MERCURY A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES
J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS
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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1
Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Mercury: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-11072-5 1. Mercury-Popular works. I. Title.
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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.
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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on mercury. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.
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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.
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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health
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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON MERCURY .................................................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Mercury ........................................................................................ 4 E-Journals: PubMed Central ....................................................................................................... 60 The National Library of Medicine: PubMed ................................................................................ 73 Academic Periodicals covering Mercury.................................................................................... 116 CHAPTER 2. PATENTS ON MERCURY ............................................................................................ 117 Overview.................................................................................................................................... 117 Patents on Mercury ................................................................................................................... 117 Patent Applications on Mercury ............................................................................................... 120 Keeping Current ........................................................................................................................ 121 CHAPTER 3. BOOKS ON MERCURY ................................................................................................ 123 Overview.................................................................................................................................... 123 Book Summaries: Federal Agencies............................................................................................ 123 Book Summaries: Online Booksellers......................................................................................... 124 Chapters on Mercury ................................................................................................................. 124 CHAPTER 4. RESEARCHING MEDICATIONS .................................................................................. 127 Overview.................................................................................................................................... 127 U.S. Pharmacopeia..................................................................................................................... 127 Commercial Databases ............................................................................................................... 128 Researching Orphan Drugs ....................................................................................................... 128 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 133 Overview.................................................................................................................................... 133 NIH Guidelines.......................................................................................................................... 133 NIH Databases........................................................................................................................... 135 Other Commercial Databases..................................................................................................... 137 APPENDIX B. PATIENT RESOURCES ............................................................................................... 139 Overview.................................................................................................................................... 139 Patient Guideline Sources.......................................................................................................... 139 News Services and Press Releases.............................................................................................. 144 Newsletter Articles .................................................................................................................... 146 Finding Associations.................................................................................................................. 146 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 149 Overview.................................................................................................................................... 149 Preparation................................................................................................................................. 149 Finding a Local Medical Library................................................................................................ 149 Medical Libraries in the U.S. and Canada ................................................................................. 149 ONLINE GLOSSARIES................................................................................................................ 155 Online Dictionary Directories ................................................................................................... 156 MERCURY DICTIONARY........................................................................................................... 159 INDEX .............................................................................................................................................. 225
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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with mercury is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about mercury, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to mercury, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on mercury. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to mercury, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on mercury. The Editors
1
From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON MERCURY Overview In this chapter, we will show you how to locate peer-reviewed references and studies on mercury.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and mercury, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “mercury” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •
Urate and Calcium Stones: Picking Up a Drop of Mercury With One's Fingers? Source: American Journal of Kidney Diseases. 17(4): 426-430. April 1991. Summary: In this article, the evidence cited to support the suspicion that urinary urate is a predisposing factor in calcium oxalate (CaOx) stone formation is critically reviewed. Analysis of the relevant literature shows that speculation is based on the clinical impression that CaOx stone-formers appear to excrete more urate than do normal subjects, and that allopurinol reduces the rate of CaOx stone recurrences. The authors review the evidence for two theories that have dominated thinking in this area. The authors conclude that dissolved urate in urine, at normal physiological pH values, directly provokes CaOx crystal nucleation by the phenomenon of salting-out. 1 figure. 35 references. (AA-M).
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•
Mercury
Alzheimer's Disease, Dental Amalgam and Mercury Source: JADA: Journal of the American Dental Association. 130: 191-199. February 1999. Summary: Mercury (Hg) is a neurotoxin that may play a role in the pathogenesis of Alzheimer's disease (AD). This article describes an investigation that evaluated the relationship among AD, Hg levels in the brain, and exposure to dental amalgam. Dental amalgam is generally made up of approximately 50 percent Hg and releases low levels of Hg vapor making it a potential source of Hg for a large segment of the adult population. The authors studied 68 subjects with AD and 33 controls and ascertained dental amalgam status during life and at autopsy. They also determined Hg levels in multiple brain regions at autopsy and developed three dental amalgam index scores to use with the numbers of and surface area of dental amalgam restorations. The data showed no significant association of AD with the number, surface area, or history of dental amalgam restorations. The authors found no statistically significant differences in brain Hg level between subjects with AD and controls and conclude that Hg in dental amalgam restorations does not appear to be a neurotoxic factor in the pathogenesis of AD. This study demonstrated that brain Hg levels are not associated with current or previous dental amalgam history. 1 figure, 5 tables, 58 references (AA-M).
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Determination of Blood Mercury Concentrations in Alzheimer's Patients Source: Journal of Toxicology: Clinical Toxicology. 33(3): 243-247. 1995. Summary: This cross sectional study measured blood mercury in patients with diagnosed Alzheimer's disease (AD) as compared to people without known central nervous system and renal disorders. Researchers put all participants on a diet without any fish or seafood for a period of 3 months. At the end of this period, nursing staff collected 20 mL of blood from each participant for analysis. Blood mercury levels were determined by radiochemical neutron activation analysis, and selenium levels were determined through instrumental neutron activation analysis. Results suggest that blood mercury concentrations detected in subjects with AD were not statistically different than those of control subjects. Ratios of blood mercury to blood selenium also were determined, and no statistical difference was found between these two groups. 1 table, 23 references. (AA-M).
Federally Funded Research on Mercury The U.S. Government supports a variety of research studies relating to mercury. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to mercury.
2
Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).
Studies
5
For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore mercury. The following is typical of the type of information found when searching the CRISP database for mercury: •
