTH RELEVANCE Over the last several decades, several distressing health trends, including increases in breast cancer, autism rates, and fertility problems have been linked to hormone-mimicking compounds known as endocrine disruptors. The work described in this proposal seeks to develop a unique biosensor system wherein bacterial cells indicate the presence of endocrine disrupting compounds through a simple, inexpensive and reliable growth/no growth assay. This system has many advantages over conventional approaches, and may provide an effective first-line evaluation of natural and artificial compounds, alone and in mixtures, for activity against specific hormone receptor targets.
DESCRIPTION (provided by applicant): Air pollution and tuberculosis (TB) each present major challenges to public health and specifically to lung health globally. This grant will address the pressing question of whether air pollutants can acutely alter human antimycobacterial immunity. [PARAGRAPH] Urban air pollution, contributes substantially to morbidity and mortality worldwide. Diesel Exhaust Particles (DEP) from diesel engines are generated by various industries, contribute to 40% of particulate respirable matter in big cities and accumulate in underground mines. DEP represent an important model pollutant for the study of biological and health effects of respirable particulate matter (PM). [PARAGRAPH] There is mounting evidence that DEP (PM) alters the function of respiratory immune cells and increases susceptibility to infectious pathogens such as viruses and bacteria. Experimental aerogenic infections with intracellular bacteria such as Mycobacterium tuberculosis (M.tb), Bacille Calmette Guirin (BCG) or Listeria monocytogenes result in increased pulmonary bacterial burden in rodents exposed to DEP. [PARAGRAPH] We have novel preliminary data that indicate that human blood phagocytes take up both M.tb and DEP. During simultaneous addition of DEP and M.tb, M.tb-induced cytokine production from peripheral blood cells is altered (IFN-gamma, TNF-alpha, IL-6 decreased, IL-10 increased) in a DEP dose-dependent manner. Exposure to DEP 20 hours before M.tb infection abrogated M.tb induced IL-6 and IL-10 production, perhaps indicating a DEP-induced state of cellular unresponsiveness/tolerance to subsequent stimuli, similar to endotoxin tolerance. Our unique preliminary studies in healthy volunteers after DEP inhalation exposure show increased M.tb-induced IFN-gamma, and decreased M.tb-induced IL-6 and IL-10 release. Both DEP in vitro addition and in vivo exposure studies indicate that DEP decreases the capacity of blood cells to control M.tb growth in vitro. [PARAGRAPH] The proposed studies in this grant differ from previous DEP (PM) effect studies in several important ways. DEP effects will be studied (1) on immunity to a pathogen of overriding public health importance (M.tb), (2) in humans with and without pathogen (M.tb)-specific memory immunity, and (3) in in vitro and in vivo DEP-exposed primary human blood cells. We propose to expand our studies of dose and time kinetic effects of DEP exposure. Changes in antigen-specific cytokine production, M.tb-induced cell proliferation, growth control of M.tb and Th1 and Th2 as well as toll like receptor (TLR) gene expression and their signaling pathways will be assessed. [PARAGRAPH] We hypothesize that the combined effects of PM (DEP) and M.tb on the human host may alter antimycobacterial immune responses thus increasing susceptibility to M.tb infection and TB disease with potentially important public health effects on a population level. PUBLIC HEALTH RELEVANCE: Air pollution and tuberculosis (TB) present public health challenges to lung health on a global scale. This grant will address whether air pollutants can severely alter the human bodily defenses against tuberculosis. We will investigate how the combination of diesel exhaust particles and tuberculosis on the human body affect human immune response thus increasing vulnerability to tuberculosis infection and TB disease which may impact on the public health on a population level.
