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Extramural Research

2000 Progress Report: Center for Child Environmental Health Risks Research

EPA Grant Number: R826886
Center: University of Washington
Center Director: Faustman, Elaine
Title: Center for Child Environmental Health Risks Research
Investigators: Faustman, Elaine
Institution: University of Washington
EPA Project Officer: Callan, Richard
Project Period: August 1, 1998 through December 31, 2003
Project Period Covered by this Report: August 1, 1999 through July 31,2000
Project Amount: $3,545,396
RFA: Centers for Children's Environmental Health and Disease Prevention Research (1998)
Research Category: Children's Health , Health Effects , Human Health

Description:

Objective:

Neurobehavioral Assessment Core

Goals and Specific Aims. The overall goals of this research core are to: (1) conduct studies aimed at defining the effects of early pesticide exposure on neurobehavioral development; and (2) utilize the results of these studies as a basis for integrating behavioral and mechanistic approaches for defining the dose-response characteristics of effects due to early pesticide exposure.

The specific aims of this research core are to: (1) evaluate the role of paraoxonase polymorphism in defining the susceptibility to the neurobehavioral effects of postnatal organophosphorus (OP) insecticide exposure; (2) determine the concentration-dependent relationship between prenatal exposure to pesticides and alterations in neurobehavioral development; and (3) correlate these neurobehavioral effects with observed alterations in cell cycle progression.

Exposure Assessment Core

Four specific aims were identified for the Exposure Core in the original proposal: (1) provide analytical chemical support to the intervention project, (2) manage an exploratory arsenic exposure supplement to the field projects, (3) coordinate mechanistic modeling of exposure and dose among all center projects, and (4) provide exposure modeling support to the Pathways Project.

Risk Characterization Core

The specific aims of this core project have not changed, they are to: (1) provide statistical collaboration and consultation on study design and data analysis; (2) develop new methods for study evaluation; (3) develop and characterize new risk assessment methods that specifically improve models used for assessing children’s environmental risks; and (4) collaborate in the writing of manuscripts.

Risk Communication Core

The goal of the Risk Communication Core is to provide a critical link between Center researchers and the regional and national community on issues of environmental impacts to children’s health. The specific aims of the Risk Communication Core include: (1) working with our community partners in our field-based projects; (2) developing, with our national scientific colleagues and health professionals, a library of materials relevant to understanding the potential impacts from the environment on children’s health; (3) developing continuing education courses for regional health, safety, and regulatory professionals on child health; and (4) disseminating research findings and making a difference for risk assessment for children.

Administrative Core

The Administrative Core is responsible for oversight, coordination, and management of the scientific and administrative aspects of the University of Washington Center for Child Environmental Health Risks Research (CHC). The Administrative Core also facilitates communication with our funding agencies, other Children’s Centers, and interested individuals and organizations. Center Director, Dr. Elaine Faustman, is assisted by two Deputy Directors, Dr. Thomas Burbacher (Associate Professor, Department of Environmental Health) and Dr. Richard Fenske (Professor and Director, Pacific Northwest Agricultural Safety and Health Center, Department of Environmental Health); Ms. Ruth Woods (Program Administrator); Ms. Tiffany Potter-Chiles (Program Coordinator), and Ms. Donna Prisbrey (Program Assistant).

Progress Summary:

Neurobehavioral Assessment Core

During the second year of the Center grant, we successfully advertised and hired a Research Scientist to direct the core research activities. Dr. Kristina Dam was hired as of July 1, 2000. Dr. Dam has extensive experience in the area of pesticide developmental neurotoxicity. Her initial efforts thus far have been directed at developing the design for the behavioral studies for the Pon1-knockout mice. It was decided, in collaboration with our external advisory committee, that the knockout mice studies should be prioritized using both postnatal and prenatal exposure models. We were able to exchange some of the equipment that we had ordered for testing rats as well as purchase new equipment for mice to accommodate these studies. Equipment is on hand for assessing spontaneous motor activity (The Open Field) and learning and memory (The Radial Arm Maze and the Morris Maze). This equipment utilizes the Poly-Track Video Tracking System (San Diego Instruments), which automates the collection and summary of the data. Additional equipment is being ordered to provide testing capabilities for acoustic startle response and operant testing. Dr. Dam will continue to work with Drs. Burbacher, Furlong, and Costa during the next couple of months to finalize the design for the paraoxonase studies and begin testing.

Significance. The results of the behavioral studies will provide critical data for the evaluation of the functional consequences of the changes observed in initial molecular mechanism and paraoxonase studies. The data from the behavioral core, integrated with the results from these studies, will provide the basis for biologically based risk models. These models will utilize the results to provide a better understanding how to extrapolate across doses and species for molecular and functional effects of pesticides.

Exposure Assessment Core

Specific Aim 1—Provide Analytical Chemical Support to the Intervention Project. The primary activity of the Exposure Core in Years 1 and 2 has been support of the Community Intervention Project (CIP; R826886C003). Analyses have been completed for adult and child urine samples and house and vehicle dust samples. CIP personnel gathered samples from 219 households. Because sufficient sample mass was not obtained in every case, sample totals are ≤ 219 for individual sample types. Adult and child urine samples were analyzed for five OP metabolites (dimethylphosphate, dimethylthiophosphate, dimethyldithiophosphate, diethylphosphate, and diethylthiophosphate). House and vehicle dusts were analyzed for six parent compounds (chlorpyrifos, diazinon, azinphos-methyl, malathion, parathion, and phosmet). No difference between CIP communities designated “intervention” and “control” with respect to urinary metabolites (diethyl or dimethyl OP) in adults or children was found.

