Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page R1
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
OCR for page R2
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
OCR for page R3
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
OCR for page R4
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
OCR for page R5
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.
OCR for page R6
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
OCR for page R7
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
OCR for page R8
OCR for page R9
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
OCR for page R10
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
OCR for page R11
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.
OCR for page R12
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
OCR for page R13
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
OCR for page R14
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