DESCRIPTION (provided by applicant): Lead (Pb) continues to pose health risks for those sectors of the population in which exposure is highest, particularly individuals of lower socioeconomic status and workers in the construction trades. In addition to notorious effects on cognitive function, chronic Pb exposure is associated with hypertension and cardiovascular disease. Experimental studies from our laboratory reveal that chronic Pb exposure permanently alters corticosterone levels and stress reactivity in rats. If similar alterations in the hypothalamic pituitary adrenal axis (HPA) are demonstrated among humans chronically exposed to Pb, then such alterations may contribute over time to disease vulnerability. Aim 1 of this translational study is to assess HPA axis, sympathoadrenergic (SAS), and blood pressure reactivity to an acute stressor among healthy workers whose chronic exposure to Pb is documented by Cd K x-ray fluorescence (K-XRF). Aim 2 is to evaluate the effect of genetic polymorphisms associated with glucocorticoid receptors and Pb metabolism on glucocorticoid response to stress. Fifty-five healthy Pb-exposed subjects and 55 healthy unexposed controls, ages 30 to 50, will be recruited from the construction trades. Tibial K-XRF will be used to estimate chronic exposure to Pb. Subjects will perform the Trier Stress, comprised of a public speaking and math task. ACTH, cortisol, epinephrine, norepinephrine, and blood pressure will be assessed before, during and following the stressor. Heart rate reactivity will be used to assess the effect of individual stress reactivity on glucocorticoid and catecholamine response to stress. In coordination with an existing R01, basic science animal studies are planned to incorporate catecholamine and blood pressure stress responsivity among animals exposed to Pb in regimens similar to those observed in human populations and to elucidate mechanisms underlying the relationship between Pb exposure, HPA axis alterations, and blood pressure.
DESCRIPTION (provided by applicant): The long-term objective of this project is to provide information that will be useful in assessing the risks posed to human health by the neurotoxic organophosphorus insecticides. It seeks to accomplish this objective by investigating preliminary observations that suggest the current view of how these toxic insecticides inhibit acetylcholinesterase is inadequate to describe the insecticide-enzyme interactions over a wide range of insecticide concentrations. Preliminary data indicates that the capacity of certain organophosphates to inhibit acetylcholinesterase changes as a function of inhibitor concentration. Moreover, evidence presented indicates that the organophosphate paraoxon causes a transient activation of acetylcholinesterase prior to inhibition. Collectively, these data suggest the presence of a secondary binding site on human recombinant acetylcholinesterase for certain organophosphates. Therefore, the overall hypothesis of this application is that organophosphates and their parent insecticides bind to a site on human recombinant acetylcholinesterase distinct from the catalytic triad, and that occupation of this site alters events at the active site. As a consequence of such binding, low exposures to certain organophosphorus insecticides could pose a greater health risk than is currently estimated based on dose-response relationships using higher exposure levels. The specific aims of this application are as follows: 1) To determine the bimolecular inhibition rate constant &,, for the inhibition of human recombinant acetylcholinesterase by the test organophosphates over a wide range of inhibitor concentrations; 2) To determine if the test organophosphates and their parent compounds can transiently enhance the hydrolysis of the substrate acetylthiocholine by human recombinant acetylcholinesterase prior to inhibition of the enzyme through phosphorylation; 3) To determine if the test organophosphates and their corresponding parent insecticides bind to the peripheral anionic site on human recombinant acetylcholinesterase; and 4) To determine if the rate of dephosphorylation of organophosphate- inhibited human recombinant acetylcholinesterase (reactivation) is altered by the occupation of the peripheral anionic site or some other secondary site for organophosphates.
Crisp Terms/Key Words: environmental exposure, recombinant protein, active site, phosphorylation, organophosphorus insecticide, intermolecular interaction, enzyme inhibitor, environmental health, acetylcholinesterase, spectrometry, hydrolysis, chemical kinetics, chemical binding
DESCRIPTION (provided by applicant):
Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by core features of impulsivity, hyperactivity, and attention deficits. ADHD is estimated to affect 8-12% of
school-aged children worldwide. ADHD is a complex disorder with significant genetic contributions.
