DRINKING WATER 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 2003 by ICON Group International, Inc. Copyright 2003 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., 1960Drinking Water: 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: 0-597-83655-8 1. Drinking Water-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.
Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail:
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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 drinking water. 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 DRINKING WATER .................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Drinking Water............................................................................. 5 E-Journals: PubMed Central ....................................................................................................... 61 The National Library of Medicine: PubMed ................................................................................ 64 CHAPTER 2. NUTRITION AND DRINKING WATER ........................................................................ 151 Overview.................................................................................................................................... 151 Finding Nutrition Studies on Drinking Water ......................................................................... 151 Federal Resources on Nutrition ................................................................................................. 157 Additional Web Resources ......................................................................................................... 157 CHAPTER 3. ALTERNATIVE MEDICINE AND DRINKING WATER .................................................. 159 Overview.................................................................................................................................... 159 National Center for Complementary and Alternative Medicine................................................ 159 Additional Web Resources ......................................................................................................... 162 General References ..................................................................................................................... 164 CHAPTER 4. DISSERTATIONS ON DRINKING WATER .................................................................... 165 Overview.................................................................................................................................... 165 Dissertations on Drinking Water .............................................................................................. 165 Keeping Current ........................................................................................................................ 169 CHAPTER 5. PATENTS ON DRINKING WATER............................................................................... 171 Overview.................................................................................................................................... 171 Patents on Drinking Water........................................................................................................ 171 Patent Applications on Drinking Water.................................................................................... 209 Keeping Current ........................................................................................................................ 246 CHAPTER 6. BOOKS ON DRINKING WATER .................................................................................. 247 Overview.................................................................................................................................... 247 Book Summaries: Federal Agencies............................................................................................ 247 Book Summaries: Online Booksellers......................................................................................... 248 The National Library of Medicine Book Index ........................................................................... 271 Chapters on Drinking Water ..................................................................................................... 273 CHAPTER 7. MULTIMEDIA ON DRINKING WATER ....................................................................... 275 Overview.................................................................................................................................... 275 Bibliography: Multimedia on Drinking Water .......................................................................... 275 CHAPTER 8. PERIODICALS AND NEWS ON DRINKING WATER .................................................... 277 Overview.................................................................................................................................... 277 News Services and Press Releases.............................................................................................. 277 Newsletter Articles .................................................................................................................... 279 Academic Periodicals covering Drinking Water........................................................................ 280 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 281 Overview.................................................................................................................................... 281 U.S. Pharmacopeia..................................................................................................................... 281 Commercial Databases ............................................................................................................... 282 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 287 Overview.................................................................................................................................... 287 NIH Guidelines.......................................................................................................................... 287 NIH Databases........................................................................................................................... 289 Other Commercial Databases..................................................................................................... 294 APPENDIX B. PATIENT RESOURCES ............................................................................................... 295 Overview.................................................................................................................................... 295
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Patient Guideline Sources.......................................................................................................... 295 Finding Associations.................................................................................................................. 303 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 305 Overview.................................................................................................................................... 305 Preparation................................................................................................................................. 305 Finding a Local Medical Library................................................................................................ 305 Medical Libraries in the U.S. and Canada ................................................................................. 305 ONLINE GLOSSARIES................................................................................................................ 311 Online Dictionary Directories ................................................................................................... 311 DRINKING WATER DICTIONARY ......................................................................................... 313 INDEX .............................................................................................................................................. 395
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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 drinking water 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 drinking water, 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 drinking water, 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 drinking water. 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 drinking water, 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 drinking water. The Editors
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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON DRINKING WATER Overview In this chapter, we will show you how to locate peer-reviewed references and studies on drinking water.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and drinking water, 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 “drinking water” (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: •
Geographical Relation Between Alzheimer's Disease and Aluminium in Drinking Water Source: Lancet. 1(8629): 59-62. January 14, 1989. Summary: The study reported in this journal article examined the geographical relation between Alzheimer's disease and aluminum in drinking water in Great Britain. In a survey of 88 county districts in England and Wales, rates of Alzheimer's disease in people under the age of 70 years were estimated from the records of the computerized tomographic scanning units that served these districts. Rates were adjusted to compensate for differences in distance from the nearest scanning unit and for differences in the size of the population served by the units. Aluminum concentrations in water over the past 10 years were obtained from water authorities and water companies. The risk of Alzheimer's disease was 1.5 times higher in districts where the
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Drinking Water
mean aluminum concentration exceeded 0.11 mg/l than in districts where concentrations were less than 0.01 mg/l. There was no evidence of a relation between other causes of dementia, or epilepsy, and aluminum concentrations in water. 13 references. (AA-M). •
Making Sure Your Drinking Water is Safe Source: Digestive Health and Nutrition. 4(3): 14-17. May-June 2002. Contact: Available from American Gastroenterological Association. 7910 Woodmont Avenue, 7th Floor, Bethesda, MD 20814. (877) DHN-4YOU or (301) 654-2055, ext. 650. Email:
[email protected]. Summary: The United States water supply is arguably the safest in the world, but spot contaminations occur from time to time and cause gastrointestinal illness. This article describes the causes of and solutions to these occasional incidents and helps readers find out how to ensure the safety of their own water supply. Topics include the presence of minerals and trace elements in groundwater, water treatment methods, microbial agents that are resistant to existing treatment methods, problems with the parasites Cryptosporidium parvum and Giardia lamblia, the bacterium Escherichia coli, Brainerd diarrhea, the possibility of Helicobacter pylori being transmitted through water, special precautions for people with compromised immune systems, home treatment systems, gastrointestinal symptoms that should trigger a visit to a health care provider, and information for people who get their water from a private well. The article concludes with a list of five websites and the telephone number of the Safe Drinking Water Hotline (800-426-4791) for readers wanting to obtain additional information on water safety.
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Dental Caries Among 10-to-14-year-old children in Ugandan Rural Areas with 0.5 and 2.5 mg fluoride per Liter in Drinking Water Source: Clinical Oral Investigations. 5(1): 45-50. March 2001. Contact: Available from Springer-Verlag, New York Inc. Journal Fulfillment Services Department, P.O. Box 2485, Secaucus, NJ 07096-2485. Fax (202) 348-4505. Summary: This article reports on a study that reported on dental caries among Ugandan children residing in rural areas with either a low or high fluoride concentration in the drinking water, and to assess factors associated with caries. A random sample of 481 children aged 10 to 14 years was selected from Mpondwe (n = 81) and Kyabayenze (n = 82) in the Kasese district with 0.5 milligrams and from the Mutolere and Kagera (n = 163) and Kabindi (n = 155) in Kisoro with 2.5 milligrams of fluoride per liter in the drinking water. The children were examined for caries (cavities) using the DMFT (decayed, missing, filled teeth) index, as described by the World Health Organization in 1987. The mean DMFT was 0.34 in the in the whole material. In one low fluoride area, Kyabayenze, all children were caries-free compared to 75 to 86 percent in the other areas. In Kyabayenze, tea with sugar was taken significantly less frequently than in the other low-fluoride area. In the high-fluoride district, age and consumption of tea with sugar were positively and significantly correlated with caries. Multivariate analyses showed age to be the only significant risk indicator. 3 tables. 34 references.
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Acidic Drinking Water and Risk of Childhood-Onset Type 1 Diabetes Source: Diabetes Care. 25(9): 1534-1538. September 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org.
Studies
5
Summary: This article reports on a study undertaken to estimate the associations of acidity and concentration of selected minerals in household tap water with the risk of type 1 diabetes. The authors designed a population-based case control study with 64 cases of type 1 diabetes and 250 randomly selected control subjects. Acidity, color, and mineral content were measured in tap water from each participant's household. Tap water pH 6.2 to 6.9 was associated with a fourfold higher risk of type 1 diabetes compared with pH greater than 7.7. This result was similar after exclusion of individuals with the highly protective HLS-DQB1*0602 allele, but adjustment for maternal education, urban or rural residence, sex, and age tended to strengthen the estimated association. Higher tap water concentration of zinc was associated with lower risk of type 1 diabetes after adjustment for pH and other possible confounders, but the overall association was strictly not significant. The results suggest the possibility that quality of drinking water influences the risk of type 1 diabetes. The possible mechanisms by which water acidity or mineral content may be involved in the etiology of type 1 diabetes remains unknown, but the mechanisms are most likely indirect and may involve an influence on survival of microorganisms in the water. 3 tables. 26 references. •
Relation Between Aluminum Concentrations in Drinking Water and Alzheimer's Disease: An 8-Year Follow-Up Study Source: American Journal of Epidemiology. 152(1): 59-66. 2000. Summary: This journal article describes a study that examined the effect of aluminum and silica in drinking water on the risk of Alzheimer's disease (AD) and dementia. Researchers analyzed data from a cohort of 3,777 people over age 64 years who lived at home in rural or urban parishes in France. Study participants were screened at baseline, and 102 people with dementia were excluded. At followup, researchers identified 253 cases of dementia, with 17 cases exposed to high aluminum levels, including 182 cases of AD with 13 cases of high aluminum levels. The relative adjusted risk of dementia was 1.99 for people exposed to an aluminum concentration of more than 0.1 mg/liter. Though this result was confirmed for AD, no dose-response relation was found. The adjusted adapted relative risk of dementia for people exposed to silica was 0.74. The researchers concluded that high concentrations of aluminum in drinking water may be a risk factor for AD. 8 tables, 36 references.
Federally Funded Research on Drinking Water The U.S. Government supports a variety of research studies relating to drinking water. 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 drinking water. 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).