Project Title: A NEW APPROACH FOR BIOMEDICAL IMAGING Principal Investigator & Institution: Winefordner, James D.; Chemistry; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2003; Project Start 01-APR-2000; Project End 28-FEB-2005 Summary: (Verbatim from the Applicant's Abstract): The goal of this research program is to develop an ultranarrowband imaging detector which can be used for in vivo biomedical imaging. The device will be capable of providing real time velocity information in images of arterial blood flow and compositional information via selective Raman imaging. Functioning in the near infrared, it will be capable of obtaining images at tissue depths of up to several cm. The extremely high spectral resolution is achieved by using an atomic vapor as the active sensing element. Laser pumped multi-step resonance ionization provides a near unity quantum efficiency and a large solid angle for optical collection, approaching 2m sr, is possible. When coupled with a microchannel plate amplification stage and a CCD detector, such devices offer unparalleled performance for specialized imaging applications. This research project will develop and optimize resonance ionization image devices using mercury and cesium as active elements. Studies will include the ionization spectroscopy of Hg and Cs, optimization of the detector response function (spectral bandwidth, quantum efficiency, spatial resolution), design and development of functional devices for imaging in biomedical systems and finally, applications to imaging of arterial blood flow in patients with peripheral vascular disease and the Raman imaging of arterial plaque. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A NOVEL SENSOR FOR TOTAL MERCURY IN FISH TISSUE Principal Investigator & Institution: Sarangapani, Shantha; Innovative Chemical/Environmental Tech Environmental Technologies, Inc Norwood, Ma 02062 Timing: Fiscal Year 2002; Project Start 15-MAY-2002; Project End 14-NOV-2003 Summary: (Applicant's abstract): There is a current need to monitor food and fish tissue samples for total mercury and other toxic metals, onsite, using portable instruments. Currently the determination of mercury requires complex instrumentation, which is beyond the means of potential users. Moreover, the samples have to be shipped to an accredited lab with typical turnaround times of 10 days or more. The fish tissue sample preparation involves a tedious procedure of hot, concentrated, acid digestion. This Phase I research will examine the feasibility of using screen-printed electrodes with dendrimer-gold nano composite for the "in situ" anodic stripping voltammetric analysis (ASV) of total mercury in fish tissue samples. Alternate methods of sample preparations will be tested. The dendrimeric structure due to its hydrophilicity and density of the molecular arms are expected to prevent the influx of large organic and biomolecules. With the advent of nano scale molecular reservoirs such as the dendrimers, and excellent opportunity exists to test the idea of rapid chemical sensing in a biomimetric manner. The screen-printed electrodes will be fabricated at the New Mexico State University Microfabrication Labs using our proprietary formulations. A thorough characterization of the proposed electrode, using certified fish tissue samples for "proof of the concept" will be carried out. The product from this research would be well suited
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Mercury
for portable automated commercial instruments such as the MetalyzerTM, SA-5000 or Tracelab TM systems using the current EPA protocols for mercury analysis by stripping methods. The cost of the proposed electrode strips is comparable to the current cost of electrodes. The ASV has remarkably low detection limits and can analyze a variety of toxic metals due to the unique stripping potentials for each metal. PROPOSED COMMERCIAL APPLICATION: The proposed electrodes strips have a massive potential for use in field tests for agriculture and food industry. Water quality as well as for routine monitoring of industrial waste water treatment facilities to monitor low levels of toxic mercury and other medals. Multianalyte sensing capabilities could be incorporated. The US and European market for the proposed sensors is projected to be close to 400 million dollars by the year 2005. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ACETYLCYSTEINE: AN ANTIDOTE FOR METHYLMERCURY POISONING Principal Investigator & Institution: Simmons-Willis, Tracey A.; Environmental Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 29-FEB-2004 Summary: (provided by applicant): Chronic methylmercury (MeHg) exposure and toxicity continues to be of environmental concern. MeHg can cause severe neurological and developmental defects. Removal of MeHg from the body is the only effective remedy. Our recent work has shown that MeHg-L-cysteine is a substrate for the human amino acid transporters, LAT1 and LAT2, facilitating MeHg's rapid distribution in the body (Simmons-Willis et al. Biochem. Journal, in press). Recent work from our laboratory (Ballatori et al. Env. Health Perspectives, 106(5):267-271, 1998) demonstrated that N-acetylcysteine (NAC) added to drinking water of mice greatly increases the excretion of MeHg from the body. The molecular mechanism for this process was recently explored (Koh et al. Mol. Pharmacol., in press). This study indicates that a major renal organic anion transporter, Oat1, plays a significant role in MeHg removal from the kidney. The overall goals of the proposed work are to examine the mechanisms of MeHg elimination and determine the role of NAC as an antidote. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ACTIVITIES NEPHROTOXIN
OF
BILIVERDIN
REDUCTASE-EFFECT
OF
Principal Investigator & Institution: Maines, Mahin D.; Professor; Biochemistry and Biophysics; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 06-DEC-1985; Project End 31-AUG-2005 Summary: Biliverdin reductase (BVR) is a unique dual pH/cofactor-dependent enzyme that catalyzes the last step in the heme degradation pathway (i,e reduction of biliverdin to bilirubin). Biliverdin, the substrate for BVR, is generated, with carbon monoxide (CO), in the course of heme degradation by the stress/heat shock family of proteins: heme oxygenase (HO)-1 and HO-2. CO functions as NO. BVR is the ultimate regulator of heme metabolism, in that, biliverdin regulates HO activity in vivo. Biliverdin is also a liver tumor promoter and inhibits human Herpes virus-6 replication and HIV-1 proliferation. Bilirubin is a potent antioxidant; low levels of serum bilirubin are associated with increased risk of coronary artery heart disease and retinopathy of prematurity. We are the only laboratory in the country actively pursuing molecular toxicology research on BVR that, by virtue of being an -SH-dependent enzyme, is a
Studies
7
target for environmental agents and nephrotoxins. We have now discovered that BVR is a kinase and a protein kinase C (PKC)-interacting and -activating protein and translocates into the nucleus in response to nephrotoxins: such as mercury, bromobenzene and bacterial endotoxins (LPS) as well as in cancerous transformation. In addition, in human kidney tumors, ischemic rat brain and kidneys, and in kidneys of rats exposed to nephrotoxins, BVR levels are increased. Also, the ability to produce biliverdin in advanced human prostate tumor cells is increased. PKCs play an important role in the field of cancer research and are key components of cellular response to oxidative stress. Based on the ability of BVR to activate PKC, it is likely that BVR plays a significant role in modulating a multitude of cellular functions including cell growth and differentiation. The Specific Aims of the proposed studies are 1) To further characterize BVR for molecular properties and requirements of kinase and reductase activities. 2) To further investigate BVR/PKC interaction. 3) To characterize BVR interactive proteins in the cells and to identify the proteins that interact with BVR under normal and oxidative stress conditions, such as exposure to nephrotoxic agents and cancer. Also, to explore the nuclear function of BVR in the context of HO-1's response to oxidative stress. 4) To isolate the human BVR gene, characterize its promoter region and analyze its regulation by various toxins and effector agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ADVANCED TECHNOLOGY
MERCURY
FREE
RESTORATIVE
ALLOYS
Principal Investigator & Institution: Lashmore, David S.; Synergy Innovations, Inc. Lebanon, Nh 03766 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-MAR-2003 Summary: (provided by applicant): This application summarizes a new approach to Dental restoration using semi-automatic condensation of a silver containing slurry with new type of impacting Dental instrument. This instrument is unique in that it combines the functions of impact condensation, slurry feeding and waste liquid removal in a single ergonomic handpiece. This instrument employs the available expertise in magnetic design and consists of a solenoid driven impactor whose impact energy and frequency are independently selectable. Some design considerations are presented here. This instrument is unique in that it acts as both repetitive impact condensation device and a waste-solution removal device and will enable, for the first time, a mercury-free silver alloy to be used in commercial Dentistry. The driving forces for this program are the demonstrated superior properties of the pure silver restoration and the need to achieve reproducibly high restoration density independent of the skill of the operator and consistent with patient comfort. An additional obvious benefit of this mercury-free restoration is safety for Dentists and the environment. Using these mercury free alloys, Dentists would no longer need to handle, breath, or dispose of mercury containing waste products. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AFRICAN HYPERTENSION
AMERICAN
STUDY
OF
KIDNEY
DISEASE
&
Principal Investigator & Institution: Randall, Otelio S.; Professor of Medicine; Medicine; Howard University Washington, Dc 20059 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 30-JUN-2003
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Mercury