However, no single gene has been linked to a significant percentage of cases, suggesting that
environmental factors or gene-environment interactions may contribute to the etiology or clinical
manifestation of ADHD. Dopamine transporter (DAT) polymorphisms and elevated expression of the DAT have been observed in ADHD patients, suggesting alterations in DAT levels may contribute to ADHD. Since environmental factors, such as pesticides, have been shown to alter DAT expression, we have hypothesized that in utero pesticide exposure may contribute to the incidence or severity of ADHD. Recent data from this laboratory have demonstrated that the offspring of mice exposed to low levels of the pyrethroid pesticide deltamethrin during development exhibit similar symptoms as observed in children with ADHD, including elevated DAT levels, hyperactivity, a paradoxical calming response to psychostimulants, behavioral deficits, and a male gender-preference of these effects. Importantly, the doses that elicited these effects were at or below the no observable adverse effect level (NOAEL) established by the EPA for deltamethrin. This is particularly notable because the NOAEL used by the EPA when making regulatory decisions on pesticides. Because there has been documented exposure of pregnant women to pyrethroids and pyrethroid use has increased dramatically in the last decade, it may be prudent to evaluate pesticide exposure as a potential risk factor for ADHD. Furthermore, these mice represent a novel animal model to test therapies for ADHD and provide insight into the basic mechanisms underlying this disorder. Here, the investigators propose three Specific Aims to investigate mechanisms underlying the effects of deltamethrin on the dopamine system and characterize the behavioral effects of developmental deltamethrin expsoure. The investigators will then use this information to exploit this novel model to identify molecular targets for therapeutic intervention in ADHD.
DESCRIPTION (provided by applicant): Attention deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder characterized by marked impulsivity, hyperactivity, and impaired working memory. ADHD is estimated to affect 3-7% of school-age individuals in the United States alone, with a significant percentage of these cases persisting through adulthood. Although the pathophysiology of ADHD is not completely understood, disruption of the dopamine system appears to play a central role. Specifically, polymorphisms and elevated levels of the dopamine transporter (DAT) have been found in both adolescents and adults with ADHD. Elevated DAT levels are also found in the spontaneously-hypertensive rat, a well characterized animal model of ADHD. The primary medications utilized in the treatment of ADHD, methylphenidate and amphetamine, produce much of their therapeutic effects through blockade of DAT. Thus, alteration of DAT levels or function significantly contributes to the behavioral abnormalities and treatment of ADHD. Although genetic factors account for a large percentage of ADHD, an estimated 20-40% of cases do not appear to have a primary genetic etiology, suggesting that environmental factors may contribute to ADHD. Accordingly, exposure to environmental agents that alter the proper development of the dopaminergic system and enhance DAT levels may contribute to development of behaviors associated with ADHD. Our laboratory and others have demonstrated that repeated exposure of adult mice to the pyrethroid pesticide, deltamethrin, increases striatal DAT levels. We now have evidence that gestational and lactational exposure of mice to deltamethrin, at doses 4 to 40-fold below the developmental no-observable adverse effect level (NOAEL), causes longterm up-regulation of DAT and hyperactivity in adolescent mice. Therefore, the purpose of this proposal is to determine the effects of developmental pyrethroid exposure on the dopamine system and whether alterations of the dopamine system result in a behavioral phenotype similar to that of ADHD.