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Drinking Water
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 drinking water. The following is typical of the type of information found when searching the CRISP database for drinking water: •
Project Title: A NEW POINT-OF-USE DISINFECTION METHOD Principal Investigator & Institution: Hitchens, G Duncan.; Lynntech, Inc. College Station, Tx 77840 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-MAY-2002 Summary: Outbreaks of infectious diseases caused by waterborne microbes are a major public health concern. Infectious agents can be transmitted from many sources, including drinking water and recreational water and can occur even in highly purified water sources if not properly maintained. A potential means to combat the transmission of disease from water is through the widespread implementation of point-of-use disinfection systems. However, many existing disinfection methods are not viable as point-of-use treatments because of cost and process limitations. The aim of the work described in this proposal is to develop a small scale point-of- use ozone generator. Ozone is attractive because it is a potent biocide that produces relatively few harmful reaction by products; however, ozone is difficult and expensive to generate on a small scale. The Phase I study demonstrated the feasibility of a small scale seif-contained ozone generator that can be mass produced at low cost. The new method has the potential to provide an important water treatment capability to small or economically depressed communities, rural communities, high density neighborhoods and underdeveloped regions of the world. Hospitals requiring contaminant-free drinking water and ultra pure cleaning water could also benefit from this type of treatment. The Phase II will focus on: (l) optimization of the ozone generator's design; and, (2) optimization of the device's water disinfection arid operational capabilities. PROPOSED COMMERCIAL APPLICATION: There is a considerable need for disinfection technology to complement existing point-of -use water purification methods. The market opportunity is substantial, given the large number of point-of-use devices used in health care facilities, restaurants, food service establishments, hotels and in the home. This market is estimated to be worth over $1.5 billion annually in the U.S. ($3 billion for the rest of the world). In support of the commercialization activities and long term commercialization goals, two patents on electrochemical ozone generation have issued to Lynntech, Inc. A third will issue in approximately 3 months. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: A NOVEL TECHNOLOGY FOR MTBE REMOVAL FROM DRINKING WATER Principal Investigator & Institution: Tennakoon, Charles L.; Lynntech, Inc. College Station, Tx 77840 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-AUG-2005 Summary: (Applicant?s abstract): Some 18 billion pounds of MTBE was produced in 1995, making it the second most widely produced organic chemical in the United States. Despite its advantages in reducing air pollution, it has now been found that both ground water surface water sources are being contaminated with MTBE. The most serious contamination to date occurred in ground ware supplies in California, where 20 production wells are closed due to high MTBE contamination. USEPA currently classifies MTBE as a possible carcinogen in its largest directive this year and has decided
Studies
7
to phase out the use of MTBE in gasoline. In the coming years, this nation faces a formidable task of ensuring that our drinking water supplies are free of MTBE. MTBE is not readily amenable to treatment by conventional techniques. It is high solubility in water (50g/L) limits adsorption on to activated carbon. Other oxidative techniques produce bromate ions far exceeding the allowed maximum concentration level (MCL) of 10mg/L in drinking water. Hence, efficient non-oxidative alternatives to remove MTBE from water are highly desirable and are urgently needed. The aim of this proposal is to develop a cartridge filter using a remarkably effective separation technology developed at Lynntech. Based upon the Phase I results, this technology would lead to the development of a cartridge that could supply MTBE safe drinking water for more than six months to household of four. Projected sale price of such a cartridge is about $25.00. During the Phase II, practical issues related to long-term stability, regenerability and reusability of the absorbent, large scale manufacturing, and production will be addressed. Phase II will also include designing and assembling prototype cartridges for further evaluation and demonstration to potential industrial partners. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ALUMINUM BIOAVAILABILITY FROM FOODS Principal Investigator & Institution: Yokel, Robert A.; Pharmaceutical Sciences; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2002; Project Start 08-FEB-2002; Project End 31-DEC-2004 Summary: There is concern about brain aluminum accumulation over the life span that might contribute to Alzheimer's disease and related neurodegenerative disorders. The overall objective of the proposed research is to test the null hypothesis that the bioavailability of Al is comparable from foods and from drinking water. If the null hypothesis is accepted the concern about Al intake for typical Americans should focus on food and not drinking water. The specific aims are to produce food products containing 26Al in the normal chemical species for these foods and determine Al oral bioavailability from these selected representative foods, compared to Al oral bioavailability from drinking water. Foods to be produced are a baked good and a processed cheese, in which 26Al will be incorporated during food production, and spinach and tea, in which 26Al will be incorporated during their hydroponic production. Al bioavailability will be determined from the area under the serum 26Al concentration x time curve after bolus administration of the 26Al-containing food compared to the equivalent term obtained from serum 27Al concentration produced by continuous intravenous 27Al infusion throughout the study. 26Al will be analyzed by accelerator mass spectroscopy; 27Al by atomic absorption spectroscopy. It is hypothesized that oral Al bioavailability from food will be less than from water, due to Al binding to food components that inhibit its absorption. The results will resolve the controversy whether drinking water contributes a significant amount of the Al that is absorbed by the human. The results will suggest whether health-based standards to regulate Al in drinking water should be considered by regulatory agencies or whether reduction of absorbed Al in the human can be more effectively achieved by reducing Al in foods. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: METABOLISM
ANALYSIS
OF
METHYL
TERT-BUTYL
ETHER
(MTBE)
Principal Investigator & Institution: Steffan, Robert J.; Envirogen, Inc. 4100 Quakerbridge Rd Lawrenceville, Nj 08648
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Drinking Water
Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-MAR-2002 Summary: (provided by applicant): The goal of this Phase I SBIR research is to begin to elucidate the genetic and enzymatic mechanisms of methyl tert-butyl ether (MTBE) metabolism. MTBE has been identified as the second most common contaminant of urban ground waters in the United States, and it threatens the health of millions of Americans who may consume it through their drinking water. The results of this research will allow us to 1) better understand and predict the fate of this important groundwater contaminant in the environment; 2) better understand how tertiary carbon molecules like MTBE are metabolized in higher organisms; and 3) develop improved water treatment methods to reduce the risk of human exposure to MTBE through drinking water sources. During the six-month Phase I project we will clone, express, and sequence MTBE degradation genes from a recently isolated MTBE-degrading bacterium, strain ENV735. During follow on work we will evaluate the regulation of the MTBE-degrading genes to better understand how to improve in situ degradation of MTBE in groundwater, and to identify mechanisms for improving the performance of drinking water treatment systems to reduce human MTBE exposure. We also will evaluate the biochemistry of MTBE-degrading enzymes to help understand how human cells may metabolize small tertiary carbon molecules like MTBE. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ARSENIC CONTAINING MIXTURES IN ANGIOSARCOMA INDUCTION Principal Investigator & Institution: Pott O'brien, Wendy A.; None; Colorado State University Fort Collins, Co 80523 Timing: Fiscal Year 2001; Project Start 15-FEB-1997; Project End 31-JAN-2003 Summary: (Applicant's Description): This project will be executed at the Foothills Campus of Colorado State University by Wendy A. Pott, D.V.M. Dr. Pott's long-term goals involve integrating the disciplines of pathology, toxicology and biomedical engineering in the realm of cancer research. Her immediate goals involve investigating the roles of three common groundwater contaminants, individually and in combination, in the development of hepatic angiosarcoma. The research career development plan Dr. Pott will follow involves an interdisciplinary background of coursework and practical implementation of knowledge and development of skills in the laboratory and in the mathematical modelling arena. The long-term objectives of this project are 1) to evaluate the carcinogenic effects of sub-chronic exposure to three common groundwater contaminants-arsenic, vinyl chloride and 1,2-dichloroethane (1,2-DCE) - implicated as etiologic agents in the development of angiosarcoma; and 2) to use data from these studies with physiologically-based pharmacokinetic/pharmacodynamic (PB-PK/PD) models and statistical and mathematical modelling techniques for the purpose of health risk characterization. The specific aims of this project are 1) to determine the extent to which arsenic alone will act to induce the development of angiosarcoma; 2) to evaluate whether synergistic carcinogenic activity may result when arsenic is combined with vinyl chloride and/or 1,2-DCE; 3) to develop PB-PK/PD models for target tissue dosimetry of single chemicals and combinations of chemicals following exposure to arsenic, vinyl chloride, and/or 1,2-DCE; and 4) to develop cell turnover and carcinogenesis models and integrate them with PB-PK/PD models to characterize cancer risks associated with exposure to arsenic, vinyl chloride and/or 1,2-DCE. These goals will be accomplished using a medium-term angiosarcoma bioassay to investigate the effects of each of the above-mentioned chemicals alone and in combination in
Studies
9
inducing hepatic angiosarcoma. Data gathered from these experiments will be used to develop models to determine cancer risks and safe drinking water levels of these chemicals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ARSENIC EFFECTS ON GLUCOCORTICOID RECEPTOR ACTION Principal Investigator & Institution: Bodwell, Jack E.; Physiology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 18-SEP-2002; Project End 30-JUN-2006 Summary: (provided by applicant): The overall goal of this research project is to determine the contribution of arsenic (As) exposure to human disease risk. There is growing worldwide concern about the human health effects of chronic, low level arsenic exposure. Arsenic in drinking water has been associated with an increased risk of developing type 2 diabetes, vascular and cardiovascular diseases, reproductive and developmental problems, and several kinds of cancer, notably lung, skin, bladder and liver cancer. We had previously shown that arsenic inhibited glucocorticoid hormonemediated transcriptional gene regulation. We hypothesize that direct biochemical disruption of OR function by arsenic contributes to the pathophysiology of the diseases associated with chronic arsenic exposure. Recent experiments demonstrated that mutant GRs lacking either the N-terminal domain or the C-terminal ligand-binding domain had a similar response to As as wild-type OR. This suggested that the effects of arsenic are primarily mediated through the middle DNA binding domain (DBD). We also have preliminary data suggesting that As binds stoichiometrically to GR at very low intracellular concentrations of As. The specific goal of this project is to determine the biochemical basis for effects of arsenic on GR signaling, focusing principally on As effects on the DBD of OR. In particular, using model mammalian hepatocyte-derived cell lines, wild-type and mutant forms of OR, genetic constructs containing model GRresponsive genes, and various biochemical and genetic techniques, we will examine this question in detail with the following specific aims: 1) Determine the arsenic-OR binding stoichiometry and site(s) of interaction using mass spectrometry and site-directed mutagenesis of OR; 2) Determine the effects of arsenic on the normal functions of the GR DBD, examining in particular whether As alters: a) the formation of cytosolic GR dimers or their transport to the nucleus using mutant and tagged GRs in combination with immunoprecipitation and Western analysis; b) OR monomer-timer interactions with their glucocorticoid response element (GRE) DNA recognition sequences using gel shift and BlAcore analyses; or c) the interaction of OR-GRE complexes with co-activators and other transcription factors using a Chromatin Immuno-Precipitation (ChIP) assay; and 3) mutational analysis of the OR DBD to confirm the key results of specific aims 1 and 2. The goal of these aims is to develop a more detailed understanding of the molecular basis for the effects of arsenic on steroid receptor signaling. This will be important for determining the contribution of these effects to the overall human health effects of arsenic. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ARSENIC EXPOSURE AND BLADDER CANCER IN MICHIGAN Principal Investigator & Institution: Nriagu, Jerome; Professor; Environmental Health Sciences; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007