Specific Aim 2—Manage an Exploratory Arsenic Exposure Supplement to the Field Projects. Limited Exposure Core funds were expended for lead and arsenic analyses of samples from 28 CIP households. House and vehicle dust samples were analyzed for arsenic and lead. Child urine samples were analyzed for speciated arsenic. Households were targeted based on location in communities most likely to have been affected by historical lead arsenate use and availability of samples in excess of primary CIP needs. Results of these and additional analyses funded by other means do not support use of urinary arsenic as a marker of children’s exposure to soils treated historically with lead arsenate.

Specific Aim 3—Coordinate Mechanistic Modeling of Exposure and Dose Among All Center Projects. The physiologic model framework created in Simusolv has been translated and validated into a newer modeling system: SAAM II. This will allow us to use Bayesian parameter fitting and examine Akaike and Bayesian information criteria as measures of fit. We have established an objective model goodness-of-fit test, which will allow us to decide if each of the pesticide-specific physiologic models accurately describes a given data set. An oral route of exposure has been built into the models to account for dust and pica ingestion exposure sources. Automatic calculations of systemic clearance, volume of distribution, and half-life have been built into the models to relate model output to physiologic characteristics (such as adiposity and glomerular filtration rate) and to compare the results of our studies with those previously published. In preparation for an analysis of how child age, body weight, adiposity, gender, and paraoxygenase genotype affect pesticide kinetics, we have conducted similar analyses for toluene and xylenes. L. Wilder, a Ph.D. student in the University of Washington (UW) Department of Environmental Health, and A. Hirabayashi, an undergraduate student, are beginning independent study projects to further develop the physiologic pesticide models.

Specific Aim 4—Provide Exposure Modeling Support to the Pathways Project. An effort to reconcile OP pesticide metabolites measured in urine with OP pesticide exposures predicted on the basis of environmental is ongoing (see Editor’s note in view markup). Activity will be increased now that CIP laboratory analyses are completed and new data are available. Support of the Pathways Project will also include expansion of existing Exposure Core GIS capability to assist with GPS tracking methodology development.

Significance. A key emphasis of the CHC is understanding children’s unique exposure risks. This Core provides necessary computer modeling and analytical chemical support to specific basic research projects.

Completion of a Master’s thesis drawn almost exclusively from the results of the CIP baseline sampling is anticipated in August 2000. A related conference presentation has been accepted for the annual meeting of the International Society of Exposure Analysis in October 2000. Two journal articles are in preparation. A second M.S. thesis will incorporate the arsenic and lead results.

Risk Characterization Core

During the second year significant progress was made in addressing Specific Aims 1 and 2, providing statistical advice on study design, analyzing data, and developing methods to analyze and understand data being produced in the research projects of this grant. These have included coordinating the analysis of data on urinary metabolites for children and adults and pesticide levels in house dust and in car dust and also in the planning of the intervention study to evaluate the effectiveness of community education (Pesticide Exposure Pathways, Exposure Assessment Core and the CIPs). Progress on Specific Aim 3 has resulted in the expansion of Biologically Based Dose Response (BBDR) models for a spectrum of events occurring in neuronal development in the embryonic and fetal brain (Molecular Mechanisms Study). Relevant to Specific Aim 4, Dr. Griffith has been consulting with several graduate students that are currently writing their thesis related manuscripts.

Specific Aims 1 and 2. The risk assessment core is coordinating the analysis of data on urinary metabolites for children and adults and pesticide levels in house dust and car dust and also in the planning of the intervention study to evaluate the effectiveness of community education. The data on urinary metabolites and dust concentrations of pesticides are the endpoints that will be used to evaluate the effectiveness of community education by comparing communities who received a community education program with those which did not receive one. Key statistical issues were addressed in pairing communities based on size and demographics to eliminate the possible effect of these variables in testing whether the intervention of the education program has had an effect on exposure of children. At this time baseline data are available on the urinary metabolites and dust samples for all communities (before the start of the education programs). In addition, demographic data are available from questionnaires used in the selection of eligible homes in the communities and includes information such as income, ethnicity, education of parents, and ages of household members. This information will be used in the intervention analysis and for describing the demographics of farm workers in eastern Washington.

Because we are focusing on environmentally relevant and potentially low levels of pesticide exposure, new statistical methods were developed to analyze the urinary metabolite data. These methods were developed to account for the large fraction of samples below the detection level in the chemical analyses. The chemical analyses were for five different types of metabolites, each of which can come from the metabolism of several pesticides. Three of the metabolites are summed because they result from metabolism of pesticides with dimethyl groups, and the other two are summed because they are metabolites of pesticides with a methyl group. Each metabolite has a different detection level, and for four metabolites many samples were below the detection level. This mixture of detection levels with different fractions of the samples below the detection level for each metabolite required the development of new statistical methods.

Often when samples are below a chemical detection limit, a value of one-half of the detection limit is used for these samples. In this case this method is inadequate and will produce misleading statistical analysis because using one-half of the detection limit tends to underestimate the variability of the data and overestimate the mean of the data. In performing statistical tests this would lead us to decide that some trends were statistically significant when that was not the case. To deal with this problem a technique was developed for each metabolite using the trend of the data above the detection level to predict the trend for samples below the detection level. This method has been used to relate the concentration of urinary metabolites in children to values from the same household for adult urinary metabolites and pesticide concentrations in house dust.