Crisp Terms/Key Words: laboratory mouse, attention deficit disorder, gene expression, developmental neurobiology, neurochemistry, pyrethroid, longitudinal animal study, protein metabolism, attention, behavioral genetics, ethology, early experience, short term memory, psychomotor function, animal breeding, neurotransmitter transport, dopamine transporter, gene environment interaction, behavioral /social science research tag, environmental exposure, gene expression profiling
DESCRIPTION (provided by applicant): Ozone is a ubiquitous urban air pollutant known to damage the lung and compromise respiratory function. Our laboratories have been investigating mechanisms mediating the toxicity of ozone, in particular, the role of macrophages in the pathogenic process. We have discovered that macrophages responding to ozone-induced lung injury release mediators that not only contribute to tissue injury, but also, and perhaps more importantly, to tissue repair. Of particular interest is tumor necrosis factor-alpha (TNF-(), which appears to be involved in both of these processes. The major receptor mediating the reparative actions of TNF-( is TNFR1 (p55), which is localized in caveolin-1 (Cav-1)-containing plasma membrane lipid rafts, or caveolae. These are specialized organelles that sequester and negatively regulate various cell-signaling molecules. In rodent models, we observed that ozone-induced injury is associated with a marked suppression of Cav-1 in the lung, and the release of signaling molecules mediating type II alveolar epithelial cell proliferation and tissue repair. In preliminary studies we identified TNF-( as a major mediator regulating Cav-1 expression. We hypothesize that down regulation of Cav-1 by TNF-( initiates tissue repair by sensitizing alveolar type II cells to proliferate in response to endogenous mitogens. Down-regulation of Cav-1 after ozone inhalation is associated with activation of the (-catenin/cyclin D1 pro-mitogenic signaling pathway. We speculate that this is a key step leading to proliferation of type II cells and repair of damaged epithelium following ozone-induced injury. The experiments described in this proposal are designed to analyze the role of Cav-1 in ozone toxicity. Studies are planned to assess mechanisms by which Cav-1 is down regulated in type II cells following ozone inhalation in mice and to elucidate the role of TNF-( in this process. We will also determine if TNF-(-induced suppression of Cav-1 leads to activation of (-catenin signaling and type II cell proliferation. The results of these studies will provide new mechanistic clues about the pathways leading to repair of acute lung damage and may suggest innovative therapeutic approaches for abrogating tissue injury associated with exposure to inhaled pollutants, as well as episodic inflammatory lung diseases such as asthma. PUBLIC HEALTH RELEVANCE: Ozone is a ubiquitous urban air pollutant and the main component of photochemical smog. It remains one of the most problematic air pollutants to control because it is formed from intermediates originating from many different sources. Inhaled ozone has been shown to irritate and damage the lung in both healthy and susceptible individuals, including children and the elderly. Epidemiologic studies in the U.S. have demonstrated that for every 10 ppb increase in daily ozone levels, the total death rate for that day and for the two following days increases by 0.87%. Potential adverse effects of ozone are even greater in large cities in the developing world where ozone levels can be significantly higher than in the U.S. with a concomitantly greater health burden. Thus, elucidating the specific mechanisms contributing to the toxicity of ozone is highly relevant in terms of developing new strategies for reducing tissue injury induced by air pollutants, and potentially for other inflammatory lung diseases.
DESCRIPTION (provided by applicant): Unprecedented actions will be taken during the 2008 Beijing Olympics and Paralympics (July 25 - September 17, 2008) to ensure that ambient air quality in one of the world's most polluted regions will be substantially improved. The targeted reduction in fine particulate matter (PM2.5) is ~70% from a pre-Olympics level of >100 5g/m3. The proposed study will take advantage of this unique opportunity to test the following hypotheses: (1) Biomarkers of lung and systemic inflammation, vascular endothelial dysfunction, blood coagulation, autonomic dysfunction, and oxidative stress measured in local residents will change significantly in response to this substantial air pollution reduction. Further, these biomarkers will return to pre-Olympic levels following relaxation of air pollution controls when the Olympics are over. (2) PM2.5, ultrafine particles, and certain PM constituents will each be associated with specific biomarkers across the whole study period. (3) Subjects' responses to changes in pollutant exposure will vary depending on their inherited polymorphisms for molecular pathways related either directly to the biomarkers measured or to mechanisms of PM-induced oxidative stress. The proposed panel study will be carried out in 50 male and 50 female, healthy, non-smoking medical residents, who work and reside in the same hospital facility where both air pollutants and biomarkers will be measured. Specifically, we will: (1) measure PM constituents and co-pollutants on a continuous or daily basis throughout the three study periods (pre-Olympics, during-Olympics, and post- Olympics); (2) measure a suite of biomarkers reflecting lung and systemic inflammation, endothelial dysfunction, blood coagulation, autonomic dysfunction, and oxidative stress, in each subject twice per period (6 times total); (3) analyze candidate gene polymorphisms in each subject; and (4) perform statistical analyses to test the above hypotheses. Epidemiological evidence strongly suggests that acute and chronic cardio-respiratory diseases and events are related to exposure to air pollution especially PM2.5. However, specific mechanisms for these outcomes remain ill-defined; and mechanistic studies have been very limited and largely confined to laboratory-based exposures that may not reflect real-life conditions. By expanding the suite of PM constituent measures, measuring multiple biomarkers and pathway-related genes simultaneously, and examining a wide range of time frames (from hours to days to a few weeks) for biomarker responses, this real-world study is a comprehensive investigation of several prominently hypothesized mechanisms of PM effects. It will also provide invaluable data to improve the assessment of public health impacts of air pollution reduction.
