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DRI NKI NO WATER AND H EALTH Volume 9: Selected Issues in Risk Assessment Safe Drinking Water Committee Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C. 1989

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NATIONAL ACADEMY PRESS, 2101 Constitution Ave., NW, Washington, DC 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering. and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences. the National Academy of Engineering, and the Institute of Medicine. The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research. dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Frank Press is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members. sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineers also sponsors engineering programs aimed at meeting national needs encourages education and research. and recognizes the superior achievements of engineers' Or. Robert M. White is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and. upon its own initiative, to identify issues of medical care, research, and education. Dr. Samuel O. Thier is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is admin- istered jointly by both Academies and the Institute of Medicine. Dr. Frank Press and Dr. Robert M. White are chairman and vice chairman. respectively. of the National Research Council. The project was funded by the U.S. Environmental Protection Agency under Contract No. 68- 01-6371 (Part 1: DNA Adducts) and under Contract No. 68-01-3169 (Part 11: Mixtures) with the National Academy of Sciences. The contents of this document do not necessarily reflect the views and policies of the Environmental Protection Agency, and an official endorsement should not be inferred. Library of Congress Catalog Card Number 77-89284 International Standard Book Number 0-309-03897-9 Printed in the United States of America

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1 List of Participants SUBCOMMITTEE ON DNA ADDUCTS DAVID 3. BRUSICK, Hazleton Laboratories America, Inc., Vienna, Virginia, Chairman GAIL T. ARCE, Haskell Laboratory for Toxicology and Industrial Medicine' E. I. du Pont de Nemours & Co., Newark, Delaware JOHN C. BAlLAR, McGill University School of Medicine, Montreal, Quebec, Canada RAMESH C. GUPrA, Baylor College of Medicine, Houston, Texas ROBIN HERBERT, Mount Sinai Medical Center, New York, New York PAUL H. M. LOHMAN, Sylvius Laboratory, State University of Leiden, Leiden, The Netherlands CAROL W. MOORE, CUNY Medical School, The City College of New York, New York, New York ROBERT F. MURRAY, Howard University College of Medicine, Washington D.C. MIRIAM C. POIRIER, National Cancer Institute, Bethesda? Maryland GARY A. SEGA, Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee RICHARD B. SETLOW, Biology Department, Brookhaven National Laboratory, Upton, New York JAMES A. SWENBERG, Chemical Industry Institute of Toxicology Triangle Park, North Carolina .. . ~ Research

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iv List of Participants Advisers and Contributors ROGER W. GlESE, College of Pharmacy and Allied Health Professions, Northeastern University, Boston, Massachusetts FRANK C. RICHARDSON, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina SU BCOMM ITTEE ON M IXTU RES RONALD WYZGA, Electric Power Research Institute, Palo Alto, California, Chairman JULIAN B. ANDELMAN, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania W. HANSBROUGH CARTER JR., Virginia Commonwealth University, Richmond, Virginia NANCY R. KIM, New York State Department of Health, Albany, New York SHELDON D. MURPHY, University of Washington, Seattle, Washington BERNARD WEISS, University of Rochester School of Medicine and Dentistry, Rochester, New York RAYMOND S. H. YANG, National Institute of Environmental Health Sciences/ National Toxicology Program, Research Triangle Park, North Carolina SAFE DRI N Kl NO WATER CON M ITTEE DAVID J. JOLLOW, Medical University of South Carolina, Charleston, South Carolina, Chairman DAVID E. BICE, Lovelace Inhalation Toxicology Research Institute, Albuquerque, New Mexico JOSEPH F. BORZEULECA, Virginia Commonwealth University, Richmond, Virginia ~ DAVID I. BRUSICK, Hazleton Laboratories America, Inc., Vienna, Virginia EDWARD J. CAEABRESE, North East Regional Environmental Public Health Center, University of Massachusetts, Amherst, Massachusetts ]. DONALD JOHNSON, School of Public Health, University of Noah Carolina, Chapel Hill, North Carolina RONALD WYZGA, Electric Power Research Institute, Palo Alto, California National Research Council Staff ANDREW M. POPE, Project Director MARVIN SCHNElDERMAN, Principal Staff Scientist LESLYE B. WAKEFIELD, Project Coordinator (until September 1988) ANNE M. SPRAGUE, Research Assistant NORMAN GROSSBEATT, Editor