Specific Aim 3. The underlying hypothesis for the Molecular Mechanisms Project of this Center is that pesticides alter neurobehavioral development by altering the dynamic relationship of cell proliferation and differentiation during early brain development. Of relevance for the Risk Characterization Core activities is the need for BBDR that will allow the effective description of dynamic processes such as early brain development. As mentioned in our original application, CHC investigators have established the basic framework for BBDR models for methylmercury neurodevelopmental effects during early organogenesis. In our last non-competitive renewal, we described how this basic dynamic model was being adapted in the programming language S Plus and was interfaced with kinetic models which use Simusolv to describe temporally relevant toxicokinetic parameters. Publications describing these linked dynamic interactive models are in final draft and will be submitted for publication early in year 3. A key focus of BBDR model development over this past year has been the expansion of the dynamic model to cover a larger range of brain development. The Molecular Mechanism Project is assessing neurodevelopmental impacts to the embryonic midbrain and the newborn hippocampal and cerebellar brain regions. To accommodate processes during this larger developmental time period we have utilized models evaluating neurodevelopmental impacts of ethanol. Modifications of the Leroux, et al. (1999) model are in process and will build on these detailed research investigations.

Significance. Collaboration with investigators on statistical designs and analysis has resulted in improved power of the studies to detect statistically significant results. The BBDR models under development improve our ability to evaluate the potential for neurodevelopmental impacts by better understanding how to interpret cell cycle data in terms of basic biological mechanisms of the developing and differentiating neurons. This two-stage stochastic neurodevelopmental BBDR model also assists in understanding basic biological mechanisms on a more complex level by linking exposures to toxic substances to actual tissue concentrations of the substances and their toxic effects on neurodevelopment. The work on temporal fallacies in evaluating biomarkers of exposures assists in development of better risks assessment methods for children’s environmental exposures and in the identification of susceptible time points for chemical impacts during neurodevelopment.

Risk Communication Core

Specific Aim 1. Tiffany Potter-Chiles, the Program Coordinator, continues to work closely with the field staff of the CIP in the Yakima Valley. She provides a critical link between investigators at the University of Washington and those at Fred Hutchinson Cancer Research Center, which administers the CIP. In cooperation with the Community Intervention staff, she created a coloring book to educate children about pesticides. Ms. Potter-Chiles also assisted in researching community services available in the Yakima Valley and created two brochures in English and Spanish, “Resources in our Community: Information about Pesticides” and “Resources in Our Community: Health and Community Services.”
During the second year, the CHC sponsored the following Department of Environmental Health seminars:

  • Theodore Slotkin, Ph.D. (Duke University Medical Center), “Nicotine and chlorpyrifos: cholinergic agents targeting the developing brain,” February 10, 2000.
  • Patricia M. Rodier, Ph.D. (University of Rochester), “Autism: a disorder with genetic & teratologic etiologies,” April 6, 2000.
  • Stanley Barone, Jr., Ph.D. (U.S. Environmental Protection Agency), “Preliminary efforts at incorporating developmental effects of exposure to chlorpyrifos into a biologically-based dose response model,” April 27, 2000.
  • Rob McConnell, M.D. (University of Southern California School of Medicine), “Asthma, lung function growth, and air pollution: results from the Southern California Children’s Health Study,” May 25, 2000.

Ms. Potter-Chiles also serves as a point of contact between community agencies, community members and UW investigators, providing information when appropriate and referring people to the appropriate investigator or community agency.

Specific Aim 2. Ms. Potter-Chiles researched and collected existing materials related to pesticides and risks to human health. The collection now includes books, journal articles, brochures, videos, pamphlets and posters that were created by government agencies, universities, and community organizations. These materials are cataloged and available to CHC researchers for reference.

Specific Aim 3. The UW CHC co-sponsored a continuing education course for medical professionals titled “Environmental health issues in children: what pediatricians and other primary care providers need to know.” The course was conducted by the UW Department of Environmental Health’s Continuing Education Program on April 28, 2000.

Specific Aim 4. Members of the UW CHC presented research findings at numerous workshops, conferences, and meetings throughout the year. A list of CHC presentations is included in the 2000 Annual Reports for R826886 and R826886C001-R826886C004.

The UW CHC attracted favorable media attention this year. The UW CHC was featured on the front page of the Seattle Times under the title “Are children at risk from pesticides: UW study aims to gauge the danger” (King, Warren, Seattle Times, August 22, 1999). The Associated Press carried a lengthy news release from Fred Hutchinson Cancer Research Center (FHCRC) on the results of the Community Intervention survey of farm workers; the AP article was carried in most regional newspapers including the Seattle Times, Post-Intelligencer, and the Yakima Herald. In addition to these feature stories, key investigators discussed CHC research and results with journalists on numerous occasions throughout the year.

Significance. Through the activities described above, the Risk Communication Core facilitates communication between UW investigators and the broader community. These activities contribute to the goal of the Risk Communication core to provide a link between Center investigators and the regional and national community on issues of environmental impacts to children’s health.

Administrative Core

During the second year the Administrative Core continued to provide administrative support for CHC research studies such as: fiscal management and budget reporting, purchasing, and subcontract management; development of communication materials; meeting coordination; and basic secretarial support. The Administrative staff coordinated six Center-wide meetings throughout the academic year. These meetings provided an effective venue for Center members to meet as a group to present research activities and results and to facilitate collaborative work. In addition to these internal meetings, the Administrative staff conducted the annual External Advisory Committee meeting in May 2000.

Ms. Potter-Chiles provided graphic design and publication support to the Community Intervention staff at FHCRC. She created several informative pieces including a coloring book and two brochures.

Ms. Woods and Ms. Prisbrey are contributing to the planning efforts of the upcoming National Institute of Environmental Health Sciences (NIEHS) Town Meeting, which will be hosted by the Department of Environmental Health’s Center for Ecogenetics and Environmental Health. The title of the meeting is “Voices for Healthy Environments, Healthy Communities.” The purpose of the Town Meeting is to bring together members of the community, scientists, policy makers, and regulators in a 2-day forum for discussion regarding environmental health issues in Washington State. Health risks related to pesticide exposure has been identified as a topic of discussion by the community planning committee, and a panel discussion will be conducted on this topic. In addition, the CHC administrative staff will coordinate with the Risk Communication group to create a visual display (poster) to present at the meeting. The town meeting will be held on September 29-30, 2000. Ms. Woods and Ms. Prisbrey are members of the community planning committee and the outreach committee and have been active since January 2000.