DESCRIPTION (provided by applicant): A research study is proposed to refine and evaluate a new device to improve the estimation of indoor exposure to inhalable particulate for both children in the first year of life and toddlers. Because they frequently play on the floor, these children may experience significantly higher levels of exposure than older children and adults to PM10 particles and airborne constituents, which are known asthmagens. A total of 200 children ages 6 to 35 months will be enrolled from neighborhood clinics. Parents will be administered a standardized asthma questionnaire (ISAAC) to determine presence and frequency of asthma symtpoms. Exposures will be characterized both qualitatively and quantitatively, to examine if the more precise estimation of PM10 exposure obtained by using a surrogate for personal monitoring. The study will employ a revised iteration of a prototype Pre-Toddler Inhalable Particulate Environmental Robotic (PIPER) Sampler that has been developed and undergone preliminary testing. Sampling will be carried out with both a fixed height stationary sampling station, where inlets of all instruments will be at 110 cm height, and the self- propelled computerized PIPER sampler, where inlets of all instruments can be varied between 20 to 110cm above the floor to mirror the varied breathing heights of these children while engaged in play on the floor. Four parameters will be for each household: 1) mass concentration of PM10 particles measured by a real- time monitoring device; 2) real-time particle size and number distribution (0.3-10 urn); 3) air sampling on filters for detailed characterization of the PM10 constituents (pesticides, allergens, and endotoxins); 4) concentration and composition of airborne fungi (viable and non-viable) collected on glass slides. Measurements will be collected in tandem for each of the 4 types of monitoring. The results of the laboratory analysis for endotoxins, molds and allergens for cockroaches (Bla g Yz), dust mites (Der f 1/p 1), dog (Can f 1), cat (Pel d 1) and mouse (Mus ml) will be evaluated for association with reporting of asthma symptoms This study seeks to provide an alternative to personal monitoring for a variety of environmental exposures that may be experienced by children too young to be assessed by conventional methods, including those in their first year of life. In addition, it will open up an avenue for more precise estimation of early childhood exposures to asthmagens in the PM10 fraction of aerosols.
DESCRIPTION (provided by applicant):
Skilled Service Personnel (SSP) support emergency response organizations during an emergency incident, and include laborers, operating engineers, carpenters, ironworkers, sanitation workers and utility workers. SSP called to an emergency incident rarely have recent detailed training on the chemical, biological, radiological, nuclear and/or explosives (CBRNE) agents they may encounter or the personal protection equipment (PPE) relevant to the incident. This increases personal risk to the SSP and mission risk at the incident site. Training for SSP has been identified as a critical need by the National Institute for Environmental Health Sciences, Worker Education and Training Program. The proposed SBIR Phase II project addresses this SSP training shortfall by developing a wireless lesson delivery system called the Just-In-Time Training for Emergency Incidents System (JITTEIS). SSP dispatched to an emergency incident receive brief site-specific multimedia lessons on their cell phones derived from the Occupational Safety and Health Administration (OSHA) #7600 Disaster Site Worker Course. The lessons describe the CBRNE threats and safety protocols (including PPE) identified by the Safety Officer (SO) at the incident site. Users are permitted to upload new content for immediate broadcast, such as pictures or video clips of newly discovered hazards. JITTEIS builds upon the Phase I effort, which achieved (1) interoperability among diverse mobile devices, wireless service providers, calling plans, and incident management systems, (2) instructional designs and production procedures for lessons rendered on mobile devices user modeling and system ergonomics, (3) pushed versus pulled content delivery, and (4) training adaptation to rapidly changing threats. The proposed effort will complete the development of a fully operational JITTEIS, develop a set of available training lessons based on needs, and deploy and evaluate the system in two settings that together encompass many of the requirements of CBRNE incidents: a large New Jersey construction sites involving hazardous waste material and a distributed work force, and the command center and distributed vehicle fleet of New Jersey's largest paramedic organization. It is anticipated that JITTEIS will become a valuable commercial service to emergency response organizations and other organizations with widely dispersed, mobile workforces who need safety and health just-in-time training and information.