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Summary: (provided by applicant): The objective of this proposal is to explore the factors that have contributed to the observed geographic co-clustering in bladder cancer mortality and arsenic concentrations in drinking water in Michigan. The focus will be on the spatial and spatio-temporal patterns of arsenic exposure and how these may relate to the incidence of bladder cancer in those areas of Michigan with elevated levels of arsenic in their drinking water. Reported arsenic concentrations in well waters in the study area range from 1 to 1310 mg/I, with most common levels being 5-50 mg/L. The project being proposed will consist of three components: (1) Construction of exposure scenarios with time dimension that will involve development of the novel space-time information system (STIS) model to be validated using a combination of space-and-timedependent concentrations of arsenic measured in the study, supplementary historical information on arsenic levels in water supplies, hydrogeochemistry of the area, and selfreported residence information and water drinking habits; (2) Biomonitoring of arsenic exposure to be based on analysis of toenails (known to indicate average exposure over a relatively long time) for arsenic and a number of confounding trace elements such as selenium, zinc, copper and antimony; (3) A population-based, case-control bladder cancer study which will be used as an outcome measure for exposure to arsenic in drinking water. Bladder cancer cases (700) and controls (700, matched to cases by sex, race, and +/- 5-year age groups) will be recruited from long-term residents of the 11 counties (Genesee, Huron, lngham, Jackson, Lapeer, Livingston, Oakland, Sanilac, Shiawassee, Tuscola and Washtenaw) with elevated levels of arsenic in their groundwater. Structured personal interviews will be administered to obtain information on lifetime residential history, current and past water consumption patterns, life-style risk factors (including cigarette smoking and alcohol use), medical history, occupational history, family history of cancer, and dietary habits. The study is designed to shed some light on the dose-response relations for exposure of the U.S. population to arsenic concentrations in the 5-100 mg/L range where no information currently exists. Current efforts by the U.S. Environmental Protection Agency to reduce the maximum contaminant level for arsenic in our drinking water have been bedeviled by contradictory and unvalidated predictions of the risks of chronic exposure to low levels (< 100 mg/L) of arsenic in water. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ARSENIC INDUCED MIOTIC ARREST ASSOCIATED APOPTOSIS Principal Investigator & Institution: States, J Christopher.; Associate Professor; Pharmacology and Toxicology; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 30-APR-2008 Summary: (provided by applicant): Arsenic is a natural contaminant of drinking water in many parts of the world, is a known human carcinogen and is #1 on the EPA list of hazardous chemicals. Cancers most often associated with chronic arsenism are squamous and basal cell carcinomas of the skin. How arsenic causes cancer is unknown. However, the National Research Council Report on Arsenic in Drinking Water concluded that the most likely mode of action is induction of numerical and structural chromosomal abnormalities. Arsenite, the carcinogenic form of arsenic found in drinking water, disrupts mitosis causing an anaphase delay and induces aneuploidy in normal diploid human fibroblasts and peripheral blood lymphocytes, and mitotic arrest associated apoptosis (MAAA) in p53 deficient human fibroblasts. The sensitivity of p53 deficient human cells to arsenite induced MAAA suggests that the mechanism of arsenite carcinogenesis is different than sunlight induced skin carcinogenesis in which
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p53 mutation is an early and common event. The hypothesis to be investigated is that p53 relieves the arsenite-induced anaphase block by activation of the G2 checkpoint response which inactivates cyclin B/cdc2 and derepresses the mitotic exit network and allow the cells to escape arsenite induced MAAA. It is the prevention of apoptosis in arsenic intoxicated cells that allows genetic instability (aneuploidy) after mitotic disruption. Identification of the cellular factors that interact with p53 or the p53 regulated genes to prevent mitotic arrest associated apoptosis and to allow cells to proceed through mitosis with a delay will provide valuable information regarding the mode of action of arsenite. The specific aims proposed are: 1.) Determine activation of the G2 checkpoint pathway in p53(+) and p53(-) cells arrested by arsenite in mitosis; 2.) Test by overexpression and targeted knockdown of G2 checkpoint proteins the role of G2 checkpoint activation in the escape from arsenite induced anaphase block; 3.) Test whether arsenic associated skin tumors are p53 wild type or mutant. The results of these studies will identify players mediating release from arsenite induced mitotic arrest, and will provide valuable information on the mechanism of arsenic induced carcinogenesis, clues to the usefulness of arsenite as a chemotherapeutic agent and valuable information on the mode of action of mitosis disrupting drugs in killing human cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BIOSENSOR DETECTION OF WATER-BORNE CRYPTOSPORIDIUM Principal Investigator & Institution: Sand, Theodore T.; Disan, Inc. Box 500948, 7396 Trade St San Diego, Ca 92150 Timing: Fiscal Year 2001; Project Start 01-JUL-1998; Project End 31-MAR-2003 Summary: (Adapted from Applicant's Abstract): The proposed Phase II study will continue the development of an innovative, immunoassay-based biosensor for the detection and quantitation of Cryptosporidium oocysts in drinking water. Current methods for detection and quantitation of this pathogen frequently are characterized as technically demanding, time-consuming and labor intense, leading to poor recoveries and false positives and false negatives. The Phase I results showed that the biosensor was capable of detecting 10 oocysts/ml in buffer at a two-fold signal-to-noise cutoff. Phase II activities will focus on improving the detection limit and developing an optimized immunoassay strip device and reader. Water samples collected from a variety of natural sources will be evaluated in the prototype detection system. The irmnunoassay itself should take less than 30 minutes to complete. The availability of more rapid, quantitative methods for detecting water-home pathogens will help to identify and manage the presence of these organisms for community water supplies, thereby minimizing the exposure of the public. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CALIFORNIA NEVADA ARSENIC AND LUNG CANCER STUDY Principal Investigator & Institution: Smith, Allan H.; Professor; Environmental Health Sciences; University of California Berkeley Berkeley, Ca 94720 Timing: Fiscal Year 2002; Project Start 22-MAR-2002; Project End 31-DEC-2005 Summary: (provided by applicant): Millions of people are exposed to drinking water contaminated with arsenic, and extensive epidemiological evidence has demonstrated that these exposures can cause cancer. In fact, at high concentrations the levels of risk exceed those of any other known environmental carcinogen. At relatively low exposures such as those commonly found in the U.S., cancer risks from lifetime exposure could be
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above 1 in 1000 people, even at the newly proposed drinking water standard of 10 micrograms/L. In certain susceptible subpopulations, such as those who smoke or have poor diets, the risks may be even greater. Furthermore, our studies in Chile suggest particularly high risks for those drinking arsenic-contaminated water as children. Unfortunately, cancer risks at low exposures are uncertain since risk estimates to date involve extrapolation from high dose levels to lower exposures where the shape of the dose-response relationship is unknown. Such extrapolations are highly controversial. We therefore propose a population-based case-control study to assess the association of lung cancer with low to moderate levels of arsenic in drinking water. Current evidence indicates that lung cancer may be responsible for more deaths due to ingested arsenic than all other cancer sites combined, including bladder cancer. It is therefore particularly important to obtain a clear picture of the dose-response relationship for this cancer. The study area includes Kings County, California, and six counties in Nevada. These counties incorporate the largest population in the U.S. exposed to water supplies containing between 50 and 100 micrograms/L of arsenic. Most other water supplies in the study region contain less than 5 micrograms/L and thus provide a marked contrast in exposure. A total of 271 lung cancer cases diagnosed in the study area between 2002 and 2004 will be identified with rapid case ascertainment from local hospitals. Tumor biopsies will be archived for a potential subsequent study of DNA alterations. Random digit dialing and the rolls of the Health Care Financing Administration will be used to identify two controls for each case, frequency-matched by age and sex. Telephone interviews of all study subjects will be conducted to gather information on lifetime residential history and drinking water sources which will be used in conjunction with water arsenic measurements to construct exposure histories. A strength of the study is that exposure can be reliably ascertained retrospectively since it is largely dependent on residential history. Information on cigarette smoking will also be obtained and synergistic effects with arsenic assessed. Dietary information, medical history, and demographic data will be collected and analyzed for potential susceptibility factors. The proposed study has over 83 percent statistical power to detect a relative risk of 1.7, the risk predicted by linear extrapolation from high dose studies. The study has public health importance since finding the hypothesized relative risk would identify important health effects from low levels of exposure, whereas not finding increased risks would contribute to assurance about public health protection from the new drinking water standard. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CARDIOPROTECTIVE EFFECTS OF ETHANOL Principal Investigator & Institution: Bhatnagar, Aruni; Professor; Medicine; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): The long-term goal of this project is to elucidate the mechanisms by which moderate consumption o alcohol protects against myocardial ischemic injury. Our working hypothesis is that chronic exposure t( ethanol establishing low levels of oxidative stress in the heart, which elicits an adaptive increase in the myocardial antioxidant defenses and aldehyde metabolism. To test this hypothesis, adult male rats will be fed 6 % ethanol in their drinking water for various periods of time up to 12 weeks. Hearts from these animals, and from control untreated rats, will be excised and perfused ex vivo. The sensitivity of these hearts to ischemia-reperfusion will be determined by subjecting them to 30 and 45 min. of global ischemia, followed by 30 min. of reperfusion. The post-ischemia recovery and myocyte necrosis will be measured.