External Advisory Committee (EAC) Meeting. The EAC met for the second annual meeting on May 24, 2000. The EAC consists of six members: David L. Eaton, Ph.D. (Assistant Dean for Research, School of Public Health and Community Medicine; Professor and Director, Center for Ecogenetics and Environmental Health, Department of Environmental Health); Brenda Eskenazi, Ph.D. (Professor, University of California Berkeley; and Director of one of the Child Health Centers, “Exposures and Health of Farm Worker Children in California”); Lupe Gamboa, J.D. (Director, United Farmworkers of America); Carole A. Kimmel, Ph.D. (National Center for Environmental Assessment, U.S. Environmental Protection Agency); Rob McConnell, M.D. (Director, Pan American Health Association, Environmental Health Unit); and Lucina Suarez, Ph.D. (Senior Scientist, Texas Department of Health).

Internal Advisory Committee (IAC). The IAC comprises the Center Principal Investigator, the two Deputy Directors, the Program Administrator, and the Research Study and Core Directors. In the second year, the IAC meetings were combined with Center-wide meetings. At each of those meetings time was set aside to discuss administrative business prior to the general presentations on research activities. This format provided an excellent opportunity to discuss research collaborations and scientific review of activities.

Changes in CHC Projects and Personnel Implemented in Year 2 or Planned for Year 3. In February 2000, Susan Silbernagel accepted a position as Administrator in the UW Department of Pharmacology. Ruth Woods replaced Ms. Silbernagel as Program Administrator. Ms. Woods is the former fiscal manager of the Institute for Risk Analysis and Risk Communication (IRARC), which includes the CHC. She has been involved in the fiscal and contract management of the CHC since it was first proposed in 1997. This spring, Donna Prisbrey joined the CHC as a Program Assistant. Ms. Prisbrey brings to the Center experience working with diverse stakeholder groups and workshop planning. In the coming year, Ms. Potter-Chiles will further reduce her effort on the Center and she will focus her efforts on the design and publication of educational, outreach, and communication materials and the development of the Center Web Site. All Administrative personnel divide their effort between the Center and other IRARC programs.

Significance. N/A—administrative support core.

Future Activities:

Neurobehavioral Assessment Core

During the remainder of this year and year 3, we will concentrate our efforts on the behavioral studies for the Pon1-knockout mice. Studies will be conducted examining both prenatal and postnatal exposure effects. We will begin with using a postnatal exposure model, since our previous studies have used this model. Preliminary studies will need to be performed to examine the appropriate dose range for the prenatal behavioral studies. It is anticipated that these studies will be conducted during year 3.

Exposure Assessment Core

Baseline sampling and laboratory analysis in support of the CIP is now complete. Significant effort in year 3 will be devoted to interpreting the CIP results. Exposure Core activities will also shift substantially to modeling support of the Pathways Project and other Center projects.

Risk Characterization Core

During the third year a replacement for Dr. Mary Lou Thompson will be hired. It is anticipated that collaboration and consultation with investigators on statistical design and analysis will continue to be an important part of our efforts. Publications are being developed on the models of temporal fallacy, flow cytometry model, and the two-stage stochastic neurodevelopmental toxicity model. It is anticipated that work on development of statistical methods for analyzing gene expression data from microarrays generated in the Molecular Mechanisms project will be carried out in year 3.

Risk Communication Core

Tiffany Potter-Chiles will continue to develop risk communication materials and publications for the UW CHC, including revising the CHC Web Site. She will work with Emily Allen (a member of the UW Pesticide Exposure Study and Community Intervention Study) to develop content for the Web site in a format and language that is readily accessible to non-scientists. This activity will support specific aim 4.

Administrative Core

No changes to plans are anticipated for year 3.


Journal Articles: 73 Displayed | Download in RIS Format

Other center views: All 86 publications 76 publications in selected types All 73 journal articles