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List of Participants v Sponsoring Agency KRISHAN KHANNA, Office of Drinking Water, U.S. Environmental Protection Agency, Washington, D. C., Technical Manager BRUCE MINTZ, Office of Drinking Water, U.S. Environmental Protection Agency, Washington, D.C., Project Officer BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY GlEBERT S. OMENN, School of Public Health and Community Medicine University of Washington, Seattle, Washington, Chairman FREDERICK R. ANDERSON, Washington College of Law, American University, Washington, D.C. JOHN C. BAlUAR, McGill University School of Medicine? Montreal Quebec, Canada DAVID BATES, University of British Columbia Health Science Centers Vancouver, British Columbia, Canada JOANNA BURGER, Department of Biological Sciences Rutgers University Piscataway, New Jersey RICHARD A. CONWAY, Department of Engineering, Union Carbide Corporation, South Charleston, West Virginia WILLIAM E. COOPER, Department of Zoology, Michigan State University. East Lansing, Michigan SHELDON K. FRIEDEANDER, Department of Chemical Engineering, University of California, Los Angeles, California BERNARD D. GOLDSTEIN, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey DONALD R. MADISON, University of Arkansas for Medical Sciences Little Rock, Arkansas DUNCAN PATTEN, Arizona State University Center for Environmental Studies, Tempe, Arizona EMIL A. PFITZER, Department of Toxicology and Pathology, Hoffmann-La Roche Inc., Nutley, New Jersey PAUL RISSER, University of New Mexico, Albuquerque, New Mexico WILElAM H. RODGERS, University of Washington School of Law? Seattle, Washington F. SHERWOOD ROWLAND, Department of Chemistry, University of California, Irvine, California LIANE B. RUSSELL, Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee MILTON RUSSELL, Energy Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee EEEEN K. SIEBERGEED, Environmental Defense Fund, Washington? D.C.

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vi List of Participants I. GLENN SIRES' University of Arizona College of Pharmacy, Tucson, Arizona COMMISSION ON LIFE SCIENCES BRUCE M. AEBERTS, Department of Biochemistry and Biophysics, University of California. San Francisco, California, Chairman PERRY L. ADKISSON, Chancellor, Texas A&M University System. College Station, Texas FRANCISCO J. AYALA, Department of Ecology and Evolutionary Biology, University of California, Irvine? California ]. MICHAEL BISHOP, The G. W. Hooper Research Foundation, University of California Medical Center? San Francisco, California FREEMAN ]. DYSON? School of Natural Sciences, The Institute for Advanced Study? Princeton, New Jersey NINA V. FEDOROFF, Department of Embryology, Carnegie Institution of Washington' Baltimore. Maryland RALPH W. F. HARDY, Boyce Thompson Institute for Plant Research, Ithaca. New York RICHARD J. HAVEL. Cardiovascular Research Institute? University of California School of Medicine, San Franciso, California EER()Y E. HOOD, Division of Biology, California Institute of Technology, Pasadena? California DC)NAUD F. HORNIG, Interdisciplinary Programs in Health, Harvard School of Public Health' Boston. Massachusetts ERNEST G. JAWORSKI, Division of Biological Sciences, Monsanto Company, St. Louis' Missouri SIM()N A. LEVIN, Ecosystems Research Center, Cornell University? Ithaca. New York HAROLD A. hi()ONEY. Department of Biological Sciences, Stanford University, Stanford, California STEPHEN P. PAKES, Southwestern Medical School. University of Texas, Dallas, Texas JOSEPH E. RALL. Intramural Research. National Institutes of Health Bethesda, Maryland RICHARD D. REMINGTON, Academic Affairs' University of Iowa. lowa City, Iowa PAUL G. RISSER, University of New Mexico, Alburquerque, New Mexico RICHARD B. SETEOW, Biology Department, Brookhaven National Laboratory, Upton, New York T()RSTEN N. WlESEE' Laboratory of Neurobiology? Rockefeller University? New York? New York

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List of Participants vi i National Research Council Staff JOHN E. BURRIS, Executive Director, Commission on Life Sciences DEVRA L. DAVIS, Director, Board on Environmental Studies and Toxicology JAMES I. RElSA, Associate Director RICHARD D. THOMAS, Director, Toxicology and Epidemiology Program LEE R. PAULSON, Manager, Toxicology Information Center JACQUELINE K. PRINCE, Administrative Associate JEANEhE SPOON, Administrative Assistant