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In a parallel series of experiments, the excised hearts will be homogenized and their proteins will be separated by 2-D gel electrophoresis. Changes in myocardial proteins due to chronic ethanol treatment will be identified by image analysis of the gels and by mass spectrometric analysis using matrix-assisted laser desporption ionization (MALDI) and electrospay ionization (ESI). From these experiments a data base wit be developed for categories of proteomic changes and coordinate changes in specific signal and metabolic pathways, and/or transcritional events will be identified. To elucidate the role of aldehyde metabolism, we will examine the extent and the nature of the cardiac metabolism of the prototype lipid peroxidation-derived aldehyde - 4-hydroxy trans-2nonenal in hearts removed from naive and ethanol-fed animals. To identify the contribution of the changes in aldehyde metabolism, we will examine whether pharmacologica inhibition of the pathways for aldehyde metabolism abrogates the cardioprotective effects of ethanol. The results of this exploratory project will form the basis of future detailed investigations into the mechanism, underlying the cardioprotective effects of ethanol and to identify the regulatory determinants underlying the dose-dependent transition from beneficial to the harmful effects of ethanol. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMOPREVENTION IN AN INDUCIBLE MOUSE MELANOMA MODEL Principal Investigator & Institution: Spanjaard, Remco A.; Associate Professor; Otolaryn & Head & Neck Surgery; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2003; Project Start 25-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The number of cases of malignant cutaneous melanoma has been rising at an alarming rate over the last decades, at about 4% per year, and it has been estimated that up to 1 in 80 Americans will develop melanoma. Despite years of research, there are no viable treatment modalities for advanced melanoma, and mortality rates remain exceptionally high. This saddening fact emphasizes the urgent need for new effective drugs, not only to treat existing tumors, but also to inhibit occurrence of second primary cancers after convential treatment modalities, or prevent further transformation of premalignant cells in high-risk patients. This application aims to address these issues by assessing the chemopreventive activity of a promising selection of drugs in a novel, inducible murine melanoma model. This uniquely suitable model is the only one to allow synchronization of the onset of development of cutaneous melanoma on a genetic background, which accurately mimics that of human disease. By adding doxycyclin (Dox) to the drinking water, expression of H-RASV12G is induced in melanocytes on a p16INK4A-ARF null background. This cooperativity then results in development of largely non-metastatic, cutaneous melanomas in 25% of mice with an average latency of 60 26 days. The mouse model itself has already been thoroughly analyzed in terms of tumor pathology, which closely resembles that of human disease, and the essential role for H-Ras in maintaining tumor growth. However, these mice have never been used to develop new chemoprevention protocols. We will test the efficacy of the following drugs: suberohydroxamic acid (SHA), celecoxib, retinoic acid (RA) and lovastatin. These drugs were selected because they i) are non-toxic (except for RA, but 13-cisRA provides a less toxic clinical alternative), ii) are widely used already, iii) affect different biochemical pathways, iv) have shown promise as chemopreventive agents in other studies, and v) have shown potential to enhance each other's activity when combined. Our working
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hypothesis is that these drugs will inhibit tumor growth to some degree, but that the combination of at least some of these drugs will inhibit proliferation of premalignant melanoma cells to a much larger extent than any drug alone can achieve, without significantly increasing toxicity. We propose to induce 4-week old animals drugs, and determine chemopreventive antitumor efficacy by monitoring size, number and location of skin tumors. Specific Aim I proposes to establish an optimal chemoprevention drug protocol to suppress tumor development. Specific Aim II proposes to establish expression of key cell cycle regulatory genes in control, drug-responsive and nonresponsive transgenic tumors to determine whether expression is associated with tumor growth and responsiveness to therapy. The results of these experiments in this inducible melanoma model will allow us to assess whether our protocol should be considered for use in phase I trials in high risk patients, which is the long term goal of this application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMOPREVENTION OF PULMONARY CARCINOGENESIS Principal Investigator & Institution: Wattenberg, Lee; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2003; Project Start 23-MAY-2003; Project End 30-APR-2008 Summary: The long-term objectives of the present proposal are to obtain data from chemopreventive studies in the hamster that will be useful in identifying agents likely to have efficacy in preventing cancer of the respiratory tract in the human. One specific aim is to evaluate three agents administered as single compounds for their capacity to inhibit squamous cell carcinogenesis of the upper respiratory tract of the Syrian Golden hamster. The three agents and their routes of administration are: green tea extract powder administered in the drinking water, budesonide administered by aerosol and myo-inositol administered in the diet. A second specific aim is to evaluate the efficacy of administration of combinations of two agents on their capacity to inhibit squamous cell carcinogenesis of the upper respiratory tract of the Syrian Golden hamster. The combinations will be selected from the agents enumerated above and also aerosol difluoromethylornithine which previously has been shown to have an inhibitory effect in the hamster model. The use of agent combinations can be valuable in decreasing the dose of individual compounds and thus possibly reducing adverse effects. The sequence of studies of agent efficacy will be selected so as to coordinate their use in the Clinical Trials Section-Project 1. A third aim is to determine molecular changes during squamous cell carcinogenesis of the upper respiratory tract of the hamster and to compare these with squamous cell carcinogenesis of the respiratory tract in the human. The hamster model employed entails six intratracheal administrations of the carcinogen MNU. With this procedure approximately 90% of the animals receiving carcinogen but no protective agent develop infiltrating squamous cell carcinomas of the upper respiratory tract, inhibition of the occurrence of these cancers would indicate that the chemopreventive agent has considerable potency and is a potential compound to further evaluate for use in the human. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHITIN CATABOLIC CASCADE IN VIBRIO CHOLERAE Principal Investigator & Institution: Roseman, Saul; Professor; Biology; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-JUL-2006
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Summary: (provided by applicant): We are in our 8th cholerae pandemic, a disease that infects millions and kills over 100,000 humans annually. In one stage of its life cycle, the infective agent, Vibrio cholerae, lives as a commensal with copepods, a microcrustacean found in drinking water. Because the bacteria "burrow" into the cuticle, they escape the stomach acid barrier, to which free-living cells are sensitive. Thus, the chitinolytic properties of V. cholerae are directly relevant to human health and disease. In previous work with Vibrio furnissii, we found that chitin degradation involves a cascade, with at least three signalling systems and numerous genes and proteins, many of which were isolated. One of these was a sensor HK (histidine kinase) protein, which represents a breakthrough in this research. An in frame deletion of the sensor has a global effect on chitin utilization in that none of the characterized chitin cascade genes or processes were expressed. When the sequence of the V. cholerae genome became available, the predicted protein sequences of genes involved in chitin utilization that we had characterized in V. furnissii exhibited considerable identity to the corresponding ORFs in the V cholerae genome. For example, the V. furnissii sensor is 84% identical and 93% similar to VC0622 over the full length of the predicted protein sequences. The sensor is homologous to the E. coli ArcB sensor, part of a two component signal transduction system. Over 21 ORFs in the V. cholerae genome are annotated as related to chitin catabolism (independent of GlcNAc catabolism). Of these, ten were characterized in V. furnissii but nothing is known about the remainder. We shall determine which genes are regulated by VC0622, using first an in frame deletion of VC0622. A second goal is to isolate and characterize the sensor HK protein from V. cholerae. Finally, we plan to identify and characterize the cognate HPt and RR protein(s) that interact with the sensor. The work will rely heavily on molecular biological and biochemical techniques, as well as genomics. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COMMUNITY EXPOSURE TO PERFLUOROOCTANATE Principal Investigator & Institution: Emmett, Edward A.; Emergency Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 30-JUN-2007 Summary: (provided by applicant) This project is a partnership between environmental researchers at the University of Pennsylvania, local health care providers at Health South Hospital, Parkersburg WV, and the -Decatur Community Association, to address exposure of residents in the Little Hocking Water Association district (LHWAD) to C8. Little Hocking is a village in the Appalachian region near Parkersburg WV, located directly across the Ohio River and downwind of a plant with significant discharges of C8 to air, ground, and water. Residents of LHWAD have known exposures to C8 through air, residential drinking water domestic well water, and community water; some residents have occupational exposure (with possible domestic household contamination). There are other potential exposure sources. C8 is known to be very persistent in both the environment and in humans (serum half-life approximately 4 years). C8 can be toxic to the liver, causes testicular cancer and mammary hyperplasia and may have reproductive effects in experimental animals. Human data is limited but adverse effects have been reported from occupational exposure. Events surrounding C8 contamination in Little Hocking and surrounding areas have led to substantial community skepticism and lack of trust. Through this project the partners will measure C8 in a stratified sample of residents and identify the relative importance of the various potential exposure sources. To help assess C8 risk levels in residents will be compared with those in other population and occupational groups and by determining if early
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biomarkers of toxic effect are associated with higher C8 levels. This information will be shared with the community, and an implementation plan developed to reduce exposures. A community participation model will be used to involve stakeholders at all stages. Two-way communication, and education of community residents and local health practitioners will be emphasized. The effectiveness of communication and education and the level of participation of residents will be evaluated. Outcome measures to be evaluated include the reduction of levels of blood C8, and whether community trust is restored through an independent participatory study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: COMMUNITY OPERATIONS
HEALTH
EFFECTS
OF
INDUSTRIAL
HOG