Type Citation Sub Project Document Sources
Journal Article Andersen ME, Conolly RB, Faustman EM, Kavlock RJ, Portier CJ, Sheehan DM, Wier PJ, Ziese L. Quantitative mechanistically based dose-response modeling with endocrine-active compounds. Environmental Health Perspectives 1999;107(Suppl 4):631-638. R826886 (2000)
not available
Journal Article Bartell SM, Ponce RA, Takaro TK, Zerbe RO, Omenn GS, Faustman EM. Risk estimation and value-of-information analysis for three proposed genetic screening programs for chronic beryllium disease prevention. Risk Analysis 2000;20(1):87-99. R826886 (2000)
not available
Journal Article Bogdanffy MS, Daston G, Faustman EM, Kimmel CA, Kimmel GL, Seed J,Vu V. Harmonization of cancer and non-cancer risk assessment:proceedings of a consensus-building workshop. Toxicological Science 2001;61(1):18-31. R826886 (2000)
not available
Journal Article Brophy VH, Jarvik GP, Richter RJ, Rozek LS, Schellenberg GD, Furlong CE. Analysis of paraoxonase (PON1) L55M status requires both genotype and phenotype. Pharmacogenetics 2000;10(5):453-460. R826886 (2000)
not available
Journal Article Brophy VH, Jampsa RL, Clendenning JB, McKinstry LA, Jarvik GP, Furlong CE. Effects of 5' regulatory-region polymorphisms on paraoxonase-gene (PON1) expression. American Journal of Human Genetics 2001;68(6):1428-1436.
abstract available   full text available
R826886 (2000)
R826886C002 (2001)
R831709 (2007)
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  • Journal Article Brophy VH, Hastings MD, Clendenning JB, Richter RJ, Jarvik GP, Furlong CE. Polymorphisms in the human paraoxonase (PON1) promoter. Pharmacogenetics 2001;11(1):77-84.
    abstract available   full text available
    R826886 (2000)
    R826886C002 (2001)
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  • Full-text: Pharmacogenetics Full Text
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  • Journal Article Burbacher TM, Grant KS. Methods for studying nonhuman primates in neurobehavioral toxicology and teratology. Neurotoxicology and Teratology 2000;22(4):475-486. R826886 (2000)
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    Journal Article Cavanaugh JE, Ham J, Hetman M, Poser S, Yan C, Xia Z. Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. Journal of Neuroscience 2001;21(2):434-443. R826886 (2000)
    not available
    Journal Article Chan GC, Lernmark U, Xia Z, Storm DR. DNA elements of the type 1 adenylyl cyclase gene locus enhance reporter gene expression in neurons and pinealocytes. European Journal of Neuroscience 2001;13(11):2054-2066. R826886 (2000)
    not available
    Journal Article Costa LG, Li WF, Richter RJ, Shih DM, Lusis A, Furlong CE. The role of paraoxonase (PON1) in the detoxication of organophosphates and its human polymorphism. Chemico–Biological Interactions 1999;119-120:429-438.
    abstract available   full text available
    R826886 (2000)
    R826886C002 (2000)
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  • Journal Article Costa LG. The emerging field of ecogenetics. Neurotoxicology 2000;21(1-2):85-89.
    abstract available  
    R826886 (2000)
    R826886C002 (2000)
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  • Journal Article Costa LG, Guizzetti M, Lu H, Bordi F, Vitalone A, Tita B, Palmery M, Valeri P, Silvestrini B. Intracellular signal transduction pathways as targets for neurotoxicants. Toxicology 2001;160(1-3):19-26. R826886 (2000)
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    Journal Article Costa LG. Pesticide exposure:differential risk for neurotoxic outcomes due to enzyme polymorphisms. Clinics in Occupational and Environmental Medicine 2001;1:511-523. R826886 (2000)
    not available
    Journal Article Costa LG, Guizzetti M, Burry , Oberdoerster J. Developmental neurotoxicity:do similar phenotypes indicate a common mode of action? A comparison of fetal alcohol syndrome, toluene embryopathy and maternal phenylketonuria. Toxicology Letters 2002;127(1-3):197-205. R826886 (2000)
    not available
    Journal Article Costa LG, Richter RJ, Li W-F, Cole T, Guizzetti M, Furlong CE. Paraoxonase (PON1) as a biomarker of susceptibility for organophosphate toxicity. Biomarkers 2003;8(1):1-12.
    abstract available  
    R826886 (2000)
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    R831709 (2005)
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    R831709C002 (2004)
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  • Journal Article Costa LG, Cole TB, Jarvik GP, Furlong CE. Functional genomics of the paraoxonase (PON1) polymorphisms:effects on pesticide sensitivity, cardiovascular disease, and drug metabolism. Annual Review of Medicine 2003;54:371-392.
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    R826886C002 (2002)
    R831709 (2005)
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  • Journal Article Curl CL, Fenske RA, Kissel JC, Shirai JH, Moate TF, Griffith W, Coronado G, Thompson B. Evaluation of take-home organophosphorus pesticide exposure among agricultural workers and their children. Environmental Health Perspectives 2002;110(12):A787-792.
    abstract available   full text available
    R826886 (2000)
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    R826886C004 (2002)
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  • Journal Article Elgethun K, Fenske RA, Yost MG, Palcisko GJ. Time-location analysis for exposure assessment studies of children using a novel global positioning system instrument. Environmental Health Perspectives 2003;111(1):115-122.
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    R826886 (2000)
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    R831709 (2007)
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  • Journal Article Faustman EM, Lewandowski TA, Ponce RA, Bartell SM. Biologically based dose-response models for developmental toxicants:lessons from methylmercury. Inhalation Toxicology 1999;11(6-7):559-572. R826886 (2000)