Summary: Hypertension is considered one of the major causes of end stage renal disease (ESRD) in the general population, and the number one cause in African Americans. Despite the availability of potent antihypertensive drugs, the number of hypertensive African Americans progressing to ESRD continues to rise. This disproportionately high prevalence of ESRD in African Americans cannot be explained by the higher prevalence of hypertension. Whether this is due to more susceptibility of the kidney of African Americans to hypertensive injury or due to concurrent existence of unidentified renal factors is not known. There is preliminary evidence suggesting that antihypertensive drugs may retard the progression of hypertensive renal disease, but no clinical trial has been conducted to test this hypothesis in African Americans. This proposed multi-center project is designed to study the following: if the pathological lesion in "hypertensive renal disease" is purely a result of persistent hypertension; if one anti-hypertensive drug is better than another in terms of preservation of renal function; and the level of blood pressure suitable for the survival of the kidney. Hypertensive African Americans, 18-70 years of age with no other known disease that can affect the kidney, will be screened for blood pressure qualification, and will undergo glomerular filtration rate (GFR) tests. Those who qualify, based on blood pressure levels and the GFR results will then be randomized in a double-masked fashion to one of the three major antihypertensive classes (converting enzyme inhibitor, calcium channel blocker, or beta blocker) and to one of two pressure levels: mean blood pressure greater than 92 millimeter of mercury (mmHg), or 102 to 107 mmHg. Other antihypertensive drugs will be added to keep the blood pressure at the desired level. The blood pressure of the randomized subjects will then be monitored on a monthly basis and compliance to medication(s) will be checked at the same time. Their renal function will also be tracked with periodic GFR tests throughout the study period, which will last approximately four years. All data will be collected and sent to the Data Coordinating Center (DCC) for analyses and interpretation. The goal of the African American Study of Kidney Disease and Hypertension (AASK) full- scale trial is to better understand the physiopathology of hypertensive renal disease in an effort to develop guidelines to prevent the increasing prevalence of ESRD in African Americans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AFRICAN AMERICAN STUDY OF KIDNEY DISEASE AND HYPERTENSIO Principal Investigator & Institution: Toto, Robert D.; Professor of Internal Medicine; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 30-JUN-2003 Summary: (taken directly from the application) The African-American Study of Kidney Disease and Hypertension (AASK) is a multi-center, randomized double-blind controlled trial designed to determine whether long-term lowering of blood pressure to two different levels of mean arterial pressure (MAP) less than 92 versus 102-107 millimeters of mercury (mmHg) with a calcium channel blocker, an angiotensin converting enzyme inhibitor, or a beta-blocker can prevent deterioration in renal function in African-Americans with hypertensive nephrosclerosis and chronic renal insufficiency. The full-scale trial will involve 900 adult African-Americans of both sexes with hypertensive nephrosclerosis and a baseline glomerular filtration rate of 25-70 milliliters per minute per 1.73 meters squared. The study is designed to answer two key questions in this study population: 1) can long-term blood pressure control (102-107 mmHg) slow progression of renal disease; and 2) is strict blood pressure control (mean arterial pressure less than (92 mmHg) more effective than usual control (102-107 mmHg)
Studies
9
in preserving renal function? During the pilot study for AASK, the applicant reports that they have recruited and randomized 11 patients over a six and one- half month period. Eight of these patients have undergone successful renal biopsy. They report a 100 percent retention of randomized subjects with no serious adverse events thus far, and that the participants have been 100 percent compliant with protocol procedures and greater than 90 percent compliant with medications and have been able to achieve the blood pressure goal level in 9 out of 11 patients thus far. The team of investigators appears to have worked cooperatively with the data coordinating center and has been able to transmit data in a timely and efficient manner. The investigators report preliminary studies which suggest that the AASK protocol is acceptable and well tolerated by participants, and is feasible for application to the full- scale trial. The trial is unique because for the first time: 1) African- Americans with a single progressive renal disease will be studied in a multi-center trial; 2) the relative efficacy and safety of a calcium channel blocker, an angiotensin-converting enzyme inhibitor and a betablocker for preserving renal function will be assessed; and 3) investigators will obtain an assessment of the best methodologies for recruitment and retention of this population in a long-term clinical trial. The goal of the study is to provide a means by which the incidence of end stage renal disease can be effectively forestalled or prevented altogether in this high-risk population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALTERED GENE EXPRESSION BY MGCL2 IN TARGET ORGANS Principal Investigator & Institution: Mansour, Mahmoud M.; Tuskegee University Tuskegee Institute, Al 36088 Timing: Fiscal Year 2002; Project Start 01-JUN-1978; Project End 30-JUN-2006 Summary: (provided by applicant): Mercury is a significant contaminant of the environment and poses a serious systemic toxicity risk to humans, animals, and the aquatic food web. Published data indicate that inorganic mercury accumulates and induces strong renal toxicity and adversely affects spermatogenesis and fertility in male rats. Such effects underscore the threat to human health because mercury is ubiquitously present in the environment and is widely used in the industry. Hence, the long-term goal of this project is to understand how environmental exposure to mercury induces toxicity. The specific aim of this application is to determine the effects of mercuric chloride on differential gene expression in the kidney and two male reproductive organs. We hypothesize that the toxicity of mercuric chloride largely results from the loss of control of differential gene expression. This hypothesis is formulated based on published reports which indicated that mercuric chloride induced apoptosis, and transcriptional activation and/or suppression of several genes in the kidney, and based on our initial studies, that mercuric chloride down-regulated estrogen receptor alpha mRNA expression in the efferent ductules, and induced apoptosis in the testis of adult male rats. To test this hypothesis, we will test the effects of oral administration of mercuric chloride on differential expression of genes (repressed versus induced) using differential display PCR and relevant toxicity endpoints. Using micro-array, we will determine the effects of mercuric chloride on unique genes related to phase I and II metabolism, apoptosis, inflammation, DNA damage, cell transport, and oxidative stress in the kidney, efferent ductules, and the testis. Semi-quantitative PCR will be used to determine the effect on steroid hormone receptors (estrogen and androgen) in the efferent ductules and testis. The proposed experiments will identify pathways by which mercuric chloride causes toxicity, and identify molecular
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Mercury
biomarkers for exposure to inorganic mercury. Such approach will be valuable in the identification of new drug targets for treatment of mercuric chloride. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AUTOANTIGEN CLEAVAGE DURING APOPTOSIS AND NECROSIS Principal Investigator & Institution: Casiano, Carlos A.; Associate Professor; Medicine; Loma Linda University Loma Linda, Ca 92350 Timing: Fiscal Year 2002; Project Start 01-APR-1998; Project End 31-MAR-2003 Summary: Apoptosis and necrosis are two fundamental cell death pathways that may be the end result of response to physiologic activators, physical trauma, or environmental toxins and chemicals. These modes of cell death are associated with a wide range of human pathological conditions, including systemic autoimmunity, cancer, AIDS, and neurodegenerative disorders. Emerging evidence indicates that activation of cysteine proteases of the ICE/CED-3 family is a central mechanism in the execution of apoptosis. Although the mechanisms driving cell necrosis are still obscure, recent studies also point to activation of proteases as a key event in this cell death process. However, the nature of these proteases and their substrates remains largely unknown. Using human antinuclear autoantibodies as probes, we have demonstrated that both apoptosis and necrosis involve the selective, but distinctively different, proteolytic cleavage of a specific set of nuclear protein autoantigens. It is proposed that different proteolytic mechanisms underlie the execution of apoptosis and necrosis, and that dissecting these mechanisms should be helpful for establishing a clear distinction between these cell death processes. The broad, long term objectives of this research is to dissect and differentiate events associated with these mechanisms. Three specific aims are proposed to test our hypothesis. (1) To use a panel of antinuclear autoantibodies where the antigen targets are well characterized nuclear proteins, as probes to define and differentiate patterns of substrate proteolysis associated with Fas-mediated apoptosis and with necrosis induced by the toxic xenobiotic mercury. (2) To characterize proteolytic activities involved in the cleavage of specific autoantigens in both cell death processes. Cell free systems of apoptosis and necrosis will be used in these studies to analyze the inhibition profile of autoantigen cleavage and to determine whether activation of ICE/CED-3 proteases occurs during necrosis. The ability of purified proteases to cleave specific antigens and the identify of specific cleavage sites will be also investigated. (3) To exploit the differences in autoantigen cleavage observed in apoptosis and necrosis for the development of monoclonal antibodies which react specifically with epitopes associated with either apoptotic or necrotic cell death. It is anticipated that these studies should contribute to enhancing our understanding of cell death in molecular terms and establishing additional criteria that would help to differentiate between apoptosis and necrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CASA PIA STUDY OF DENTAL AMALGAMS IN CHILDREN Principal Investigator & Institution: Derouen, Timothy A.; Professor and Chairman; Dental Public Health Sciences; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 30-SEP-1996; Project End 31-JUL-2006 Summary: This proposed project is a competing renewal to the Casa Pia Study of the Health Effects of Dental Amalgams in Children, a cooperative agreement funded by the National Institute of Dental and Craniofacial Research as one component of the