Principal Investigator & Institution: Wing, Steven B.; Associate Professor; Epidemiology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Recent expansion of large scale confined animal feeding operations (CAFOs) is generating a wide variety of health concerns in the USA and other nations. Air and ground water pollution from swine CAFOs are of particular concern in North Carolina, where industrial hog production has expanded rapidly since the 1980s. Airborne emissions are composed of hundreds of agents including hydrogen sulfide, ammonia, volatile organic compounds, and dusts or particulate matter that contains biological materials including proteins and endotoxins. Nitrates, pathogens, and antibiotic residues have been documented in ground water near swine CAFOs. The investigators propose a series of community-based participatory studies that will (1) quantify community exposures to hydrogen sulfide, volatile organic compounds, dusts, and endotoxins; (2) evaluate relationships between air emissions and perceptions of odor and irritation; (3) measure exposures to airborne emissions from livestock operations to strengthen the design of an already-funded health symptom survey; and (4) prospectively quantify relationships between ambient exposures and respiratory symptoms, lung function, and other health status measures among persons residing near swine CAFOs in North Carolina. They will also (5) conduct surveillance for nitrates and antibiotic residues in well water of study participants. Bacterial flora of any participants who report a history of drinking water contaminated by veterinary antibiotic residues will be tested for antibiotic resistance. Due to widespread distrust of biomedical research in poor and people of color communities where NC swine CAFOs are concentrated, community-based participatory research approaches are required for addressing these health issues. The proposed studies build on five years of communitydriven research conducted by Concerned Citizens of Tillery and the University of North Carolina School of Public Health, as well as on extensive research on chemical odorants and their effects, and on water quality, conducted by other project collaborators. This project will provide new scientific data on exposures and human health effects of swine CAFOs and increase the capacity of communities in eastern NC to improve public health conditions in an underdeveloped region of the United States. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--ANALYTICAL SERVICES Principal Investigator & Institution: Donnelly, K.C.; Texas A&M University System College Station, Tx 778433578
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Timing: Fiscal Year 2002; Project Start 05-APR-1998; Project End 31-MAR-2007 Summary: The specific aims of this facility core are: (1) to provide routine analytical support including sample preparation, extraction, and standard analytical measurements to all Center investigators; (2) to provide assistance to Center investigators in the development and implementation of a sampling strategy for field investigations conducted in support of epidemiologic studies; and, (3) to assist in the development and implementation of quality assurance project plans for all Center research. A major focus of the Field Services Facility (FSF) core will be to assist investigators conducting epidemiologic studies. Safety and sampling equipment are maintained for collecting air, soil, surface water, groundwater, or sediment samples. For mechanistic studies, the FSF will assist investigators in quantifying specific chemicals or metabolites of compounds that are responsible for a specific metabolic response. Routine analytical support, to include sample preparation, extraction and HPLC or GC/MS analysis will also be provided by the FSF. Resources will be provided to assist investigators in the development of a Quality Assurance/Quality Control plans for Center research. The capabilities of the FSF were initially developed as a component of the NIEHS Superfund Basic Research Grant at TAMU. This component includes a field sampling team consisting of research scientists, professors, and graduate students who have received the OSHA 40 hour Safety Training course and associated refresher training. In addition, safety equipment is maintained to permit Level C sampling, as well as sampling equipment to allow for collection of surface and subsurface soils, sediment, surface water, groundwater, drinking water, dust, and air samples. Standard Operating Procedures (SOPs) have been developed for each of these media. Sampling has been done at over 50 Superfund sites in all geographic regions of the United States; these samples have been used by several investigators in the CMBT research core. For the South Texas Pregnancy Project, quarterly sampling has been conducted at 65 sampling stations, totaling over 150 samples of soil, surface water, sediment, and Rio Grande River water. Current activities of the FSF have focused on complex mixture risk assessment, biological methods of detoxification, and epidemiological and environmental investigations of disease clusters. In support of planned expansion of epidemiological studies to El Paso County, Texas and northern Mexico, the FSF will include planning in the identification of sample collection areas and media, as well as actual collection and extraction of field samples. The main facilities of the FSF are in the Agronomy Field Lab adjacent to the College of Veterinary Medicine, consisting of two laboratories with over 1,800 square feet of space. The FSF also includes approximately 2,300 square feet of laboratory space in the Veterinary Medical Administration Building. These facilities include sample preparation, analysis, and storage areas. Analytical instrumentation such as HPLC, GC/MS and fraction collector. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--ANIMAL Principal Investigator & Institution: Gahring, Lorise C.; Associate Professor; University of Utah 200 S University St Salt Lake City, Ut 84112 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2007 Summary: (provided by applicant): The animal core will facilitate all aspects of the mouse studies proposed in this program project. This includes management of; 1) mouse strains to be used for genetic/microarray dissection of strain-specific responses to nicotine, 2) animal husbandry of genetically modified animals through homologous recombination, 3) genotyping of mouse strains and the generated backcrosses, 4) animals for immunohistochemical and protein chemistry studies, 5) timed-pregnant
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strains for tissue culture applications, 6) animals for peripheral immune cell function studies and 7) animals pertaining to inflammation and COPD modeling. This animal core therefore provides a central shared facility allowing for the coordinated use of animals for Project 2 (Drs. Rogers and Capecchi) and Project 3 (Drs. Hoidal and Gahring). This core will maintain barrier-sustained, disease-free colonies of conventional and neurologically and peripherally modeled mice. Further, this core will implement and maintain nicotine treatment of mice (oral administration in drinking water as well as the smoke inhalation model, 7 days per week) for Projects 2 and 3. Mouse colonies are presently housed in the University of Utah School of Medicine Animal Resource Center (ARC) facility that is free of infectious agents and constructed to support new barrier housing areas that operate with regulated environmental conditions. A second IACUC accredited mouse facility at the Veterans Administration research facility presently houses the smoking chamber that is used for inhalation studies. The housing and treatment of all mice by this core assures minimal experimental variability between projects. All animals will be uniquely identified including the use of implanted electronic chip identification transponder chips where applicable. Animal databases will be networked to all investigators and will be accessible between Projects to assure maximum utilization of animals and this resource. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--MARINE /FRESHWATER TOXINS AND HUMAN HEALTH Principal Investigator & Institution: Fleming, Lora E.; Associate Professor; University of Miami Coral Gables University Sta Coral Gables, Fl 33124 Timing: Fiscal Year 2002; Project Start 22-APR-2002; Project End 31-MAR-2007 Description (provided by applicant): Benign and harmful algal blooms (HABS) have likely been occurring since the very beginnings of life on this planet. However, it appears that the incidence of harmful algal blooms has been on the rise in recent years. For the applicant's purposes, an algal bloom is harmful if its toxins become available to human populations, either directly or indirectly, through food, water and other routes of exposure. As indicated in the application, toxins may adversely affect both aquatic animals and humans, and thus it is advisable to follow both human and wildlife effects, because wildlife can ultimately become food sources for humans, but they can also serve as early warning sentinels of new toxins or new HABs. The traditional primary exposure route of concern to humans has been bio-accumulation in finfish (e.g., ciguatoxin) or shellfish (e.g., saxitoxin and brevetoxin). University of Miami Center scientists have been at the forefront of dealing with the human health aspects of these phenomena. However, anecdotal evidence has been accumulating about the toxic effects of other exposure routes (e g., aerosols and even drinking water), and in the next grant period, Center scientists will be conducting a definitive evaluation of such effects in both animal and human models. Awareness of these new routes of exposure came about as a consequence not only of our wildlife work on manatees, but also as a result of reports on out Marine and Freshwater Hotline and through work with the Florida Harmful Algal Bloom Taskforce, i.e., via our outreach activities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CORE-NEUROTOXICOLOGY/NEURODEGENERATIVE DISEASE RESEARCH Principal Investigator & Institution: Graziano, Joesph H.; Columbia Univ New York Morningside 1210 Amsterdam Ave, Mc 2205 New York, Ny 10027
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Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: The developing nervous system is vulnerable to adverse effects due to exposures to a variety of substances in the environment, particularly metals and pesticides. At the same time, chronic exposure to low levels of neurotoxicants throughout life can lead to impaired neurologic functioning later in life, particularly in the elderly. As life expectancy increases, and the baby-boom generation approaches retirement age, neurodegenerative diseases such as IPD, Essential Tremor and Alzheimer's Disease will have a significant impact on quality of life, and will represent significant financial costs to the health care system. Collectively, the investigators in this research core are interested in understanding the extent to which, and mechanisms 295 whereby, populations exposed to known quantities of neurotoxicants suffer adverse consequences on the nervous system. The populations under investigation, which include birth cohorts in Yugoslavia and northern Manhattan, populations of adults and children chronically exposed to arsenic in drinking water in Bangladesh, and populations of the elderly in northern Manhattan, represent groups of individuals who have been remarkably well characterized for a variety of chemical exposures and other risk factors for adverse neurologic outcomes. At the same time, laboratory based scientists are exploring the mechanisms whereby the compounds of interest alter normal function. The overall goals of the Neurotoxicology/Neurodegenerative Disease Research Core are: I) to promote and facilitate interdisciplinary neuroscience-related research that will define the magnitude of effect of exposure to substances in the environment that are believed to be involved in the etiology of neurologic disease. These substances include metals (Pb, Mn, Fe and As), pesticides (chlorpyrifos, diazinon, propoxur, and others), 13- carboline alkaloids (harmane and harmine), and other factors; and 2) to unravel the cellular and molecular mechanisms whereby these substances exert their effects. The core is responsible for furthering the development of existing and new investigations of environmental exposures that affect the incidence and/or progression of diseases of the central and peripheral nervous systems. The Specific Aims currently under investigation include: 1) to define the cellular and molecular events involved in chemical models of Parkinsonism and in IPD, with the goal of defining those that are common to each; 2) to elucidate the environmental risk factors associated with the onset of IPD, Essential Tremor, and Alzheimer's Disease; 3) to examine, in both humans and animal models, the relationship between environmental Pb exposure and brain function, with particular interest in the possible mediating effects of Pb on thyroid hormone fate and transport; 4) to determine whether exposure to arsenic in drinking water is associated with adverse neuropsychologic effects in children, and polyneuropathy in adults; and 5) to develop biomarkers of prenatal pesticide exposure in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--RESPIRATORY TOXICOLOGY Principal Investigator & Institution: Plopper, Charles G.; Professor and Chairperson; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 22-APR-2002; Project End 31-MAR-2003 Description (provided by applicant): As a primary interface between the organism and its environment, the respiratory system is the target for a wide range of toxicants, including reactive gases, agricultural chemicals, and airborne pathogens and particles. Since it also receives the entire output of the right heart, it is also the target for a variety of circulating toxic compounds that enter the organism via the skin or gastrointestinal tract; as a consequence, agricultural chemicals that have the lungs as a target but are not