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Preface The 1974 Safe Drinking Water Act (U.S. Public Law 93-523) authorized the U.S. Environmental Protection Agency (EPA) to establish federal stan- dards to protect the public from harmful contaminants of drinking water. The law also provided for the establishment of a joint national-state system to ensure compliance with the standards and to protect underground water sources from contamination. Section 1412(e) of the act and its amendments (42 U.S. Code, Subpart 300f et seq., 1977) mandated that the National Research Council (NRC) conduct studies to identify adverse health effects associated with contaminants in drinking water, to identify relevant research needs, and to make recommendations regarding such research. Amendments to the law in 1977 requested revisions of the NRC studies to report "new information which had become available since the NRC's most recent report, and every two years thereafter." This is the ninth volume in the series Drinking Water and Health issued by the Safe Drinking Water Committee of the Board on Environmental Studies and Toxicology of the NRC. Each volume has reviewed toxicologic data and assessed risks associated with specific drinking water contaminants. This volume focuses on two important current topics: the first part examines the possible uses of DNA adducts (addition products) in risk assessment, and the second part examines the issue of multiple toxic chemicals in drinking water and the assessment of their health risks. A comprehensive index to all nine volumes of the Drinking Water and Health series is also provided in this volume. As described in Part 1, studies of DNA have been rapidly refined and developed in the past few years. The ability to detect ever-smaller molecular IX

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x Preface alterations of DNA provides important opportunities for estimating and re- ducing public health risks associated with drinking water contaminants, foods, and workplace chemicals that bind to DNA to form adducts. In addition, protein adducts found in easily accessible body fluids sometimes reflect potential DNA-adduct formation. In recognition of the potential of these recent advances for protecting human health, the EPA's Office of Drinking Water asked the NRC's Safe Drinking Water Committee to convene a small group of experts in DNA- adduct research to review developments in the field (with special attention to possible uses of DNA adducts in risk assessment). EPA was especially interested in whether current techniques could confirm exposure or signal tumor initiation. The group was also to point out gaps in research and suggest priorities for additional research. The introduction of new methods to measure DNA adducts and protein adducts has already made some types of direct human population monitoring technically and economically feasible. That application of DNA technology might permit epidemiologic confirmation of reported human exposures and offer opportunities to validate extrapolation of data from animal bioassays. Participants in several recent meetings on research in this field have agreed that the new methods can have a marked impact on the biologic bases for estimating the risks associated with human exposure to several important classes of environmental pollutants. Use of the technology in risk assessment will depend on an understanding of the mechanistic relationships between DNA alterations and the ultimate expression of toxic effects. Recent devel- opments in the study of DNA binding and protein binding have provided a useful tool to begin to acquire that understanding, but additional information, such as clarification of the role of background or baseline adducts that are continually formed in animals and humans, will be needed for full use of the techniques. New methods of measuring DNA adducts are useful for several other reasons: They have permitted increasingly refined measurements of genetic ma- terial. They meet requirements of high intrinsic sensitivity and specificity at exposures approaching those in occupational and environmental settings. They seem in many instances to be relatively inexpensive, fast, and reproducible. They can be applied to readily available samples of such body fluids as blood, urine, and semen and to small samples of cells, such as of buccal mucosa and skin. Analytic instrumentation and relatively noninvasive methods for measuring DNA adducts and protein adducts could eventually lead to improved under