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Children's Amalgam Trial. The University of Washington is the applicant organization with a subcontract to the University of Lisbon, Portugal, as the clinical site. The Study is a randomized clinical trial in which 507 children of ages 8 to 10 at entry with substantial dental treatment needs and who are students of Casa Pia Schools in Lisbon, have been randomized to the use or non-use of mercury amalgams in their dental treatment. The project is currently in the second year of follow-up, with 95% retention thus far in the study. Mercury exposure is measured from urine samples at baseline and follow-up exams at one-year intervals. Four primary endpoints are monitored from baseline at one-year intervals: three neurobehavioral (combined assessments from neurobehavioral tests for attention, memory, and motor/visual motor domains) and one neurological (nerve conduction velocities). Secondary endpoints include two renal (two Glutathione Transferase isozymes specific to renal tubular damage), a clinical neurological exam, porphyrin profiles, urinary albumin levels and the occurrence of sentinel health events. Comparison between the two groups of children for the four primary endpoints are made annually using a combination of Hotelling's T2 test and an extension of the O'Brien test for multiple endpoints adapted for longitudinal data and multiple tests over time. If significant adverse health effects of exposure to dental amalgams (or to the alternative dental material, composites) are detected during the course of the study, the children treated with the harmful material will be re-treated with the other. The purpose of this renewal application is to extend the funding period to cover the seven years of follow-up proposed in the original grant. We intend to continue collecting data in the study po2ulation for the same four endpoints currently in use, with the same methodology as during the initial 3 follow-up years, utilizing the same personnel currently employed. in obtaining the data, with only some minor revisions in the neurobehavioral tests to account for the maturation of the test, population. The introduction of some new secondary endpoints is proposed. This international collaboration has resulted in a study team that has demonstrated its expertise in all relevant areas and its capability to successfully complete this important study and settle the controversy over whether amalgam has even any subtle health effects associated with its use in the most susceptible population, children. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CERAMIC WHISKER REINFORCEMENT OF DENTAL COMPOSITE RESINS Principal Investigator & Institution: Xu, Huakun; American Dental Association Foundation Chicago, Il 60611 Timing: Fiscal Year 2002; Project Start 15-SEP-1998; Project End 31-JUL-2004 Summary: Concerns about mercury in dental amalgam have created a need to extend the use of composite resins to posterior applications. However, current composites are not suitable for large stress-bearing applications involving cusps due to excessive wear and fracture. The glass fillers in resins provide only limited reinforcement because of their brittleness and rounded shapes. Preliminary studies with ceramic whiskers having high strength and elongated shapes showed a two-fold increase in composite strength and toughness, and promising results on polishability, water absorption and strength durability, enamel wear and esthetics. The goals of this project are to i) to investigate the whisker reinforcement mechanisms for dental resins; ii) to understand the key microstructural and processing variables that determine reinforcing efficacy; and iii) to develop optimized prototypes. To accomplish these goals, the following studies are proposed: (1) the effects of whisker size and aspect ratio will be evaluated to improve reinforcing efficacy and filler packing; (2) dental silicate fillers will be fused onto the
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Mercury
individual whiskers to minimize whisker entanglement, enhance silanization, and improve retention in matrix by providing rougher whisker surfaces; (3) the effect of whisker content will be systematically investigated on composite mechanical properties and reinforcing mechanisms, translucency, color and depth of cure; (4) the mechanical and physical properties of water-aged composites will be characterized to identify the reinforcing mechanisms and the key microstructural parameters, and this knowledge will be used as feedback to improve microstructural design; (5) three- and two-body enamel against composite wear will be evaluated to understand the effect of whiskers on wear mechanisms and wear rates; and (6) the whisker composite will be veneered with conventional composites and the effect of whisker reinforcement on properties of the final restoration will be evaluated by using Hertzian cyclic fatigue and flexural tests. This project will provide (1) an understanding of the effects of whisker- glass filler hybridization and fusion on composite properties; (2) mechanisms of whisker reinforcement for dental resins; (3) guidelines on microstructural design and processing of whisker-reinforced composite resins; and (4) a basis for the next generation of high performance composite resins for dental restorative and potentially other biomedical applications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CEREBELLAR NEUROTOXICITY
GABA-A
AS
TARGETS
OF
MERCURY
Principal Investigator & Institution: Atchison, William D.; Professor; Pharmacology and Toxicology; Michigan State University 301 Administration Bldg East Lansing, Mi 48824 Timing: Fiscal Year 2002; Project Start 27-MAR-2002; Project End 28-FEB-2006 Summary: (provided by applicant): Methylmercury (MeHg) is a prominent environmental neurotoxicant which is responsible for several episodes of mass poisoning, and remains an environmental concern today- especially among populations with high dietary intake of fish. Cerebellar-based ataxia is a hallmark sign of MeHg poisoning. The granule cell layers of the cerebellum are particularly sensitive to MeHg especially during development. The primary objective of this project is to understand the basis for this unique sensitivity of cerebellar granule neurons to MeHg. Recent data from our lab suggest that GABAA receptor function is highly sensitive to inhibition by MeHg-particularly in cerebellar granule cells. Inasmuch as these cells express a unique phenotype of GABAA receptor, we propose to investigate the hypothesis that disruption of inhibitory GABAergic transmission at granule neuron synapses is uniquely sensitive to MeHg due to the presence of a unique phenotype of GABAA receptor expressed in these cells. GABAA receptors are heteropentameric membrane proteins consisting of combinations of several distinct subunits. They are responsible for mediating fast inhibitory synaptic transmission in the mammalian CNS by gating entry of Cl-. Typically, GABAA receptors consist of combinations of alpha, beta, gamma, or delta, subunits; multiple isoforms of many of the subunits exist. Subunit composition has been shown to affect pharmacological sensitive of GABAA receptors. Only granule cells contain the a6 subunit which lacks benzodiazapine agonist sensitivity; they frequently also contain the delta subunit. These two subunits also confer sensitive to Zn2+, which is released in cerebellar granule neurons by MeHg, and which inhibits GABAA receptor function. The approach will involve application of whole cell voltage clamp techniques to native cerebellar neurons in culture or in isolated slice to compare the sensitivity of the GABAA receptors to MeHg in granule cells and purkinje cells, which lack the alpha6 and delta subunit. Additionally, heterologous expression of cloned GABAA receptors in HEK 293 cells will be used to examine specifically the role
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that the alpha6 and delta subunit play in sensitivity to MeHg. Specific aims are to determine 1) Does MeHg differentially affect the functional properties of GABAA receptors in granule cells and Purkinje cells? If so, by what mechanism(s)? 2) Are recombinant GABAA receptors containing alpha6 subunits more sensitive to MeHg than those containing alpha1, subunits, and what if any role do other subunits, specifically gamma or delta subunits, play in MeHg-induced effects on GABAA receptors? 3) Are the effects of MeHg on cerebellar synaptic transmission, particularly inhibitory synaptic transmission, altered by knockout or mutation of genes for subunits such as the alpha6 or delta subunit which are unique to cerebellar granule cells? Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DENTISTRY
CLINICAL
EPIDEMIOLOGY OF
MERCURY
EXPOSURE
IN
Principal Investigator & Institution: Martin, Michael D.; Director; Oral Medicine; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-AUG-2004 Summary: The proposed Mentored Patient-Oriented Research Career Development Award would provide Michael D. Martin the opportunity to devote a minimum of 85 percent of his time to preparation toward becoming qualified as an independent clinical researcher. Dr. Martin is a dually trained dentist - epidemiologist on a tenure-track faculty position in the Department of Oral Medicine at the University of Washington's School of Dentistry with an adjunct appointment in the Department of Dental Public Health Sciences. Dr. Martin's focus of interest within epidemiology is on the epidemiology of mercury exposures from dental sources. He conducts clinical research that is of practical significance to dentistry/medicine and has theoretical importance to our understanding of the mechanisms-by which elemental mercury exposures affect the human. Prior projects have examined the risk factors for mercury exposure among dentists; the neurobehavioral effects of mercury among dentists; biomarkers for lowlevel mercury exposure; the effects of ethanol on mercury absorption in humans, and the relationship between dental metals (i.e., mercury amalgam) and mucosal disease, among others. He is currently participating in related projects including a large clinical trial of the effects of mercury amalgam in children; a study of the neurobehavioral effects of low-level mercury exposure among dentists; further study of biomarkers for mercury exposure, and in this application proposes a five year-plan which includes both didactic as well as practical clinical research training experiences directed toward his research plan involving continued work in the area of epidemiology of mercury exposure from dental sources and carrying it further forward into the area of autoimmune mucosal diseases and their relationship to dental metals. His primary goal is to achieve sufficient training and experience to become an independent researcher. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE SURVEILLANCE OF OCCUPATIIONAL HEALTH IN NEW YORK Principal Investigator & Institution: Gelberg, Kitty H.; Bureau of Environmental Health 547 River St Troy, Ny 12180 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: New York, with the assistance of the SENSOR and ABLES programs, has established a structure for occupational disease surveillance and follow-up in New York State. Provisions of the New York State (NYS) Public Health Law mandate the reporting