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incorporated into dusts or sprays can still cause toxicity by ingestion of contaminated food and drinking water or absorption through the skin. The overall goals of this research Core are to: (1) promote interdisciplinary research that will elucidate the cellular, metabolic, and molecular mechanisms that define and modulate the response of the respiratory system to environmental toxicants, and (2) provide information relative to the harmful effects of photochemical air pollution and other inhaled toxicants that will be useful in understanding the relative susceptibility of humans to harm from exposure to agricultural contaminants whose toxicity results from other metabolic pathways. Currently the Core members are pursuing projects focused on a number of areas of general concern for public health, especially as they relate to crosscontamination of urban and agricultural sectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CRITICAL TIME PERIODS IN DENTAL FLUOROSIS Principal Investigator & Institution: Jackson, Richard D.; Oral Health Research Institute; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 31-AUG-2003 Summary: It is generally accepted that there has been an increase in the prevalence of dental fluorosis in both negligibly- and optimally-fluoridated communities in the United States. Data are available concerning the contribution various fluoride sources have made to this increase in prevalence. In contrast, little data are available concerning the possible time periods of susceptibility. Identification of the time periods of susceptibility, as well as the sources of fluoride, will make it possible to achieve the maximum level of caries prevention while minimizing the risk of dental fluorosis. The goal of this study is to expand upon the data collected by earlier investigators utilizing a population of children in the United States to test the hypothesis that the critical time periods during tooth formation when excessive fluoride intake may result in dental fluorosis can he identified. The specific aims will be to: 1, identify and recrnit approximately 300 children (7-12 years-of-age) who are lifetime residents of a community whose communal water supply has undergone an alteration in fluoride content which should result in a definable variation in the degree of dental fluorosis on the labial surfaces of the permanent teeth of these children; 2, examine, in the Year 2000, the labial surfaces of the available permanent dentition of these children using established dental fluorosis indices to identify the periods of susceptibility for the development of dental fluorosis and to also determine the prevalence of dental fluorosis; 3, gather retrospective data by means of a questionnaire to determine sources of fluoride ingestion during infancy and early childhood; and, 4, develop a data analysis plan to identify the time periods associated with the development of dental fluorosis in the permanent dentition and determine the prevalence of dental fluorosis in these children for comparison to data previously collected in the community by the investigators. These children will be essentially lifetime residents of Lowell, Indiana and will have used the communal water supply as their primary source of drinking water. They will be examined using the Tooth Surface Index of Fluorosis and the Chronological Fluorosis Assessment. Data will also be collected to determine each panelist's level of fluoride ingestion during early childhood. Analyses of the data will allow the investigators to confirm the critical time periods for the development for the remaining dentition. This investigation will be the first in a series of studies relating to this topic to take advantage of this timely opportunity and this unique population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DENDRITIC CELL FUNCTION AND ETHANOL Principal Investigator & Institution: Schlueter, Annette J.; Pathology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): This proposal investigates a largely unexplored mechanism by which ethanol (EtOH) consumption may lead to increased risk of infection, namely, impairment of dendritic cell (DC) function. The long-term objective of the planned experiments is to understand how EtOH-exposed DC contribute to dysfunctional immune responses. In collaboration with the other IRPG members (investigating EtOH-induced B, T, and NK cell dysfunction), these studies will ultimately lead to new therapies designed to decrease infectious morbidity in alcoholics. DC are critical for initiation of effective immune responses, as they provide antigenspecific activation of naive T cells. EtOH has been shown to affect antigen-presenting cell function in alcoholic humans and animal models of EtOH consumption, but the specific mechanisms and cell types responsible for this deficit have not been closely examined. Our laboratory studies the effect of EtOH on DC function in vivo using a model in which mice receive 20% EtOH in their drinking water. Mice maintained on this regimen for many months show no stress-induced changes, thus allowing evaluation of alterations induced by chronic EtOH exposure. EtOH-exposed mice show persistently decreased DC numbers, as well as altered DC function. The specific aims of this study focus on understanding the mechanisms by which EtOH exposure results in diminished DC numbers, and delineating aspects of DC function that are affected by EtOH. Investigations into the mechanism of diminished DC numbers include studies of the effect of EtOH on DC precursor differentiation, DC lifespan, sensitivity to apoptosis, and migration of newly formed DC into peripheral tissues. Investigations into mechanisms for loss of DC function include studies of the effect of EtOH on antigen processing, presentation, costimulatory molecule expression, cytokine secretion, migration in response to maturation stimuli, and the ability of EtOH-exposed DC to induce tolerance/anergy. All proposed experiments are performed using in vivo or very short term in vitro approaches. This serves to maintain the effect of "physiologically" relevant EtOH concentrations throughout the course of the study, and to allow assessment of DC function within their usual microenvironment. The results will lead to new information on the effect of EtOH on DC function. This in turn will elucidate new approaches for enhancing immunity and preventing infection in alcoholics, as the appropriate points of intervention become clear. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: DOES PKU PROTECT AGAINST CANCER? Principal Investigator & Institution: Sidell, Neil; Professor; Gynecology and Obstetrics; Emory University 1784 North Decatur Road Atlanta, Ga 30322 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): The disease phenylketonuria (PKU) is caused by mutations in the gene coding for phenylalanine hydroxylase (PAH) which results in hyperphenylalaninemia and elevated levels of abnormal phenylalanine metabolites. Among these metabolites is phenylacetic acid, or the ionized form of the molecule phenylacetate (PA). Recently, PA has come under intense investigation due to its demonstrated anticancer activity against a variety of malignancies, including breast and prostate cancers. These findings suggest the possibility that PKU may offer protection against cancer through chronically elevated blood levels of PA. The investigator's
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overall objective is to test this hypothesis. This will be accomplished by studies involving two in vivo mouse models. Specific Aim 1 will assess the ability of therapeutic intervention with a PA analogue to inhibit estrogen-dependent carcinogenesis using the investigator's existing aromatase transgenic mouse colony. In these experiments, the PA derivative 4-chloro-PA will be chronically administered to the mice in their drinking water and its chemopreventative activity on the development of preneoplastic / neoplastic lesions assessed. Specific Aim 2 will test the hypothesis that PKU can protect against breast cancer using "PKU mice". These studies will utilize an established PKU mouse model (ENU2/2), which has a mutation in the gene coding for PAH and display a range of phenotypic characteristics comparable to those of affected human individuals. The ENU2/2 mice will be treated with the chemical carcinogen DMBA under different protocols and the resulting induction of mammary tumors compared with control mice of the same genetic background. Taken together, the information gained from these in vivo studies will determine whether the genetic disorder that results in PKU can protect against breast cancer whose etiology may involve hormonal and/or environmental factors (carcinogens). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECT OF CAPTOPRIL ON THE DIABETIC-HYPERTENSIVE HEART Principal Investigator & Institution: Heyliger, Clayton E.; Ponce School of Medicine G.P.O. Box 7004 Ponce, Pr 00731 Timing: Fiscal Year 2001; Project Start 30-SEP-1986; Project End 31-MAY-2005 Description (provided by applicant): Hypertension and diabetes mellitus commonly occur together. Unfortunately, very few randomized, controlled trials of antihypertensive treatment have been carried out in diabetic patients. Thus, decisions regarding the efficacy of such treatment must be based upon evidence, often controversial, extrapolated from studies in non-diabetic populations. A classic example can be seen in studies on the effect of antihypertensive therapy on lipids. Although abnormal myocardial lipid metabolism is a serious complication of diabetes mellitus and is strongly implicated in diabetes-induced primary cardiomyopathy, studies on antihypertensive therapy-induced lipid abnormality are confined to the development of atheroscelerosis and ischemic heart disease. We believe that the effect of antihypertensive agents on lipid metabolism in the cardiovascular system is not limited to the blood where they either have no effect, adversely affect or have a beneficial effect on lipid levels, but also extends to the myocardium, where they also influence lipid levels. Further, this alteration in myocardial lipid metabolism is associated with changes in cardiac contractile performance. In this regard, it is our hypothesis that the beneficial effect of captopril on lipid metabolism in the circulation is not confined to the blood where it decreased total cholesterol, triglycerides, and low density lipoproteins (LDL) as well as increased high density lipoproteins (HDL), but is also beneficial to the myocardium where it likewise positively influences lipid metabolism. This study will, therefore, provide evidence to support this hypothesis. It will assess the effect of captopril on myocardial lipid metabolism of the diabetic-hypertensive rat. Specifically, it will assess the effect of this agent on myocardial levels of cholesterol, triglycerides and long chain acyl carnitines and CoAs. These lipids and lipid intermediates accumulate in the diabetic heart and are strongly implicated in its depressed contractile performance. The male spontaneously hypertensive rat (SHR) will be the animal model. It will be made diabetic with a single tail vein injection of streptozotocin (60 mg/kg). Captopril will be administered in the drinking water (100 mg/kg) 3 days after diabetes induction.