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    Journal Article Faustman EM, Silbernagel SM, Fenske RA, Burbacher TM, Ponce RA. Mechanisms underlying children's susceptibility to environmental toxicants. Environmental Health Perspectives 2000;108(Suppl 1):13-21.
    abstract available   full text available
    R826886 (2000)
    R825173 (1999)
    R825173 (2000)
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  • Journal Article Faustman EM, Ponce RA, Ou YC, Mendoza MA, Lewandowski T, Kavanagh T. Investigations of methylmercury-induced alterations in neurogenesis. Environmental Health Perspectives 2002;110(Suppl 5):859-864. R826886 (2000)
    not available
    Journal Article Fenske RA, Kissel JC, Lu C, Kalman DA, Simcox NJ, Allen EH, Keifer MC. Biologically based pesticide dose estimates for children in an agricultural community. Environmental Health Perspectives 2000;108(6):515-520.
    abstract available   full text available
    R826886 (2000)
    R826886C004 (2001)
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  • Journal Article Fenske RA, Lu C, Simcox NJ, Loewenherz C, Touchstone J, Moate TF, Allen EH, Kissel JC. Strategies for assessing children’s organophosphorus pesticide exposures in agricultural communities. Journal of Exposure Analysis and Environmental Epidemiology 2000;10(6 Suppl 2):662-671.
    abstract available   full text available
    R826886 (2000)
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  • Journal Article Fenske RA, Kedan G, Lu C, Fisker-Andersen JA, Curl CL. Assessment of organophosphorous pesticide exposures in the diets of preschool children in Washington State. Journal of Exposure Analysis and Environmental Epidemiology 2002;12(1):21-28. R826886 (2000)
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    Journal Article Fenske RA, Lu C, Barr D, Needham L. Children's exposure to chlorpyrifos and parathion in an agricultural community in central Washington State. Environmental Health Perspectives 2002;110(5):549-553. R826886 (2000)
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    Journal Article Figueroa-Masot XA, Hetman M, Higgins MJ, Kokot N, Xia Z. Taxol induces apoptosis in cortical neurons by a mechanism independent of Bcl-2 phosphorylation. Journal of Neuroscience2001;21(13):4657-4667. R826886 (2000)
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    Journal Article Furlong CE, Li WF, Richter RJ, Shih DM, Lusis AJ, Alleva E, Costa LG. Genetic and temporal determinants of pesticide sensitivity: role of paraoxonase (PON1). NeuroToxicology 2000;21(1-2):91-100.
    abstract available  
    R826886 (2000)
    R826886C002 (2000)
    R826886C002 (2001)
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  • Journal Article Furlong CE. PON1 status and neurologic symptom complexes in Gulf War veterans. Genome Research 2000;10(2):153-155. R826886 (2000)
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    Journal Article Furlong CE, Li WF, Brophy VH, Jarvik GP, Richter RJ, Shih DM, Lusis AJ, Costa LG. The PON1 gene and detoxication. Neurotoxicology 2000;21(4):581-587.
    abstract available  
    R826886 (2000)
    R826886C002 (2001)
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  • Journal Article Furlong CE, Li W-F, Shih DM, Lusis AJ, Richter RJ, Costa LG. Genetic factors in susceptibility:serum PON1 variation between individuals and species. Human and Ecological Risk Assessment 2002;8(1):31-43.
    abstract available   full text available
    R826886 (2000)
    R826886C002 (2002)
  • Abstract: Ingenta Connect Abstract
    Exit
  • Other: Science Direct PDF
    Exit
  • Journal Article Furlong CE, Cole TB, Jarvik GP, Costa LG. Pharmacogenomic considerations of the paraoxonase polymorphisms. Pharmacogenomics 2002;3(3):341-348.
    abstract available  
    R826886 (2000)
    R826886C002 (2002)
  • Abstract from PubMed
  • Journal Article Garlock TJ, Shirai JH, Kissel JC. Adult responses to a survey of soil contact-related behaviors. Journal of Exposure Analysis and Environmental Epidemiology 1999;9(2):134-142. R826886 (2000)
    not available
    Journal Article Ghatan S, Larner S, Kinoshita Y, Hetman M, Patel L, Xia Z, Youle RJ, Morrison RS. p38 MAP kinase mediates bax translocation in nitric oxide-induced apoptosis in neurons. Journal of Cell Biology 2000;150(2):335-47. R826886 (2000)
    not available
    Journal Article Gohlke JM, Griffith WC, Bartell SM, Lewandowski TA, Faustman EM. A computational model for neocortical neuronogenesis predicts ethanol-induced neocortical neuron number deficits. Developmental Neuroscience 2002;24(6):467-477. R826886 (2000)
    not available
    Journal Article Goldstein BD, Erdal S, Burger J, Faustman EM, Friedlander BR, Greenberg M, Leschine TM, Powers CW, Waishwell L, Williams B. Stakeholder participation:Experience from the CRESP program. Environmental Epidemiology and Toxicology 2000;2:103-111. R826886 (2000)
    not available
    Journal Article Hetman M, Kanning KC, Smith-Cavanaugh JE, Xia Z. Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular-signal-regulated kinase and phosphatidylinositol-3 kinase. Journal of Biological Chemistry 1999;(274):22569-22580. R826886 (2000)
    not available
    Journal Article Hetman M, Cavanaugh JE, Kimelman D, Xia Z. Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. Journal of Neuroscience 2000;20(7):2567-2574. R826886 (2000)
    not available
    Journal Article Jarvik GP, Rozek LS, Brophy VH, Hatsukami TS, Richter RJ, Schellenberg GD, Furlong CE. Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype. Arteriosclerosis, Thrombosis, and Vascular Biology 2000;20(11):2441-2447. R826886 (2000)
    not available
    Journal Article Judd NL, Griffith WC, Ylitalo GM, Faustman EM. Alternative strategies for PCB risk reduction from contaminated seafood:options for children as susceptible populations. Bulletin of Environmental Contaminants and Toxicology 2002;69:847-854. R826886 (2000)
    not available
    Journal Article Koch D, Lu CS, Fisker-Andersen J, Jolley L, Fenske RA. Temporal association of children's pesticide exposure and agricultural spraying: Report of a longitudinal biological monitoring study. Environmental Health Perspectives 2002;110(8):829-833.