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of a number of occupational conditions in NYS. Since 1981, the New York State Department of Health, Bureau of Occupational Health (BOH) has operated a Heavy Metals Registry for the reporting of cases of lead, mercury, arsenic, and cadmium poisoning, and an Occupational Lung Disease Registry for the reporting of cases of work related lung disease. Since 1991, BOH has operated a Pesticide Poisoning Registry and receives reports from healthcare providers of suspected pesticide poisonings. While all of these registries are operational, the extent to which there is active surveillance, with aggressive case finding, ascertainment and follow-up, varies. There are a number of reasons for this variability, including differences in how the diseases are diagnosed and the different reporting sources for the various registries. Additional federal resources will permit us to build upon existing reporting laws and infrastructure and expand current surveillance efforts to help us achieve the NIOSH standards for a model core surveillance system for a range of significant occupational conditions. We propose to conduct general surveillance of existing databases available to the Department of Health such as death certificates and hospital discharge data to assist with documenting the magnitude of occupational injuries and illnesses in New York, and to identify trends and industries occupations at elevated risk. Focus will be primarily upon upgrading our Occupational Lung Disease Registry; however, we will also focus more attention on conducting educational outreach for all of our registries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--NEUROTOXICOLOGY Principal Investigator & Institution: Cory-Slechta, Deborah; Professor; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2003 Summary: The basic research goal of the Neurotoxicology Core is to understand the nature of the effects of environmental chemicals on nervous system function, their consequences over the life span, the mechanisms by which these effects are produced, and the risks they pose to human health. A key element in this goal is to understand the contribution of combined effects of genetic predisposition and environmental chemical exposures on neurological dysfunctions, particularly as it relates to neurodegenerative diseases. The research within this Core involves both basic neuroscience research and neurotoxicology and explores the age spectrum from development to aging. The general theme of the Core is that both early and late stages of life represent periods of potentially enhanced vulnerability to neurotoxic effects. Embedded within this theme is the emerging concept that neurological effects of toxic exposures may not manifest themselves until years after exposure, and that toxicants interact in complex ways with the genetic composition of the human to influence the nature and severity of functional outcomes. The Core consists of seven members of which five are continuing members and two are new members, drawn from the Departments of Neurology, Environmental Medicine, and Obstetrics-Gynecology. The members have been chosen on the basis of their productivity, commitment to multidisciplinary neuroscience research, and experience in areas of thematic interest to the Center. In the past funding period, the Core was called the Neurobehavioral Toxicology Research Core to reflect its focus on behavioral toxicology. The present Core, now named the Neurotoxicology Core, has expanded its focus to include a broader spectrum of issues, ranging from mechanisms, genetic predispositions and contributions to human diseases, and human risk assessment, while maintaining strengths in behavioral toxicology. Of particular note are the inclusions of sophisticated molecular biology and neurochemistry into the battery of Core skills. The present proposal continues to advance the traditional strengths in metal
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neurotoxicology, while venturing into several new initiatives as well. A major change is the plan to recruit a new faculty to replace Dr. Cory-Slechta as Core Director. The individual will be selected to further integrate the neurotoxicology and basic neuroscience. Another change is the new initiative into molecular neuroscience and genetic-toxicant interactions, which has been developed through the addition of Drs. Federoff and Gelbard to the Core. This group will focus particularly on toxicant contributions to the development of neurodegenerative disorders. The major thematic areas of the Neurotoxicology Core are the following: 1) Neurochemical mechanism of lead-induced behavioral toxicology (Cory-Slechta). This project examines the neurochemical and neuroanatomical sites through which lead alters neural functions. Work had identified neurotransmitter alterations, neural pathways and behavioral deficits in animal models of lead exposure. 2) Environmental neurotoxicant genetic interaction: murine model (Federoff). This work would test the hypothesis that neurotoxicants interact with yet uncharacterized genetic determinants to produce selective vulnerability. Focusing on the dopamine transporter (DAT), the principal investigator will engineer a population of dopaminergic neurons overexpressing DAT by means of a somatic mosaic approach and directed gene expression to compare the responses of expressing and non-expressing neurons in the same animal. 3) A murine model of genetic and environmental neurotoxicant action (Richfield). This project would look at the role of the alpha-synuclein gene and gene product in Parkinson?s disease using the somatic mosaic approach. Studies will determine whether mice overexpressing alpha-synuclein show an enhanced dopaminerigic vulnerability when exposed to low does of paraquat. 4) Genotype and phenotype of autism spectrum disorders (Rodier). This project will continue the investigator?s work linking injury during early development (as early as neural tube fusion) and specific genes with the development of the autism disorders. Work will continue to examine the valproic acid model of brain injury (which phenocopies some aspects of autism spectrum disorders), and the toxicant involves the HOX family of genes. 5) The role of inflammation and oxidative stress in human immunodeficiency virus type 1- associated neurologic disease (Gelbard). This project has been investigating how HIV type 1 results in neurotoxicity. In the proposed research, the principal investigator would examine the role of tumor necrosis factor alpha (TNF-a) and platelet activating factor (PAF) in the pathogenesis of neurotoxicity. Future plans include the development of TNF-overexpressing mice by somatic mosaic methods, and subsequent examination of neuronal death under various challenges. 6) Neurobehavioral and developmental effects of methylmercury exposure (Clarkson). This represents a continuation of the large human study of methylmercury exposure via fish and its consequences on development. This is one of two definitive epidemiological studies of human methylmercury exposure, which will continue and expand during the next funding period. In addition, the project director will continue his involvement in a prospective study of mercury exposure via dental amalgams. 7) Persisting functional consequences of neurotoxicant exposure during early development (Weiss). This work will continue studies of developmental exposure to several classes of toxicants. These will include solvents in addition to ongoing work in metals, endocrine disruptors (e.g., TCDD), and drugs (e.g., cocaine). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEATH IMMUNOTOXICITY
RECEPTOR
SIGNALING
AND
MERCURY
Principal Investigator & Institution: Mccabe, Michael J.; Associate Professor; Environmental Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627
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Mercury
Timing: Fiscal Year 2003; Project Start 03-APR-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Mercury (Hg) toxicity affects numerous organ systems including the immune system. The immunotoxicity of Hg is complex, in that, immunosuppression and immunostimulation occur upon exposure to this metal, and both of these outcomes may have adverse effects on human health. This proposal is constructed around the conceptual framework that Hg is an environmental agent that contributes to the development of autoimmune disease. Animal studies have established a connection between experimental exposure to Hg and lupus-like autoimmune disease. Similarly, case reports demonstrating a correlation between accidental Hg exposure and either the onset or the severity of autoimmune disease symptoms support a link between Hg intoxication and the etiology of human autoimmune disease. From this perspective, Hg is one of the few suspected environmental agents where a link between exposure to the agent and autoimmune disease has been indicated. However, the mechanisms whereby Hg initiates, potentiates, or perpetuates autoimmune responses have not been established. In particular, there is a dearth of information regarding the biochemical/molecular mechanisms involved in Hg-mediated autoimmunity. Accordingly, the long-term goal of our research is to identify biochemical/molecular mechanisms underlying Hg-mediated autoimmune disease. Non-cytotoxic concentrations of Hg2+ interfere with the CD95 apoptotic signaling pathway and also interfere with protein tyrosine mediated signaling. Thus, this proposal focuses on lymphocyte signaling pathways involved in the regulation of CD95-induced apoptosis. Since CD95-mediated apoptosis is involved in the regulation of peripheral tolerance, dysregulation of CD95-signaling by Hg may be one factor (together with other genetic or environmental factors) that contributes to autoimmune disease. The hypothesis guiding this proposal is that Hg2+ disrupts CD95-mediated apoptosis, which contributes to a breakdown in peripheral tolerance to autoantigens leading to the development of autoimmune disease. Using cell lines and human CD4+ lymphoblasts this hypothesis will be tested by determining; 1) the influence of Hg2+ on components of the CD95 apoptotic machinery and 2) the effects of Hg2+ on non-receptor kinase signaling pathways that may interact with and regulate CD95. A third specific aim will employ a mouse model to test whether disruption of CD95-mediated cell death by Hg intoxication in vivo enhances the survival of autoreactive T lymphocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DENTAL AMALGAMS & NEUROPSYCHOLOGICAL FUNCTION Principal Investigator & Institution: Factor-Litvak, Pam R.; Associate Professor; Columbia University Health Sciences Po Box 49 New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DEVELOPMENTAL EFFECTS OF METHYLMERCURY Principal Investigator & Institution: Burbacher, Thomas M.; Associate Professor; Environmental and Occupational Health Studies; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 10-DEC-1986; Project End 31-JAN-2004 Summary: The broad, long-term objective of this research is to provide a comprehensive evaluation of the effects of in utero methylmercury (MeHg) exposure at different stages of the life span of Macaca fascicularis monkeys. Previous studies of Macaca fascicularis