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Preface xi standing of the mechanisms of carcinogenesis, mutagenesis, and other health effects of exposure to DNA damaging agents. The Executive Summary of Part 1 summarizes the findings of the subcommittee. Chapter 1 describes where and how DNA adducts are formed and repaired; what is known of their relationship to protein adducts and to exposure to, and toxic effects of, contaminants; and some differences in adduct formation between humans and laboratory animals. The uses and limitations of current techniques for detecting DNA adducts and protein adducts and the outlook for the application of the techniques in toxicity testing, biologic monitoring, and epidemiology are described in Chapter 2. Chapter 3 presents the subcommittee's conclu- sions and recommendations. An appendix characterizes selected contami- nants found in drinking water and identifies those known to bind to DNA and form adducts, and a glossary defines terms. Part 2 of this volume addresses mixtures of toxic chemicals. The toxicity of chemicals is traditionally studied in terms of the effects of exposure to single toxic substances, rather than mixtures of substances. Regulatory agen- cies have used results of studies of single toxicants to form procedures for regulating exposure. But predicting effects of mixtures solely from knowledge of effects of their components can be erroneous. Some agents interact when combined to produce biologic responses different from those expected, and interactions and the magnitude of responses might not be considered properly. Many components of drinking water produce similar biologic effects. For example, the volatile, halogenated hydrocarbons are known to form common metabolites in mammalian systems. Other components inhibit enzymes in common, follow common metabolic pathways, or have common mechanisms of action in target organs. EPA's Office of Drinking Water asked the Safe Drinking Water Committee to convene a workshop to address the issue of mixtures of chemicals in drinking water and explore the improvement of methods for assessing the risk associated with chronic, low-level exposure to such mixtures. In light of the apparently common characteristics of some of the many chemicals in drinking water, EPA was particularly interested in the possibility of grouping some drinking water constituents for combined risk assessment. As part of the workshop, the Safe Drinking Water Committee's Subcommittee on Mix- tures reviewed the 1988 NRC report Complex Mixtures and related literature. The subcommittee then suggested to regulators that some drinking water contaminants, such as the volatile organic chemicals or organophosphorus and carbamate insecticides, could be grouped for combined risk assessment. Furthermore, the subcommittee suggested that even the risks associated with exposures to unlike chemicals that produce a wide variety of health effects might be weighed and combined. On behalf of the members of our two subcommittees, we would like to express our gratitude to the NRC staff members who assisted in these projects.

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xii Preface Leslye Wakefield served as project coordinator; her tireless efforts greatly aided both subcommittees in completing their work. We thank Lee Paulson, manager of the Toxicology Information Center, and Anne Sprague, who completed the final manuscript. Richard Thomas directed the NRC Safe Drinking Water programs for several years and was the initial director of this study. He also served as technical adviser on the DNA adducts portion of this report. Andrew Pope served as project director of the Mixtures portion of the report. The subcommittee also acknowledges the efforts of Norman Grossblatt, who edited the report, and those of Alison Kamat, Linda Poore, Erik Hobble, and Bernidean Williams, who assisted in extensive searching of the scientific literature and in reference verification. We also acknowledge the help of Robin Bowers in preparing manuscripts and Erin Schneider in providing general secretarial support. We especially thank Marvin Schneiderman, whose expertise and invaluable assistance were necessary to complete the second part of this report on chemical mixtures. We are grateful to Frank Richardson, who served as an adviser to our subcommittees; to Safe Drinking Water Committee Chairman David Jollow for his valuable participation; and to Devra Davis and Alvin Lazen for their creative insight and guidance. Our special thanks go to John Bailar for guiding this report to completion. Finally, we thank our colleagues on the two subcommittees for their contributions to this report. DAVID BRUSICK, Chairman Subcommittee on DNA Adducts RONALD WYZGA, Chairman Subcommittee on Mixtures

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Contents PART I: DNA ADDUCTS Executive Summary ........... 1 Biologic Significance of DNA Adducts and Protein Adducts 2 DNA-Adduct Technology 3 Conclusions and Recommendations ............. Appendix A: Drinking Water Contaminant Candidates for Development of Baseline Data on Formation of DNA Adducts Glossary . . Biographical Sketches Executive Summary 1 Introduction PART II: MIXTURES 2 Pharmacokinetics and the Risk Assessment of Drinking Wate Contaminants . . . x''' 3 ... 6 .. 38 ...... 61 ......... 79 .......... 89 ................ 101 108

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xiv Contents Risk Assessment of Mixtures of Systemic Toxicants in Drinking Water ............................................. 4 Assessment of Exposure to Organophosphorus Compounds Carbamates, and Volatile Organic Chemicals 5 Acetylcholinesterase Inhibitors: Case Study of Mixtures of Contaminants with Similar Biologic Effects 6 Volatile Organic Compounds (VOCs): Risk Assessment of Mixtures of Potentially Carcinogenic Chemicals 7 Conclusions and Recommendations for Research . 121 ............ 133 146 ......... 162 ............... 16X Appendix A: An Approach for Risk Assessment of Volatile Organic Chemicals In Drinking, Water That Uses Experimental Inhalation Data and a Physiologically Based Pharmacokinetic Model Appendix B: A Model Illustrating Synergism Appendix C: Models of Response: Dose Additivity and Response Additivity ........ Biographical Sketches ................ Index ................ ........... 171 .............. 175 .......... 177 PART 111: CUMULATIVE INDEX ....... 189 ........ 187