    abstract available  
    R826886 (2000)
    R825171 (2000)
    not available
    Journal Article Kornhauser JM, Cowan CW, Shaywitz AJ, Dolmetsch RE, Griffith EC, Hu LS, Haddad C, Xia Z, Greenberg M. CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events. Neuron 2002;34:221-233. R826886 (2000)
    not available
    Journal Article Lewandowski TA, Pierce CH, Pingree SD, Hong S, Faustman EM. Methylmercury distribution in the pregnant rat and embryo during early midbrain organogenesis. Teratology 2002;66(5):235-241. R826886 (2000)
    R825358 (Final)
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    Journal Article Li WF, Costa LG, Richter RJ, Hagen T, Shih DM, Tward A, Lusis AJ, Furlong CE. Catalytic efficiency determines the in- vivo efficacy of PON1 for detoxifying organophosphorus compounds. Pharmacogenetics 2000;10(9):767-779.
    abstract available  
    R826886 (2000)
    R826886C002 (2000)
    R826886C002 (2001)
  • Abstract from PubMed
  • Journal Article Little SA, Mirkes PE. Teratogen-induced activation of caspase-9 and the mitochondrial apoptotic pathway in early postimplantation mouse embryos. Toxicology and Applied Pharmacology 2002;181(2):142-151. R826886 (2000)
    not available
    Journal Article Lu CS, Knutson DE, Fisker-Andersen J, Fenske RA. Biological monitoring survey of organophosphorus pesticide exposure among preschool children in the Seattle metropolitan area. Environmental Health Perspectives 2001;109(3):299-303.
    abstract available  
    R826886 (2000)
    R825171 (2000)
    not available
    Journal Article Lu C, Fenske RA. Dermal transfer of chlorpyrifos residues from residential surfaces: comparison of hand press, hand drag, wipe, and polyurethane foam roller measurements after broadcast and aerosol pesticide applications. Environmental Health Perspectives 1999;107(6):463-467.
    abstract available   full text available
    R826886 (2000)
    R826886C004 (2001)
  • Abstract from PubMed
  • Associated PubMed link
  • Full-text: Environmental Health Perspectives Full Text
    Exit
  • Journal Article Lu C, Fenske RA, Simcox NJ, Kalman D. Pesticide exposure of children in an agricultural community: evidence of household proximity to farmland and take home exposure pathways. Environmental Research 2000;84(3):290-302.
    abstract available   full text available
    R826886 (2000)
    R826886C004 (2001)
  • Abstract from PubMed
  • Other: Science Direct PDF
    Exit
  • Journal Article Mendoza MAC, Ponce RA, Ou YC, Faustman EM. p21WAF1/CIP1 inhibits cell cycle progression but not G2/M-phase transition following methylmercury exposure. Toxicology and Applied Pharmacology 2002;178(2):117-125.
    abstract available   full text available
    R826886 (2000)
    R825358 (Final)
  • Abstract from PubMed
  • Full-text: Science Direct PDF
    Exit
  • Abstract: Science Direct
    Exit
  • Journal Article Mirkes PE, Little SA. Teratogen-induced cell death in postimplantation mouse embryos:differential tissue sensitivity and hallmarks of apoptosis. Cell Death and Differentiation 1998;5(7):592-600. R826886 (2000)
    not available
    Journal Article Mirkes PE, Cornel LM, Wilson KL, Dilmann WH. Heat shock protein 70 (Hsp70) protects postimplantation murine embryos from the embryolethal effects of hyperthermia. Developmental Dynamics 1999;214(2):159-170. R826886 (2000)
    not available
    Journal Article Mirkes PE, Little SA. Cytochrome c release from mitochondria of early postimplantation murine embryos exposed to 4-hydroperoxycyclophosphamide, heat shock, and staurosporine. Toxicology and Applied Pharmacology 2000;162(3):197-206.
    abstract available   full text available
    R826886 (2000)
    R826886C001 (2001)
  • Abstract from PubMed
  • Other: Science Direct PDF
    Exit
  • Journal Article Mirkes PE, Wilson KL, Cornel LM. Teratogen-induced activation of ERK, JNK, and p38 MAP kinases in early postimplantation murine embryos. Teratology 2000;62(1):14-25.
    abstract available  
    R826886 (2000)
    R826886C001 (2001)
  • Abstract from PubMed
  • Journal Article Mirkes PE. 2001 Warkany lecture:to die or not to die, the role of apoptosis in normal and abnormal mammalian development. Teratology 2002;65(5):228-239. R826886 (2000)
    not available
    Journal Article Moate TF, Lu C, Fenske RA, Hahne RMA, Kalman DA. Improved cleanup and determination of dialkyl phosphates in the urine of children exposed to organophosphorus insecticides. Journal of Analytical Toxicology 1999;23(4):230-236.
    abstract available  
    R826886 (2000)
    R826886C004 (2001)
    R825171 (1999)
    R825171 (2000)
  • Abstract from PubMed
  • Journal Article Moate TF, Furia M, Curl C, Muniz JF, Yu J, Fenske RA. Size exclusion chromatographic cleanup for GC/MS determination of organophosphorus pesticide residues in household and vehicle dust. Journal of the AOAC International 2002;85(1):36-43.
    abstract available  
    R826886 (2000)
    R826886C004 (2001)
    R826886C004 (2002)
  • Abstract from PubMed
  • Journal Article Namgung U, Xia Z. Arsenite-induced apoptosis in cortical neurons is mediated by c-Jun N-terminal protein kinase 3 and p38 mitogen-activated protein kinase. Journal of Neuroscience 2000;20(17):6442-6451. R826886 (2000)
    not available
    Journal Article Namgung U, Xia Z. Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases. Toxicology and Applied Pharmacology 2001;174(2):130-138.
    abstract available   full text available
    R826886 (2000)
    R826886C001 (2002)
  • Abstract from PubMed
  • Other: Science Direct PDF
    Exit
  • Journal Article Ou YC, Thompson SA, Ponce RA, Schroeder J, Kavanagh TJ, Faustman EM. Induction of the cell cycle regulatory gene p21 (Waf1, Cip1) following methylmercury exposure in vitro and in vivo. Toxicology and Applied Pharmacology 1999;157(3):203-212.
    abstract available   full text available
    R826886 (2000)
    R825358 (Final)
  • Abstract from PubMed
  • Full-text: Science Direct PDF
    Exit
  • Abstract: Science Direct
    Exit