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exposed in utero to MeHg and controls have described effects during infancy, adolescence and adulthood. The primary goal of the initial 2 years of this application is to continue to assess the effects of in utero MeHg exposure on the adult functioning of these same monkeys using operant procedures that are also sensitive to changes in function typically observed in primates during aging. The primary goal of the last 3 years is to provide housing and care for these monkeys to keep the group together for later studies of MeHg and aging effects on performance. The specific aims of the studies proposed in years 1 and 2 of this application are to test the following hypotheses: (1) In utero MeHg exposure results in high-frequency hearing impairment in adult Macaca fascicularis. MeHg exposed monkeys will exhibit elevated hearing thresholds at frequencies of 25,000 Hz and above on a test of pure tone detection, (2) In utero MeHg exposure slows the speed of information processing in adult Macaca fascicularis. MeHg exposed monkeys will exhibit increased reaction times compared to controls on a Choice Reaction Time test as the number of response choices increase, and (3) In utero MeHg exposure results in impaired spatial memory in adult Macaca fascicularis. MeHg exposed monkeys will exhibit significant decreases in % correct responses on an Indirect Delayed Response test that uses irrelevant stimuli to interfere with attention and memory. During years 3-5, the specific aims of the project are to: (1) provide housing and care for these monkeys to keep the group together for further studies after this grant period, and (2) evaluate visuospatial orientation, fine and gross motor coordination, menstrual cyclicity, and the general health status of these monkeys using observational techniques in order to detect gross changes related to MeHg exposure and/or aging. Future studies will be aimed at evaluating the effects of in utero MeHg exposure on the performance of these monkeys at a stage in the life span when impaired functions due to aging are typically observed. Exposure of the fetus to MeHg via maternal consumption of contaminated fish continues to be a major public health concern. The major focus of the public health concern regarding MeHg exposure is the possible immediate and longterm effects of in utero exposure on postnatal growth and function. This study was designed to complete our evaluation of the effects of in utero MeHg exposure on adult primate sensory and N cognitive functioning, while providing baseline data for studies of these monkeys after this grant period, when the monkeys are 19 years of age and over. The proposed studies take full advantage of the history of these monkeys and represents the best possible use of this valuable resource. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DEVICE FOR RAPID SCREENING OF PLASMA HOMOCYSTEINE Principal Investigator & Institution: Davies, Malonne I.; Bioanalytical Systems, Inc. (Basi) 2701 Kent Ave West Lafayette, in 479061389 Timing: Fiscal Year 2002; Project Start 01-SEP-1999; Project End 31-MAY-2003 Summary: (Applicant's abstract) The objective of the proposed work is fast, sensitive integrated clinical analyzers for the diagnosis of two metabolism disorders, homocysteinuria and phenylketonuria (PKU). The assays are based on microchip capillary electrophoresis with electrochemical detection. This format has several advantages, including small sample requirements, fast analysis times, and inexpensive manufacture of multiple chips. Electrochemical detectors are ideally suited to microchip CE because they can be easily miniaturized and integrated into the analysis system. Monitoring phenylanlanine concentration in plasma samples of newborns is required by law. The current assay has a relatively high rate of failure (1:70) and requires instrumentation frequently not found in-house, especially in small hospitals. High levels of homocysteine in plasma has been associated with cerebrovascular, peripheral
18
Mercury
vascular, and coronary heart diseases. The assay for homocysteine involves online reduction of the protein-bound homocysteine with tris-(2-carboxyethyl)phosphine, separation by electrophoresis, and electrochemical detection at a gold/mercury electrode. Phenylalanine will be determined in plasma in a similar manner using a copper electrode. The chips will be used with a portable analysis system based on a battery-powered high voltage power supply, miniaturized potentiostat, and integrated data analysis system. The chips we develop will generate a foundation for other clinical assays based on electrochemical detection. PROPOSED COMMERCIAL APPLICATION: The current trend in clinical analysis is away form large centralized labs and toward point of care testing. Thus, a compact device for performance of assays for homocysteine and other clinically relevant animo acids in the clinic or physician's office has large commercial potential. Recently, the American Heart Association recommended homocysteine screening for patients at risk for cardiovascular disease. This should lead to a large demand for accurate and cost-effective assays for homocysteine similar to the current cholesterol screening assays. The development of a small, fast and reliable assay for phenylalanine in blood will make it possible to test infants quickly and accurately for PKU. The electrochemical based clinical analyzers developed here will provide a format that can be used for the development of a number of other assays for clinically important analytes. What is demonstrated with homocysteine and phenylalanine is just the beginning of a large array of clinical analyzers based on microchip CEEC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DIGITAL X-RAY IMAGED BASED ON HGL2 POLYCRYSTALLINE FILMS Principal Investigator & Institution: Iwanczyk, Jan S.; Vice President; Photon Imaging, Inc. 19355 Business Center Dr, Ste 8 Northridge, Ca 91324 Timing: Fiscal Year 2002; Project Start 01-JUL-2000; Project End 31-AUG-2003 Summary: The goal of this proposal is to develop a new detector technology for digital x-ray imaging based on HgI2 polycrystalline films coupled to large area flat panel amorphous silicon (a-Si:H) thin-film transistor (TFT)-addressed readout arrays. This novel imaging detector when optimized will provide order of magnitude improvements in sensitivity to x-rays and superior spatial resolution compared to detectors utilizing scintillating phosphors coupled to a-Si:H readout arrays. The increased sensitivity of the detector will allow for a ten-fold reduction in radiation dose to a patient for an equivalent quality image. The enhancement of the spatial resolution will have a direct impact on the quality of the image, which has paramount importance in many medical diagnostic procedures such as mammography. In addition, digital capabilities will allow for convenient film-less image acquisition, retrieval, and storage. Digital image processing, computer-assisted diagnosis, and the ability to provide real time images have distinct advantages in many medical diagnostics. During Phase I of this proposal we developed techniques for highly controlled growth of polycrystalline HgI2 films in terms of their thickness, sizes of the polycrystalline grains, uniformity of layers and good electrical properties. In the Phase II effort we will finalize the HgI2 film development and construct x-ray imaging detectors using initially small commercial flat panel a-Si:H readouts (approximately 2"x2"). Then we will scale up the film growth equipment and construct large area (approximately 14" x 17") x-ray imaging detector. The film growth process will be optimized for low production cost. This new x- ray imager will be characterized and compared with current commercial detectors in terms of spatial resolution, gain, linearity, noise, uniformity, and detective quantum efficiency. The imaging capabilities will be tested in our laboratory and at UCLA School of
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Medicine with the use of slits and phantoms. PROPOSED COMMERCIAL APPLICATIONS: There is a strong interest in application of digital radiographic detectors for medical diagnostic applications, nondestructive evaluation of materials, xray diffraction of biological and other material samples, and astronomical observations. Conservative estimates are that in the medical area alone there are over 600 x-ray images produced per 1000 population per year. The proposed detectors will be highly attractive to this enormous commercial market segment due to the order of magnitude performance improvements that they will offer. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: DISRUPTION OF LYMPHOCYTE SIGNAL TRANSDUCTION BY HG+2 Principal Investigator & Institution: Rosenspire, Allen J.; Scientist; Biological Sciences; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 19-FEB-2002; Project End 30-NOV-2006 Summary: (provided by applicant): Mercury is a widespread environmental contaminant whose toxic potential to the nervous and immune systems is well known. Surprisingly little is known about its molecular mechanism of action. While high level exposure is no longer common, large segments of the population currently absorb low (.10 ug/day) levels of mercury as a result of ubiquitous environmental factors, including air, food, water, and dental amalgam. For about 3 percent of the population with no known special risk factors, blood levels of mercury exceed 0.25 uM. 4 percent of the population exceed 0.125 uM mercury in urine, with the highest concentrations reported in individuals with no known special risk factors to be about 1 uM. Preliminary and recently published results from our laboratories support our hypothesis that concentrations of inorganic mercury in the range of 0.1- 1.0 uM may directly impair immune system homeostasis, and contribute to autoimmune disease by interfering with protein tyrosine phosphorylation (PTK)mediated signal transduction, implying that substantial numbers of individuals may unknowingly be at risk. In this proposal it is our objective to critically and comprehensively test our hypothesis in several different cell systems relevant to autoimmune disease. In particular, we will test mercury's ability to interfere with antigen receptor mediated and P1K-dependent signal transduction and proliferative control in established T and B cell lines, as well as in freshly isolated human peripheral blood lymphocytes. We will also examine the effect that low concentrations of mercury have on antigen receptor mediated apoptosis in lymphocytes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EFFECTS RELATED BIOMAKERS OF TOXIC EXPOSURES Principal Investigator & Institution: Checkoway, Harvey L.; Professor; Environmental and Occupational Health Studies; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 30-SEP-1987; Project End 31-MAR-2005 Summary: This proposal is for a 5-year competing renewal of the UW Superfund Basic Research Program Project. The theme of this Program Project is that biomarkers measured in accessible tissues are predictive of: a) toxicant exposures; b) early indicators of damage; and/or c) unusual susceptibility to toxic agents that commonly occur at hazardous waste sites. The UW Program Project includes 9 research projects (7 biomedical, 2 bioremediation), an administrative core, a service core dedicated to molecular biology assays, a training core and an outreach core. The research projects can