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Rats will be sacrificed after 6 weeks of diabetes with sodium pentobarbital (75 mg/kg, i.p.). This study will present new findings about captopril therapy during diabetes plus hypertension. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EFFECT OF ETHANOL ON THE MURINE B CELL COMPARTMENT Principal Investigator & Institution: Waldschmidt, Thomas J.; Pathology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant): Long-term alcohol consumption progressively leads to multiple immune defects. Chronic alcoholics display lesions in both innate and adaptive immunity, and experience increased rates of bacterial and viral infection. Of particular interest, extended alcohol intake leads to abnormalities within the B cell compartment. In many alcohol abusers, total circulating B cells are depressed and Ab titers in response to vaccination are poor. In addition to humeral deficiency, regulation of B cell activity is disrupted leading to increased levels of serum Ig and the presence of autoantibodies. Taken together, it is clear that alcohol leads to impaired B cell function, and in turn, life-threatening infections. In order to understand better the extent of B cell dysfunction, and the means by which ethanol effects these changes, it is essential to utilize experimental models. A large number of studies have employed rodent models where ethanol is administered in liquid diets over short periods. Although a range of immune defects have been documented with this approach, these findings are best applied to abnormalities that appear after binge drinking in humans given the short duration of consumption and induction of the stress response. In order to better mimic the condition of chronic alcoholism, we have established a long-term murine model where ethanol is provided in drinking water. Using this system, we have found that months of ethanol intake result in loss of mature splenic B cells and diminished T celldependent (TD) antibody (Ab) responses. We have further discovered abnormalities in B cell maturation and lymphoid structure. Importantly, these defects develop without evidence of systemic stress. Using this model, proposed experiments will fully document the effects of ethanol on the B cell compartment, and the underlying mechanisms leading to humeral dysfunction. Studies in Aim 1 will test a number of hypotheses to explain the attrition of B cells after long-term ethanol intake, including defects in maturation, half-life, and production of supportive chemokines and cytokines. Aim 2 will ask whether ethanol induces cell autonomous lesions in B cells leading to abnormal activation and differentiation. Experiments in Aims 3 and 4 will assess the capacity of ethanol-consuming mice to produce Abs after immunization with T cell independent and TD antigens, respectively. Importantly, Aim 4 will thoroughly examine the effects of ethanol on T cell-driven B cell differentiation including affinity maturation, somatic mutation, generation of memory cells, and formation of long-lived plasma cells. Collectively, these studies will expand our understanding of humeral defects common to chronic alcoholics, and offer novel insights with which to fashion better therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: ETHANOL EFFECTS ON LIVER IN SELF-ADMINISTERING PRIMATES Principal Investigator & Institution: Cunningham, Carol C.; Professor; Biochemistry; Wake Forest University Health Sciences Winston-Salem, Nc 27157
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Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2005 Summary: (provided by applicant): Most protocols that employ animal models for studying the development of alcoholic liver disease utilize the rat that is being administered ethanol as part of the diet. These models have provided much of the information we presently have on the mechanisms that contribute to development of liver damage associated with alcohol abuse. To date there are no animal models where voluntary ethanol consumption has led to irreversible liver damage; i.e., damage past the fatty liver stage. The studies proposed in this application are designed to determine if non-human primates that are self-administering ethanol will demonstrate liver pathology predictive of the development of alcoholic hepatitis and fibrosis. Eleven Macaca fascicularis monkeys will be given free access to ethanol in drinking water for 1 year. These animals have been previously trained to drink ethanol voluntarily and some have consumed up to 4g/kg/day, which is equivalent to 16 drinks a day by a human. The heavier drinkers averaged blood ethanol concentrations of 170 mg/dl in a previous protocol. In the proposed studies, light, moderate and heavy drinkers will be included, which are comprised of 6 females and 5 males. Evidence for liver damage will be sought by analyses of blood samples, which will include measurements of yglutamyltransferase, aspartate and alanine transaminases, bilirubin, albumin, globulin and other blood components. Urinary concentrations of isoprostanes will be measured to screen for ethanol-related oxidative stress. Liver needle biopsy samples, taken every 3 months, will be examined by light and electron microscopy for indices of liver damage, such as hepatocyte ballooning, Mallory body formation, inflammation and fibrosis. lmmunohistochemical analyses will be implemented to measure levels of inflammation, apoptosis and stellate cell activation. The objectives of this study are 1) to determine if the self-administering M. fascicularis will develop liver pathology past the fatty liver stage and 2) to evaluate the efficacy of using blood and urine samples to follow development of alcoholic liver disease in an animal model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FURTHER STUDIES ON ANTI HIV 1 ACTIVITY OF INTERLEUKIN 16 Principal Investigator & Institution: Zhou, Paul; Southwest Foundation for Biomedical Res San Antonio, Tx 782450549 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2004 Summary: Interleukin 16 is a potent anti-HIV-1 agent. Previously, we demonstrated that at subnanomolar concentrations the C-terminal 130-amino acids (aa) of IL-16 constitutively secreted by CD4 transfectants renders these cells resistant to HIV-1. We and others also demonstrated that in CD4 T cells, IL-16 mediated HIV inhibition through repression of HIV LTR activity. In this proposal we will focus on three aspects of anti-HIV-1 activity of IL-16. First, we will search for more stable, potent version of IL16 and molecularly dissect its anti-HIV and chemoattractant activities. We will make gene constructs expressing several modified versions of human IL-16 with a heterologous signal peptide. Stable human CD4 transfectants will be generated. The expression, stability, secretion, and anti-HIV-1 activity of these various versions of IL-16 will be compared. We will also generate several single point mutants of IL-16 to dissect their anti-HIV and chemo attractant activities. Second, we will test the synergy between IL-16 and chemokines in anti-HIV-1 activity. We will generate retroviral gene constructs expressing IL-16 and methionine-modified RANTES or methionine-modified SDF-1beta. The recombinant retroviral particles produced by stable packaging cells will be used to transduce primary human CD4 T cells. The expression of transgenes and the effect of
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transgene products on both macrophage-tropic and T cell line-tropic HIV-1 replication, CD4, CXCR4 or CCR5 expression, and cell growth will be tested. In parallel, we will make rIL-16, rMet-SDFlbeta, and rMet-RANTES in bacteria. The synergy of these proteins in anti-HIV activity will be quantified. Third, we will develop an ex vivo procedure to regulate IL-16 and chemokine expression in a murine model. Using this model, the long-term regulation and safety of IL-16 and chemokine secretion in vivo will be evaluated. We will generate retroviral constructs co-expressing murine IL-16 and Met-RANTES or Met-SDF-lbeta under a tetracycline-inducible promoter. The inducibility of transgene expression will be tested in genetically manipulated mouse CD4 T cells in vitro. If the results are encouraging, we will transplant these cells into syngeneic mice. The level of transgene expression will be regulated by doxycycline administered in drinking water. TheserumlevelofIL16andchemokinesandpotentialsignsof inflammation will be closely monitored. We hope these studies will lead to an IL-16- and chemokine-based therapeutic strategy for the treatment of AIDS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: GLUTATHIONE IN ENVIRONMENTAL TOXICITY AND DISEASE Principal Investigator & Institution: Dalton, Timothy P.; Environmental Health; University of Cincinnati 2624 Clifton Ave Cincinnati, Oh 45221 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Reduced glutathione (GSH) is one of the cell's major defenses against oxidative stress. Lowered GSH levels have been implicated in susceptibility to numerous complex diseases (including neurodegenerative disorders, cancer, diabetes mellitus, cataracts, and AIDS) plus toxicity to environmental chemicals and heavy metal ions such as cadmium. Levels of GSH vary 10-fold between different cell types. The rate-limiting step in GSH biosynthesis is glutamate-cysteine ligase (GCL). GCL activity exists as the GCL catalytic subunit (GCLC) or as the GCL holoenzyme, a heterodimer composed of GCLC and a modifier subunit GCLM. Using gene targeting, we have generated conventional Gclm(-/-) and Cre-inducible Gclc(-/-) knockout mouse lines. GSH levels in Gclm(-/-) mice are only ~10% of that in Gclm(+/+) littermates in all tissues surveyed, yet, surprisingly, they are viable and fertile. Liver-specific Gclc(-/-) mice die by age 4 weeks, but can be rescued by N-acetylcysteine in the drinking water. With these mice, we are in a unique position to address the hypothesis that Gclm(-/-) mice will be susceptible to both environmental and endogenous toxicants because although the amount of GCLC controls the potential maximum level of cellular GSH, the GCLC/GCLM ratio determines the actual level. Thus, we will: [a] Evaluate endogenous, genotoxicity and oxidative stress in untreated Gclm(+/+) and Gclm(-/-) mice; [b] Assess cadmium-induced liver and kidney toxicity in Gclm(+/+) and Gclm(-/) mice; and [c] Dissect the role of GCLC and GCLM in controlling GSH levels through inducible expression of GCLC and GCLM in double-knockout Gclc/Gclm(-/-) immortalized hepatocytes. By way of these studies, we will define further the role of GCLM and GSH during both heavy metal-induced as well as endogenously-induced oxidative stress, while evaluating the Gclm(-/-) mouse as a model for a compromised oxidative stress response. Further, we will delineate the roles of GCLC and GCLM in controlling GSH levels. These studies will provide valuable insight into understanding the etiology, preventive medicine, and the possible development of therapeutic intervention in the above-mentioned diseases and toxicities. For example, studies suggest that human genetic differences exist in toxicity to cadmium and other environmental toxicants that cause oxidative stress; moreover, the GCLC and GCLM
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genes are highly polymorphic. Our proposed research should therefore help focus future genotype-phenotype association studies between the appropriate DNA variant sites in the GCLC and GCLM genes and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: HEALIH EFFECTS AND GEOCHEMISTRY OF ARSENIC AND LEAD Principal Investigator & Institution: Graziano, Joseph H.; Professor Public Health And; Div/Environmental Hlth Scis; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2001; Project Start 01-JUN-2000; Project End 31-MAR-2005 Summary: This proposal is submitted in response to RFA ES-99-001, entitled with Superfund Hazardous Substances Basic Research Program. The contamination of soils and drinking water with As and Pb are associated with major public health, remedial, and environmental policy problems. As is found in soil or water at the majority of Superfund sites while Pb is a soil-borne contaminant of concern at approximately 300. This proposal seeks to obtain new knowledge, and train multi-disciplinary pre- and post-doctoral students, concerning the bioavailability of soil Pb in humans, and the bioavailability and/or geochemistry at four Superfund sites in the U.S., two contaminated with Pb and two with As. It also encompasses epidemiologic and geochemistry studies of As in drinking water in Bangladesh which focus on carcinogenic, reproductive and childhood effects of As exposure. We also devote resources to the development of practical remediation strategies for As in wastewater in drinking water. The proposal includes four biomedical research projects: 1) Bioavailability of Soil Pb and As in Humans; 2) Genotoxic Mechanisms of As in Mammalian Cells; 3) A Cohort Study of Aresnicosis in Bangladesh; 4) Environmental As, Pregnancy, and Children's Health. The biomedical research is directly related to that which occurs in three non- biomedical projects: 5) As Mobilization and Bangladesh Groundwater; 6) Redistribution of As at Sites in NF and Maine; and 7) Assessment and Remediation for as Enrichments in Groundwater. The research projects are supported by three Research Support Core Labs: 8) Trace Metals; 9) Geochemistry; and 10) Hydrology An Administrative Core includes an Information Dissemination Program and a Government Liaison & Outreach Program. Finally, a Training Core coordinates multi- disciplinary education and interaction among pre- and post-doctoral trainees support by this proposal as well as other training grant. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: HIGH CAPACITY SNP GENOTYPING IN ARSENIC INDUCED DISEASE Principal Investigator & Institution: Jensen, Ronald H.; Professor in Residence; Cancer Center; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 94122 Timing: Fiscal Year 2002; Project Start 06-JUN-2002; Project End 31-MAR-2005 Summary: (provided by applicant): It is well known that the causes of common multifactorial diseases are both genetic and environmental in origin. Epidemiological studies (including the investigators? own international investigations) have shown that consuming drinking water with high levels of inorganic arsenic results in high health risk. A current challenge is to identify genetic polymorphisms in a set of environmentally-associated genes that may independently confer modest risk, but collectively comprise high risk profiles that predispose an individual to poor health