  • Journal Article Ou YC, White CC, Krejsa CM, Ponce RA, Kavanagh TJ, Faustman EM. The role of intracellular glutathione in methylmercury-induced toxicity in embryonic neuronal cells. Neurotoxicology 1999;20(5):793-804.
    abstract available  
    R826886 (2000)
    R825358 (Final)
  • Abstract from PubMed
  • Journal Article Polifka JE, Faustman EM. Developmental toxicity:web resources for evaluating risk in humans. Toxicology 2002;173(1-2):35-65. R826886 (2000)
    not available
    Journal Article Ponce RA, Bartell SM, Wong EY, LaFlamme D, Carrington C, Lee RC, Patrick DL, Faustman EM, Bloger M. Use of quality-adjusted life year weights with dose-response models for public health decisions:A case study of the risks and benefits of fish consumption. Risk Analysis 2000;20:529-542. R826886 (2000)
    not available
    Journal Article Ponce RA, Wong EY, Faustman EM. Quality adjusted life years (QALYs) and dose-response models in environmental health policy analysis--methodological considerations. Science of the Total Environment 2001; 274(1-3):79-91. R826886 (2000)
    not available
    Journal Article Poser S, Impey S, Trinh K, Xia Z, Storm DR. SRF-dependent gene expression is required for PI3-kinase-regulated cell proliferation. EMBO Journal 2000;19(18):4955-4966. R826886 (2000)
    not available
    Journal Article Richter RJ, Furlong CE. Determination of paraoxonase (PON1) status requires more than genotyping. Pharmacogenetics 1999;9(6):745-753. R826886 (2000)
    not available
    Journal Article Sanga RN, Bartell SM, Ponce RA, Boischio AAP, Joiris CR, Pierce CH, Faustman EM. Effects of uncertainties on exposure estimates to methylmercury:A Monte Carlo analysis of biomarkers of exposure vs. predictive dietary estimation. Risk Analysis 2001;21(5):859-868. R826886 (2000)
    not available
    Journal Article Thompson B, Coronado G, Puschel K, Allen E. Identifying constituents to participate in a project to control pesticide exposure in children of farmworkers. Environmental Health Perspectives 2001;109(Suppl 3):443-448.
    abstract available   full text available
    R826886 (2000)
    R826886C003 (2001)
    R826886C003 (2002)
    R826886C004 (2001)
    R826886C004 (2002)
  • Abstract from PubMed
  • Full-text: Environmental Health Perspectives Full Text
    Exit
  • Other: Environmental Health Perspectives PDF
    Exit
  • Journal Article Thompson B, Coronado GD, Grossman JE, Puschel K, Solomon CC, Islas I, Curl CL, Shirai JH, Kissel JC, Fenske RA. Pesticide take-home pathway among children of agricultural workers: study design, methods, and baseline findings. Journal of Occupational and Environmental Medicine 2003;45(1):42-53.
    abstract available   full text available
    R826886 (2000)
    R826886C003 (2002)
    R831709 (2005)
    R831709 (2007)
    R831709C003 (2004)
  • Abstract from PubMed
  • Abstract: Lippincott, Williams & Wilkins-Abstract
    Exit
  • Journal Article Umpierre CC, Little SA, Mirkes PE. Co-localization of active caspase-3 and DNA fragmentation (TUNEL) in normal and hyperthermia-induced abnormal mouse development. Teratology 2001;63(3):134-143.
    abstract available  
    R826886 (2000)
    R826886C001 (2001)
    R826886C001 (2002)
  • Abstract from PubMed
  • Journal Article Vicini P, Pierce CH, Dills RL, Morgan MS, Kalman DA. Individual prior information in a physiological model of 2H8-toluene kinetics: an empirical Bayes estimation strategy. Risk Analysis 1999;19(6):1127-1134.
    abstract available  
    R826886 (2000)
  • Abstract from PubMed
  • Journal Article Wong EY, Shirai JH, Garlock TJ, Kissel JC. Adult proxy responses to a survey of children's dermal soil contact activities. Journal of Exposure Analysis and Environmental Epidemiology 2000;10(6 Pt 1):509-517. R826886 (2000)
    not available
    Journal Article Wong EY, Shirai JH, Garlock TJ, Kissel JC. Survey of selected activities relevant to exposures to soils. Bulletin of Enviornmental Contaminants and Toxicology 2000;65(4):443-450. R826886 (2000)
    not available
    Journal Article Yue TL, Ni J, Romanic AM, Gu JL, Keller P, Wang C, Kumar S, Yu GL, Hart TK, Wang X, Xia Z, DeWolf Jr. WE, Feuerstein GZ. TL1, a novel tumor necrosis factor-like cytokine, induces apoptosis in endothelial cells. Involvement of activation of stress protein kinases (stress-activated protein kinase and p38 mitogen-activated protein kinase) and caspase-3-like protease. Journal of Biological Chemistry 1999;274(3):1479-1486. R826886 (2000)
    not available
    Journal Article Zhu Y, Mao XO, Sun Y, Xia Z, Greenberg DA. p38 Mitogen-activated protein kinase mediates hypoxic regulation of Mdm2 and p53 in neurons. Journal of Biological Chemistry 2002;277(25):22909-22914. R826886 (2000)
    not available
    Supplemental Keywords:

    RFA, Health, Scientific Discipline, Geographic Area, Environmental Chemistry, Health Risk Assessment, Epidemiology, State, Risk Assessments, Biochemistry, Children's Health, health effects, pesticide exposure, developmental neurotoxicology, environmental health, developmental neurotoxicity, exposure, pesticides, developmental effects, epidemelogy, developmental toxicity, children, Human Health Risk Assessment, neurotoxicity, Washington (WA), human exposure, insecticides, children's vulnerablity, assessment of exposure, harmful environmental agents, epidemeology, environmental health hazard, children's environmental health, growth & development, agricultural community, developmental disorders, exposure assessment, human health risk, organophosphate pesticides

    Relevant Websites:

    http://depts.washington.edu/chc/ Exit

    Progress and Final Reports:
    Original Abstract

    Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
    R826886C001 Molecular Mechanisms of Pesticide-Induced Developmental Toxicity
    R826886C002 Genetic Susceptibility to Pesticides (Paraoxonase Polymorphism or PON1 Study)
    R826886C003 Community-Based Participatory Research Project
    R826886C004 Pesticide Exposure Pathways Research Project

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    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.

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