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be divided into four subgroups: 1) laboratory-based development of sensitive biomarkers of adverse effects and disease susceptibility; 2) applications of biomarkers to human populations. 4) biomarker measurements of environmental chemical toxicity in terrestrial and aquatic species and 4) biomarker applications for hazardous waste remediation. Multi-disciplinary cross-project interactions among toxicologists, epidemiologists, molecular biologists and environmental engineers (e.g. measurement of the same biomarkers in various projects to assess a range of effects) have been carefully devised to maximize scientific yield. This project will continue investigations in glutathione biosynthesis biomarker as indicators of oxidative to assess a range of effects) have been carefully devised to maximized scientific yield. This project will continue investigations on glutathione biosynthesis biomarker as indicators of oxidative stress; characterization of novel biomarkers and applications to epidemiologic investigations are newer directions. This project will continue investigations on glutathione biosynthesis biomarker as indicators of oxidative stress; characterization and novel biomarkers and applications to epidemiologic investigations are newer directions. This project will identify genetic polymorphisms of porphyrin synthesis enzymes, and test these as markers of neurobehavioral toxicity in mercury-exposed humans. This project is a new project that will investigate paraoxonase phenotype and genotype inter-relations, with applications to experimental toxicokinetic studies in rats and to an epidemiologic studies of parkinsonism. This project continues to examine epidemiologically the interactions between environmental toxicants and genetic polymorphisms of enzymes involved in xenobiotic activation and detoxification. This project will apply a physiologically-based toxicokinetic model derived from controlled human exposures to organic solvents to characterize determinants of uptake, metabolism, and excretion. This project continues to examine biomarkers of exposure and effect in wildlife residing near or in hazardous waste sites. This project is a continuing study of DNA oxidative damage in fish from polluted and reference water sites. This project will continue to evaluate the effectiveness of genetically- engineered trees for bioremediation of toxic chemicals (e.g., trichloroethylene). This project will involve laboratory and field genetically-engineered trees for bioremediation of toxic chemicals (e.g., trichloroethylene). This project will involve laboratory and field experiments of in situ engineering methods for bioremediation of chlorinated aliphatic toxicants. The Administrative Core, directed by the Program Director, will oversee all major budgetary and personnel aspects of the program project, will coordinate multidisciplinary interactions among research projects and cores, and will assume responsibility for information dissemination and technology transfer. The Program Director will be advised by the Deputy Director, an Internal Executive Committee comprised of research and core directors, and an External Science Advisory Board that includes distinguished environmental scientists from academia and governmental agencies. The Bioanalytical Core will offer genotyping and/or DNA sequencing services to the research projects. The Training Core will ensure that doctoral students and postdoctoral fellows in Environmental Health and Civil Engineering receive crossdisciplinary classroom and research experience. The Outreach Core, which is a new intuitive for this Program Project, will be dedicated to the development of instructional materials relevant to hazardous waste contaminant issues, with an emphasis on biomarker applications for toxicity assessment and bioremediation. The principal audiences for outreach will be K-12 school teachers, health and engineering professionals, and interested community residents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENHANCED DENTAL AMALGAM TRAP Principal Investigator & Institution: Turchi, Craig S.; Ada Technologies, Inc. 8100 Shaffer Pky, Ste 130 Littleton, Co 801274124 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 29-SEP-2004 Summary: (provided by the applicant) Surveys conducted by municipal wastewater treatment plants across the country have concluded that 10 percent to over 70 percent of the mercury reaching the plants comes from dental offices. These findings, combined with increasingly stringent regulations on mercury discharges, have placed pressure on the dental profession to reduce their discharges of mercury-bearing amalgam. The objective of this project is to enhance the performance of sedimentation-type amalgam separators by controlling the water chemistry within the separator. Dental wastewater contains mercury in three general forms: large particles of amalgam, fine particles of amalgam, and dissolved mercury. Simple sedimentation traps can capture the large particles and many of the fine particles. However, colloidal particles and dissolved mercury can still exceed discharge limits. At present, expensive and maintenanceintensive adsorbents are needed to achieve discharge concentrations in the low-ppb range. During Phase I ADA Technologies showed that safe, inexpensive additives could be used within a sedimentation device to minimize the release of dissolved mercury. In Phase II, we intend to document the effective use of optimized versions of these additives at several dental clinics, demonstrating ppb-level mercury concentrations at costs significantly below those for adsorbent-based processes. PROPOSED COMMERCIAL APPLICATION: US dentists use some 45 tons of mercury per year for new amalgam fillings. European, Canadian, and some US municipalities limit dental office discharges of mercury. New regulations are pending across North America. Successful completion of this project would yield a low-cost, field-proven amalgam trap, capable of reducing mercury in dental wastewater to the low parts-per-billion range. ADA Technologies will utilize its network of partners and experience in dental waste treatment and equipment manufacturing to bring this enhanced trap rapidly to the marketplace. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ENVIRONMENTAL IMPACT ON THE EMBRYONIC MTDNA GENOME Principal Investigator & Institution: Knudsen, Thomas B.; Professor; Pathology, Anat/Cell Biology; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 01-FEB-1998; Project End 31-MAY-2005 Summary: (Applicant's Abstract): The long-term goal is to understand teratogenic mechanisms at the molecular level. Microphthalmia is a low level effect of methylmercury exposure and can be induced in early mouse embryos to reflect clinical disorders seen in exposed children. Gene expression arrays will be used to recognize fundamental biomolecular parameters that describe critical events leading to this malformation. Preliminary studies identified a critical response involving p53 tumor suppressor (Trp53) and peripheral-type benzodiazepine receptor (Bzrp), leading to the proposed focus on metabolic and regulatory pathways controlling mitochondrial DNA (mtDNA) genome expression. During neurulation, the embryo shifts from an anaerobic (glycolytic) to aerobic (oxidative) metabolism. This diauxic shift requires mtDNA genome expression and, consequently, a tight link between morphogenetic and metabolic differentiation. The investigators hypothesize control by retrograde regulation
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whereby a signal started in the mitochondrion leads to an adaptive response in the nucleus to culminate in mtDNA biogenesis. Four specific aims will begin to trace this pathway at the molecular level. Specific Aim 1, a teratological study, will determine exposure-disease relationships for methylmercury-induced microphthalmia with respect to dose response, genetic susceptibility (Trp53), and therapeutic intervention (Bzrp). Specific Aim 2 will use expression microarrays to profile gene expression for developing eye across the critical period of vulnerability (days 8-10 of gestation). Specific Aim 3 will profile exposure-disease pathways for methylmercury-induced microphthalmia with respect to dose-response, genetic susceptibility, and therapeutic intervention. Specific Aim 4 entails pathway integration to confirm cellular activities as they change over time. At ends we expect to build a searchable transcriptome database for the developing eye and a platform with which to discover the cellular pathways that hypothetically define a temporal sequence in dysmorphogenesis induced with methylmercury and other environmental toxicants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AMALGAMS
EVALUATION
OF
MERCURY
RELEASE
FROM
DENTAL