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consequences from arsenic exposure. The primary objective of this planning grant is to form a consortium with the capability to meet this current challenge. To accomplish this objective, this project has 3 specific aims. The first specific aim is to organize a cohesive group of multidisciplinary researchers with a shared mutual understanding of the methodologies, issues and problems involved in carrying out molecular epidemiology studies. The proposed consortium has researchers from 4 institutions: University of California San Francisco, University of California Berkeley (UC Berkeley), Children?s Hospital Oakland Research Institute and National Cancer Institute (NCI), NIH. The second specific aim is to create and perform a series of pilot studies designed to investigate concepts, hypotheses and technologies relevant to molecular epidemiology of arsenic-exposed populations. Three such studies are included in this application: (1) to determine the most feasible high output DNA SNP technology for investigating genotypic differences between individuals, (2) to identify the most appropriate set of specific genes and SNPs for investigations of arsenic-exposed populations, and (3) to develop appropriate methodologies for discriminating and prioritizing the results of the multiple statistical testing involved in epidemiology studies using SNP genotyping. After completion of these pilot projects, the third specific aim is to prepare and submit to NIH a detailed proposal to perform a molecular epidemiology study to systematically investigate genetic factors that influence susceptibility to arsenic-induced skin lesions in a population in India. About 400 blood samples for this population have already been collected and are held in frozen storage. As a result of this systematic study, individuals at particular risk for arsenic-induced effects will be identified and subject to intensified surveillance screening. In addition, mechanistic information will provide potential targets for preventive and curative interventions in exposed populations (e.g., nutrients or drugs). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: IMPLANTED MEMBRANES FOR CHARACTERIZATION AND MONITORING Principal Investigator & Institution: Engebretson, Daniel S.; Dakota Technologies, Inc. 2201-A 12Th St N Fargo, Nd 58102 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2004 Summary: (provided by applicant): Many localities across the Unites States rely upon groundwater as the source of drinking water. In our industrialized society, pollution threatens the groundwater supply and, therefore, poses a significant health risk to the population. This Phase I SBIR research proposal offers an innovative solution to current inadequacies in groundwater monitoring. With the proposed sampling membranes, it will be possible to better characterize a contaminated site before remediation begins by providing more cost-effective and timely data. Once remediation begins, the same tools can be used to actively monitor the status of the remediation and allow site managers to make better decisions about remediation strategies. In addition, both of these options can be employed at a significantly lower cost than current technologies. The proposed samplers are passive devices that can be easily deployed in the subsurface using either state-of-the-art direct push technology or conventional drilling. Also, the samplers can be retrofit into existing monitoring wells, making it possible to convert antiquated wells to state-of-the-art technology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMPROVING THE MONKEY RESEARCH FACILITIES Principal Investigator & Institution: Kraiselburd, Edmundo N.; Professor & Director; None; University of Puerto Rico Med Sciences Medical Sciences Campus San Juan, Pr 00936 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2005 Summary: (provided by applicant): The specific aim of this application is to help the UPR for repair, renovation, and modernization of its unique animal research resource (ARC) at the CS facility of the CPRC. The CPRC is an unrivaled national and international research resource for comparative studies in the biomedical and behavioral sciences that has received NCRR funding through a P40 award or the equivalent for the past three decades. The proposed renovations will improve the care of research animals and will provide much needed infrastructure support for the ongoing and planned biomedical and behavioral research program at CS. The free-ranging population of rhesus monkeys (Macaca mulatta) on the island of CS provides scientists with an unparalleled opportunity for performing biomedical and behavioral research projects utilizing primates residing in a semi-natural habitat. This population has the most extensive computerized demographic and genetics database available to researchers anywhere in the world. The population management program for CS has been designed to optimize the health and well-being of the monkeys, to enhance the value of the colony for research. In addition, the goal is to provide healthy animals to the scientific community for biomedical research, including AIDS and SlV pathogenesis and vaccine development as well as the support of National defense programs. Many of the existing structures on CS island were constructed in the 1930s and 1940s and are in dire need of renovation. This application seeks funds to renovate the dock to the island and funds to repair the roads, drinking water purification system and the three feeding and trapping corrals on CS. Renovations and modernization of these facilities are essential in order to prevent the continued deterioration of the infrastructure on CS, to maintain and enhance animal health and well being, to retain AAALAC accreditation, to comply with federal regulations and guidelines, and to continue to promote the research program and resources of the UPR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INDUCIBLE LIF RECEPTOR ABLATION IN ADULT MICE Principal Investigator & Institution: Ware, Carol B.; Comparative Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2004 Summary: The ability to selectively, inducibly and reversibly target mutations to specific proteins in adult mice would be a powerful tool in the study of aging. Toward this goal, we have made a tetracycline responsive ablation of the gene for the leukemia inhibitory factor receptor (LIFR) in ES cells. This mutation has transmitted through the mouse germline and mating pairs heterozygous for the targeted mutation are now producing pups. Loss of LIFR using standard non-inducible gene targeting techniques is a perinatal lethal profoundly affecting many systems including bone (osteoporosis) and glial cell development (agliogenesis). Thus, we are now poised to address: 1. the utility of a tetracycline inducible gene ablation approach in the study of aging 2. identification of adult consequences of LIFR loss. The inducible targeting vector incorporates a complete set of tet-off elements so that a full length rat LIFR cDNA is incorporated homologously into exon 2 of the mouse LIFR effectively ablating the mouse gene with tetracycline control of the introduced rat LIFR homolog. Because rat LIFR insertion is targeted to be
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under appropriate control of the endogenous mouse LIFR promoter elements, expression of rat LIFR is on where murine LIFR is constitutively expressed in the absence of a tetracycline derivative, doxycycline (Dox) and silenced in the presence of Dox. Expression of rat LIFR is reactivated upon removal of Dox. Sensitivity of this system will be studied both by semi- quantitative reverse transcription polymerase chain reaction (rtPCR) to measure whole tissue alterations in LIFR levels in response to Dox in the drinking water and by utilizing a beta-galactosidase reporter gene incorporated in the targeting construct which is also switched off in the presence of Dox. Beta-galactosidase will be visualized in situ by X-gal staining to analyze localized effects of Dox administration. Effects of Dox and preliminary analysis of biological consequences of adult LIFR ablation will be assessed in bone, the central nervous system, skeletal and cardiac muscle, lung, liver, pancreas, spleen and kidney. In summary, a new technique for adult genetic manipulation will be developed and characterized that will elucidate the role in aging of the multi-functional cytokines that utilize LIFR. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INFLUENCE OF FOOD PRESERVATIVES ON DENTAL CARIES Principal Investigator & Institution: Bowen, William H.; Welcher Professor of Dentistry; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2001; Project Start 01-SEP-1995; Project End 31-DEC-2004 Summary: The prevalence of dental caries has been reduced significantly in some segments of the population over the past 25 years. The observed reduction has been attributed largely to increased exposure to fluoride in drinking water and use of fluoridated dentrifrices. During the same time period the use of food preservatives e.g. benzoates, sorbates, propionates, salicylates has also increased dramatically. For example the consumption of benzoate in the U.S. has increased from 1.8 million tons in 1970 to 25.5 million in 1995. Thus humans are exposed to preservatives constantly; persons in the U.S. consuming the average amount of soda ingest 800 mg of benzoate daily. Food preservatives are weak acids and exert their anti-microbial effect in a manner similar to that of fluoride i.e. at low pH values they diffuse undissociated through the bacterial cell membrane and acidify the cytoplasm, rendering microorganisms sensitive to acid. Acid tolerance is a characteristic of cariogenic organisms. Weak acids may also affect bacterial membranes. We have preliminary data which show that benzoates reduces the production of glycosyltransferase by microorganisms without affecting the enzymatic activity. This observation is consistent with an earlier report (Bowen and Hewitt, 1971) which showed that fluoride in growth medium influences the production of glucosyltransferase by mutans streptococci. Data from preliminary studies conducted in rats show that benzoate and non-steroidal antiinflammatory agents e.g. ketoprofen (weak-acid) enhances the cariostatic effect of fluoride and also many suppress mutans populations. The purpose of the present study is to explore the effects of well-recognized food preservatives alone or in combination with fluoride on caries in our animal model. The outcome of this research could result in identifying a novel method of enhancing the effectiveness of fluoride. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IN-SITU REMOVAL OF PERCHLORATE WITH NANOSCALE PARTICLES Principal Investigator & Institution: Kim, Heekyung; Lynntech, Inc. College Station, Tx 77840
30 Drinking Water
Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 30-NOV-2002 Summary: (provided by applicant): Perchlorate has emerged in recent years to become a significant new threat to drinking water supplies and the environment and its contamination of groundwater has been estimated to potentially affect the drinking water supplies of at least 12 million people in the United States. The use of bioreactors based on anaerobic biochemical reduction processes has been evaluated as the most promising treatment technology. However, the treatment by bioreactors poses toxicological problems by the microbes, not generally accepted to the public and needs an additional treatment. These biochemical processes are naturally occurring but slow because of insufficient electron donors. Lynntech, Inc. proposes a technology, which uses nanoscale iron particles to generate dissolved hydrogen as the electron donor for the indigenous anaerobic microbes in the subsurface environment so that the natural biodegradation can be sufficient to remove perchlorate to a safe level. The nanoscale iron particles due to its size can reach pores easily, supply electrons to the anaerobic microbes in regions otherwise unreachable, and then are retrieved by pumping. This technology requires no construction of bioreactors specifically designed for the perchlorate removal but utilizes the subsurface environment as a naturally occurring anaerobic reactor so that the treatment cost will be drastically reduced. PROPOSED COMMERCIAL APPLICATION: This technology will be used by regulatory agencies like EPA, DOE, DOD and NASA, of which facilities have been found to be contaminated with perchlorates. Successful development of this technology can potentially be used in treating water contaminated with other oxidized contaminants in water such as nitrate, bromate and chlorate. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: LEAD EFFECTS ON SKELETAL STEM CELLS AND FRAC Principal Investigator & Institution: Schwarz, Edward M.; Associate Professor; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2006 Summary: (provided by the applicant): The unifying hypothesis of this Program Project is that Pb exposure causes osteoporosis, which at the cellular level is known to be the result of an imbalance between bone resorption and bone formation. This condition is also associated with defective skeletal repair, which represents a significant component of the disease, as it has been shown that ~24% of osteoporosis patients that sustain a hip fracture die from associated complications. Critical data in support of this theory are that animals feed Pb in their diet become osteoporotic. At present the mechanism of this Pb-induced osteoporosis and the effects of Pb on fracture healing are unknown. This project will test the hypotheses that 1) Pb-induced osteoporosis is caused by preferential inhibitory effects on bone stem cells (osteoblast >>osteoclast progenitors) and 2) this inhibition has significant effects on skeletal repair (fracture healing). To test this the investigators will utilize two different Pb exposure regimens: Chronic Pb exposure (adult mice continually fed Pb in their drinking water) and osteoporosis-induced exposure (adolescent mice are exposed to Pb during development to incorporate Pb into their bones following 2 month of a Pb free diet, to clear the systemic Pb, the mice are overiectomized to commence the osteoporosis-induced exposure). Utilizing these exposures regimens with the dosing of 0,200 or 500ppm of Pb in their drinking water, to achieve a blood Pb concentration of (