DESCRIPTION (provided by applicant): This project proposes to build and test a 20 L capacity Remediator for medical wastes. Infectious Medical Wastes (IMW), mainly from hospitals, represents a major component of hazardous wastes generated in the U.S.. In fact, more than 4.5 million tons are generated per year. Hospital waste remediation was a $1.5 billion industry in 2003. Incineration remains the predominant disposal method, with continued problems of environmental pollution, severe local opposition, transportation, high costs and the threat of recent (1997) laws shutting down incinerators. This firm recently demonstrated a novel technique for remediation of IMW that involves submersing the IMW in proprietary liquids that are specifically activated by microwaves to generate antimicrobial and antiviral activity in a manner as or more effective than an autoclave. This technique uses unique, microwave-active liquids, proprietary microwave enhancers and simple, ambient-pressure techniques. It yields an extremely inexpensive, rapid, environmentally benign, local, point-of-service methodology for remediation of IMW, usable much as a local-area photocopier or shredder. The Phase 1 work further developed this, demonstrating application to a wide variety of mixed IMW, including metallic parts, bandages, gloves, cotton, etc. and actual hospital wastes. Typically, 400 g of wastes in 650 mL of microwave liquid could be remediated in 7 minutes using a 1.1 KW oven, with final weight/-volume reductions to < 15% of original. Detailed analyses of thermal degradation products of the microwave liquid and wastes showed none. A mechanical prototype of a Remediator was built and a fully-microwave-functional prototype was designed and evaluated. AOAC Sporicidal Tests and microwave-vs.-heat-only tests were also done in the prior work. In the proposed Phase 2 work, a fully functional Remediator will be built, tested and refined, to arrive at a design suitable for handing over to a large contract manufacturer. AOAC Sporicidal and quantitative tests and tests with actual hospital wastes will be used to verify performance, along with comparisons with extant benchmark methods. The work is a collaborative effort with a highly specialized microwave design company, one of the world's premier university microwave chemistry groups, the Regional Bio-Defense Lab, and a large hospital. Estimated remediation costs are $900/ton for this firm's technology, vs. $2900/ton for incineration, and more for microwave-steam methods. This firm's technology's estimated capital cost is less than $8 K for a 30 kg/hr throughput, as compared to $18 K for on-site autoclaving and $80 K for microwave-steam. PUBLIC HEALTH RELEVANCE: The technology could, potentially, entirely replace incineration of medical wastes (already beset with public health problems) as well as expensive methods such as in-situ autoclaving and microwave-steaming, yielding an inexpensive, environmentally benign, and local, point-of-service method for medical waste remediation, to great public benefit [1-26]. Independent studies [2-4] show it could initially (within 5 years) capture about 10% to 30% of the more than $2 billion (in 2008) medical waste remediation market, possibly more subsequently. This firm's technology's estimated running costs are 1/3 to 1/6 that of other methods, its capital costs are 1/3 to 1/10 of other methods, and, in contrast to other methods which (with the exception of incineration) leave a large amount of residual waste, it leaves less than 15% of the original volume of waste.