Principal Investigator & Institution: Okabe, Toru; Regents Professor & Chair; Biomaterials Science; Texas A&M University Health Science Ctr College Station, Tx 778433578 Timing: Fiscal Year 2002; Project Start 15-SEP-2000; Project End 31-AUG-2004 Summary: (adapted from the Investigator's abstract): The primary goal of this application is to determine the mechanism by which changes in the formulation of the alloy reduce mercury (Hg) release from dental amalgam. A series of alloys will be prepared to test specific hypotheses about the effect of palladium (Pd) additions, silver (Ag) and tin (Sn) ratio, and copper (Cu) content. The composition of the pre-trituration alloys and the resulting amalgams will be evaluated by scanning electron microprobe and scanning transmission electron microscopy with micro-diffraction and XEDA to correlate changes in Hg release with microstructure. In addition, amalgams will be prepared from alloys mixed with pure Hg and indium (In)-Hg alloys to further understand the effect of indium on reducing Hg release, and to produce minimal Hgreleasing formulations. The investigators expect to identify commercially viable amalgams with reduced Hg vaporization during setting and after abrasion, and reduced Hg dissolution. The physical properties of these amalgams will be evaluated to verify that they are adequate for clinical use and to further describe the effect of composition on properties. Dynamic dissolution into both neutral saline and acidic solutions, as well as thermal properties, will be assessed to correlate the stability of the amalgams with composition. Finally, Hg release from aged amalgams will be correlated with changes in their microstructure. The primary hypothesis is that Hg release will be minimized when the Ag-Hg matrix phase of amalgam is most effectively stabilized and its surface oxidized and that this is accomplished by maximizing the amount of Sn present in the gamma one matrix. There are four aims: to identify the mechanism by which additions of Pd, changes in the Cu content, and alterations in the Ag and Sn concentrations in dental amalgam alloy affect the vaporization of Hg; to identify the mechanism by which those variables affect the dissolution of Hg from dental amalgam; to verify that the new alloys produce amalgams with acceptable physical properties; and to verify that the amalgams are stable over a two year period. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: EVOLUTION OF ANTIBIOTIC RESISTANCE PLASMIDS Principal Investigator & Institution: Top, Eva M.; University of Idaho Moscow, Id 838443020 Timing: Fiscal Year 2002; Project Start 23-FEB-2002; Project End 31-JAN-2007 Summary: Plasmids play a central role in the spread of resistance among bacterial species thereby decreasing the effectiveness of various chemotherapeutic agents for the treatment of infectious diseases. They carry genes that encode essential functions, such as replication, maintenance and transfer, as well as a variety of accessory functions, such as antibiotic resistance determinants. The objective of the proposed research is to obtain a more systematic and comprehensive understanding of plasmid evolution through experimental evolution studies. The specific aims are 1) To assess the tempo and mechanisms of plasmid evolution during vertical transmission in a single host as compared to vertical and horizontal transmission among phylogenetically distinct hosts, in the presence of selective pressure; 2) To characterize and compare the genetic and phenotypic changes that occur during such experimental plasmid evolution; 3) To test the ability of various algorithms to accurately reconstruct the true phylogenies of independently evolved plasmids and specific genes. The broad host range Inc-1beta plasmid pB10, which encodes resistance to four antibiotics and mercury, will be experimentally evolved in replicate cultures of three genetically distinct hosts (Escherichia coli, Pseudomonas aeruginosa, Burkholderia cepacia) as previously described in studies of microbial evolution. Plasmid evolution in one single host will be compared with evolution in alternating hosts, and in each case plasmids evolved for differing periods of time will be characterized. Phenotypic changes will be characterized by examining the effect of the evolved plasmid on host fitness and by assessing differences in the stability and broad host range characteristics of the evolved and ancestral plasmids. Genetic changes that may account for the observed phenotypic differences will be identified by characterizing macroscale and microscale variations in the evolved replicons. Possible correlations between phenotypic changes and genotypic variations will be examined. In addition an experimental plasmid phlogeny will be constructed that has the same topology as described in Project 1 (Experimental Evolution of Viruses), and which will permit us to test the ability of currently available algorithms and those developed in Project 4 to accurately reconstruct the phylogeny of a BHR plasmid that evolves in more than one genetic background. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: FETAL EXPOSURE TO ENVIRONMENTAL TOXINS & INFANT OUTCOME Principal Investigator & Institution: Ostrea, Enrique M.; Pediatrics; Wayne State University 656 W. Kirby Detroit, Mi 48202 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The exposure of pregnant women to environmental toxins is of major concern because of their potential harm on the fetus. However, the detection of fetal exposure to environmental toxins still remains a major challenge. We propose that meconium analysis is a promising tool to meet this challenge. Aims: (1) To compare the prevalence and amount of fetal exposure to environmental toxins through the analysis of meconium, cord blood and neonatal hair and to determine the degree of agreement among these three methods, (2) to determine the relationship between the prevalence and amount of maternal exposure to environmental toxins during pregnancy, as determined by serial analyses of maternal hair and blood, to the
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prevalence and amount of fetal exposure to environmental toxins as determined by meconium, cord blood and neonatal hair analyses, and (3) to compare adverse immediate (birth weight, length, head circumference, gestational age) and long term (postnatal growth and neurobehavioral development up to 2 yrs from enrollment) outcomes that are associated with antenatal exposure to environmental toxins as determined by maternal blood, maternal hair, meconium, cord blood and neonatal hair analyses. Study design: Pregnant women (n=750) will be recruited, at midgestation, from the Outpatient Clinic of the Bulacan Provincial Hospital, Philippines and their blood and hair will be obtained at the time of recruitment and at delivery. Umbilical cord blood, meconium and neonatal hair will also be obtained. The samples will be analyzed, by atomic absorption spectrometry, for lead, mercury and cadmium and by gas chromatography/mass spectrometry for the following pesticides and their metabolites: propoxur, transfluthrin, Malathion, DDT, chlorpyrifos, bioallethrin, pretilachlor, lindane, cyfluthrin and cypermethrin. Pertinent maternal and infant data will be obtained after birth. The infants will be subsequently followed up at scheduled intervals for 2 years, to study their physical growth and neurobehavioral development using a battery of tests. Data analysis: The relationship between the presence/amount of environmental toxins in meconium, maternal blood, maternal hair, cord blood or neonatal hair to the immediate and two year outcome in the infants will be studied, while controlling for potential confounders. The presence/amount of environmental toxins in maternal blood, hair, cord blood, meconium and neonatal hair will be also evaluated to determine which substrate (s) provide(s) the best index of exposure for a given toxin. Expected benefits: Meconium analysis may provide a powerful tool to study the prevalence and degree of fetal exposure to environmental toxins and its associated adverse effects. This project can also serve as a model for the study of environmental pollutant problems during pregnancy at a local, national or global level. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENERAL CLINICAL RESEARCH CENTER-FORSYTH DENTAL INSTIT Principal Investigator & Institution: Flier, Jeffrey S.; Professor; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-DEC-1977; Project End 30-NOV-2004 Summary: (provided by applicant): The BIDMC's GCRC proposes to form a satellite with the Forsyth Dental Institute (FDI), a world class center for clinical investigation of oral disease. This proposal describes a spectrum of investigations involving treatment of periodontal diseases, development of a vaccine for dental caries, testing of mercury amalgam toxicity and investigation of oral cancer. Sixteen projects are described that will be conducted at the Satellite Center that include microbiology, microbial genomics, microbial taxonomy, immunology and toxicology as these studies relate to conditions of oral health and disease and microbial biofilms. The proposed Satellite Center will include a Dental Clinic Core, a Laboratory Core and Biostatistics/Informatics support. Specific areas of investigation in this application include: 1) comparison of conventional and antibacterial_supplemented treatments of periodontal disease; 2) investigation of means to prevent periodontal disease; 3) studies on familial distribution of oral bacteria; 4) studies of oral bacteria as examples of naturally occurring biofilms; 5) studies of oral bacteria that penetrate cells; 6) studies of the ways in which early lesions of periodontal disease are initiated; 7) investigation of the microbiology associated with oral cancer; 8) studies that contribute to the development of a dental caries vaccine; 9) investigation of the potential toxicity of mercury amalgams; and 10) studies of the uncultivable bacteria
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of the oral cavity with planned development of a microbial microarray for oral bacteria identification. In addition to the planned studies as outlined above, a strategy to create bi_directional linkage between parent and satellite GCRC's is described in which a dental facility will be established at the BIDMC GCRC to be staffed by Forsyth personnel. Through this facility, it is envisioned that future studies on the oral health effects of systemic disease, and the converse, effects of systemic disease on oral health will be investigated. It is also stressed that this facility will encourage closer affiliation between the Joslin Diabetes Center (JDC) Satellite and the Forsyth Satellite. It is envisioned that this proposal will expand the research horizon of the FDI and contribute new technology to the research of the parent. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GENETIC /ENVIRONMENTAL INFLUENCES ON SLE NEPHRITIS Principal Investigator & Institution: Gilkeson, Gary S.; Professor; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2007 Summary: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies and immune complex mediated glomerulonephritis. African- Americans have a three-fold increased incidence of SLE, more frequently develop nephritis, more frequently progress to renal failure and have increased mortality compared to whites. The worse prognosis in African-Americans may represent a generalized predisposition towards renal failure following any renal injury rather than being lupus specific. Environmental exposures such as smoking and exposure to occupational or environmental agents (i.e., lead, mercury, silica) may affect the development and progression of lupus nephritis. Our central hypothesis is that there are specific genetic factors that interact with environmental exposures leading to progressive renal disease in African-Americans with lupus. The Carolina Lupus Study includes 265 SLE patients who were diagnosed between January 1, 1995 and July 31, 1999. This cohort of patients provides an opportunity to examine renal disease and its progression in African- American SLE patients matched with appropriate population based controls. The Gullah population lives on the sea islands of South Carolina. They are unique in their genetic homogeneity with minimal Caucasian admixture (