DESCRIPTION (provided by applicant)
The proposed career development and research plans will prepare the candidate to conduct independent research focusing on how the toxic effects of air pollutants may be modified in susceptible individuals, using animal models. Evidence from epidemiological studies indicates that individuals with pre-existing cardiovascular (CV) disease are at increased risk of CV effects from particulate matter air pollution (PM). The research plan will test the hypothesis that the CV effects of PM are mediated by systemic inflammatory responses to local injury and inflammation in the lungs, and that altered macrophage numbers and activity in lung and liver contribute to increased sensitivity of apolipoprotein E-deficient (ApoE-/-) mice to these effects. Moreover, toxic effects will be enhanced by co-exposure to stress. To test this hypothesis, the candidate will use freshly generated diesel exhaust (DE) as a model PM exposure. The first aim is to determine if ApoE-/- mice exhibit increased susceptibility to DE-induced pulmonary and systemic inflammation and prothrombotic activity. ApoE-/- and control mice will be exposed to DE (30-1000 mu/g/m3 PM) or control for 3-6 hours, with outcomes measured at 0-72 hours post-exposure. Markers of inflammation will be assessed in the lung, liver, blood, and blood vessels, including cell counts, cytokine expression, circulating acute phase proteins, and cell adhesion molecules. The second aim is to determine if increases in the sensitivity of ApoE-/- mice to DE are due to increased macrophage numbers and activity in the lung and liver. Dependence of DE-induced effects on macrophages will be tested by selectively depleting these cells using liposomes. The third aim is to determine if stress alters DE-induced inflammatory responses and prothrombotic activity. Inflammation and prothrombotic activity will be analyzed in ApoE-/- and control mice after exposure to DE with and without an acute stressor. Career development plans include mentorship and training in inhalation toxicology and psychoneuroimmunology through supervised research and structured educational activities. Laboratory techniques to be learned include animal exposures, surgery, cell culture, western blotting, ELISA, in situ hybridization, RT-PCR and histochemical procedures. The career development plan will enable the candidate to achieve his overall goal of conducting research that integrates animal studies with human exposure studies. The experimental studies will contribute to elucidating mechanisms underlying CV effects of PM.
DESCRIPTION (provided by applicant)
The Joint Graduate Program in Toxicology (JGPT) is a combined effort of Rutgers University and the Robert Wood Johnson Medical School-University and is centered in the Environmental and Occupational Health Sciences Institute (EOHSI). The principal underpinning of the JGPT is the toxicology training grant. This is a competing renewal request for years 21-25 to support 6 pre-doctoral students and 3 postdoctoral fellows. Since its inception, the JGPT has trained more than 100 doctoral students, postdoctoral fellows and physician-scientists. The graduates of the JGPT have forged distinguished careers in academic, industrial and governmental toxicology research.
The central goal of the program is to provide rigorous training in mechanistic toxicology and related biomedical disciplines, reinforced with focused training in a field of specialization. These specialized tracks: biochemical toxicology, cell signaling and immunotoxicology and neurotoxicology, reflect areas of scholarship in which the JGPT faculty are recognized as leaders. The training is supported by outstanding resources for state-of-the-art research and strong institutional support, and synergizes with the NIEHS Center for Excellence in Toxicology, the Center for Advanced Biotechnology and Medicine, the Cancer Institute of New Jersey and other units involved in environmental health research. The enthusiastic participation of faculty from the two universities creates an unusually rich training environment for pre-doctoral and postdoctoral fellows.
A new initiative in this proposal is to designate one senior postdoctoral fellow position for a clinical resident in the Occupational Medicine Residency in EOHSI to facilitate translational toxicology research with human subjects. In addition, all incoming trainees will rotate through the clinical facilities at EOHSI to gain experience in human subjects research. The continuing goal of the JGPT and this training grant is to prepare trainees to excel in the rapidly changing arena of environmental health sciences.
BACKGROUND
This is a competitive renewal for the Training in Environmental Toxicology program at Rutgers University that has been funded for the past 21 years. Dr. Robert Snyder served as Director until 1997 and Dr. Kenneth Reuhl assumed the leadership in 1997 and has led the Program ever since. The training program operates within the Joint Graduate Program in Toxicology (JGPT) that is a combined effort between Rutgers University and the Robert Wood Johnson Medical School. Relative to the previous funding period the number of pre-doctoral positions has been reduced by 1 and the number of postdoctoral positions increased by 1 for a total of 6 pre-doctoral and 3 postdoctoral positions. The new postdoctoral position will be used to support a clinical resident in the Occupational Medicine Residency program at the Environmental and Occupational Health Science Institute (EOHSI). Another proposed change to the program is the introduction of a mandatory one-month rotation of pre-doctoral trainees in the Occupational Medicine Clinic or Controlled Exposure Clinic to provide experience in human subject based research.
DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a progressive neurodegenerative disorder characterized clinically by motor dysfunction and pathologically by depletion of dopamine (DA)-producing neurons in the nigrostriatal DA (NSD) system. Environmental risk factors for PD are consistently reported, via epidemiological, clinical, and animal studies. Though PD typically emerges late in life, the environment in periods of neurodevelopment is gaining attention as a susceptibility factor. For example, in mice, prenatal exposure to the fungicide maneb (MB) greatly increased adulthood susceptibility to the pesticide paraquat (PQ), resulting in features of PD. Concordant with the mission of the NIEHS, the current proposal seeks to unravel the mechanism by which MB alters neurodevelopment to confer vulnerability to the progressive neurodegeneration seen in PD. To understand the role of multiple environmental hits, a cohort design will be employed in which mice prenatally exposed to MB will be followed across the lifespan, with intermittent exposure to PQ. Dopaminergic integrity will be assessed at many timepoints for evidence of progressive neurodegeneration, and toxicokinetic and toxicodynamic study of MB and PQ will be undertaken. It is hypothesized that prenatal MB exposure induces a state of altered potential (SAP), and that this SAP describes a pre-clinical phase of DAergic dysfunction. This SAP will be characterized through gene expression profiling and analysis of several biochemical systems (including those for DA homeostasis, oxidative stress response, trophic factors, and barriers); risk factors (e.g. aging, PQ) may act through these systems, and these endpoints will also be studied in the context of these risk factors. Finally, since gender plays a major role in PD, it is hypothesized that gonadal steroid hormones modulate risk; this will be assessed by characterizing the role of the estrous cycle on the normal mouse NSD system, on PQ toxicokinetics and toxicodynamics, and also by manipulating gonadal steroid exposure at various stages of development.
PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is a major health concern, and though onset of symptoms typically occurs late in the lifespan, environmental factors as early as prenatal life may have long-lasting consequences for development of this disease. Using an animal model of prenatal exposure to the fungicide maneb, this proposal seeks 1. to understand how maneb creates long-lasting susceptibility, 2. to define the biochemical and gene expression profile that describes the pre-symptomatic state of vulnerability, and 3. to clarify the role of gender in mediating these effects. In addition to providing insight into the etiology of PD and contributing to risk assessment paradigms, we will identify stable targets that may be amenable to manipulation to modify risk and/or severity of PD.
DESCRIPTION (provided by applicant)
The New Jersey/New York Hazardous Materials Worker Training Center, a NIEHS awardee since 1987, is requesting funds for four program areas: HWWT, MWT, BMWT, and HDPT. For each program area, Center members have established relationships with the target populations, and represent academia, labor, and the public sector. The goal of the Center is to prevent and reduce disability, morbidity, and mortality due to personal risk during hazardous waste operations and emergency response.
Region II, the focus of this Center, has over 1,200 Superfund sites and thousands of State sites where clean-up is underway or planned for the coming years. The populations to be trained include public and private sector site workers, union members, and emergency responders. Participants in the HWWT program are: UMDNJ-School of Public Health, Hunter College, New Jersey State Police, New York Committee for Occupational Safety and Health, NY Carpenters Labor Technical College, University at Buffalo, and the Universidad Metropolitana. The Center will provide 3,524 courses, training 71,665 students over the five years of this proposal.
The MWT and BMWT programs will provide 19 weeks of training in health and safety, job skills, and construction trades. The goal is to prepare and place people of color in environmental remediation and assessment or construction trades. The MWT program is based in New York City and the BMWT program is based in Newark, NJ and Glen Cove, NY. Center members include the UMDNJ-SPH and the Carpenters Labor Technical College. Community based organizations will be selected to assist in recruitment and retention of program participants. Thirty students will be trained in each of the MWT and BMWT programs.
The goal of the HDPT program is to provide training in disaster preparedness to public sector and union representatives. Center members include the UMDNJ-SPH, Hunter, NYCOSH, University at Buffalo and Universidad Metropolitana. The Center will provide 640 courses, training 6,825 students over the five years of this proposal.
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