National Academies Press: OpenBook
Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
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TOXICITY TESTING IN THE 21ST CENTURY

A VISION AND A STRATEGY

Committee on Toxicity Testing and Assessment of Environmental Agents

Board on Environmental Studies and Toxicology

Institute for Laboratory Animal Research

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu

Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
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THE NATIONAL ACADEMIES PRESS

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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 project was supported by Contract 68-C-03-081 between the National Academy of Sciences and the U.S. Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project.

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Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
×

THE NATIONAL ACADEMIES

Advisers to the Nation on Science, Engineering, and 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. Ralph J. Cicerone 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 Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest 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. Harvey V. Fineberg 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 administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council.


www.national-academies.org

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COMMITTEE ON TOXICITY TESTING AND ASSESSMENT OF ENVIRONMENTAL AGENTS

Members

DANIEL KREWSKI (Chair),

University of Ottawa, ON, Canada

DANIEL ACOSTA, JR.,

University of Cincinnati, OH

MELVIN ANDERSEN,

The Hamner Institutes for Health Sciences, Research Triangle Park, NC

HENRY ANDERSON,

Wisconsin Division of Public Health, Madison

JOHN BAILAR III,

University of Chicago, IL

KIM BOEKELHEIDE,

Brown University, Providence, RI

ROBERT BRENT,

Thomas Jefferson University, Wilmington, DE

GAIL CHARNLEY,

HealthRisk Strategies, Washington, DC

VIVIAN CHEUNG,

University of Pennsylvania, Philadelphia

SIDNEY GREEN,

Howard University, Washington, DC

KARL KELSEY,

Harvard University, Boston, MA

NANCY KERKVLIET,

Oregon State University, Corvallis

ABBY LI,

Exponent, Inc., San Francisco, CA

LAWRENCE MCCRAY,

Massachusetts Institute of Technology, Cambridge

OTTO MEYER,

The National Food Institute, Technical University of Denmark, Søborg, Denmark

D. REID PATTERSON,

Reid Patterson Consulting, Inc., Elkhorn, WI

WILLIAM PENNIE,

Pfizer, Inc., Groton, CT

ROBERT SCALA,

Exxon Biomedical Sciences (Ret.), Tucson, AZ

GINA SOLOMON,

Natural Resources Defense Council, San Francisco, CA

MARTIN STEPHENS,

The Humane Society of the United States, Washington, DC

JAMES YAGER, JR.,

Johns Hopkins University, Baltimore, MD

LAUREN ZEISE,

California Environmental Protection Agency, Oakland

Staff

ELLEN MANTUS, Project Director

JENNIFER OBERNIER, Program Officer

RUTH CROSSGROVE, Senior Editor

NORMAN GROSSBLATT, Senior Editor

MIRSADA KARALIC-LONCAREVIC, Manager,

Technical Information Center

JORDAN CRAGO, Senior Project Assistant

Sponsor

U.S. ENVIRONMENTAL PROTECTION AGENCY

Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY

Members

JONATHAN M. SAMET (Chair),

Johns Hopkins University, Baltimore, MD

RAMÓN ALVAREZ,

Environmental Defense, Austin, TX

JOHN M. BALBUS,

Environmental Defense, Washington, DC

DALLAS BURTRAW,

Resources for the Future, Washington, DC

JAMES S. BUS,

Dow Chemical Company, Midland, MI

COSTEL D. DENSON,

University of Delaware, Newark

E. DONALD ELLIOTT,

Willkie Farr & Gallagher LLP, Washington, DC

MARY R. ENGLISH,

University of Tennessee, Knoxville

RUTH DEFRIES,

University of Maryland, College Park

J. PAUL GILMAN,

Oak Ridge Center for Advanced Studies, Oak Ridge, TN

SHERRI W. GOODMAN,

Center for Naval Analyses, Alexandria, VA

JUDITH A. GRAHAM,

American Chemistry Council, Arlington, VA

WILLIAM P. HORN,

Birch, Horton, Bittner and Cherot, Washington, DC

WILLIAM M. LEWIS, JR.,

University of Colorado, Boulder

JUDITH L. MEYER,

University of Georgia, Athens

DENNIS D. MURPHY,

University of Nevada, Reno

PATRICK Y. O’BRIEN,

ChevronTexaco Energy Technology Company, Richmond, CA

DOROTHY E. PATTON (retired),

Chicago, IL

DANNY D. REIBLE,

University of Texas, Austin

JOSEPH V. RODRICKS,

ENVIRON International Corporation, Arlington, VA

ARMISTEAD G. RUSSELL,

Georgia Institute of Technology, Atlanta

ROBERT F. SAWYER,

University of California, Berkeley

KIMBERLY M. THOMPSON,

Massachusetts Institute of Technology, Cambridge

MONICA G. TURNER,

University of Wisconsin, Madison

MARK J. UTELL,

University of Rochester Medical Center, Rochester, NY

CHRIS G. WHIPPLE,

ENVIRON International Corporation, Emeryville, CA

LAUREN ZEISE,

California Environmental Protection Agency, Oakland

Senior Staff

JAMES J. REISA, Director

DAVID J. POLICANSKY, Scholar

RAYMOND A. WASSEL, Senior Program Officer for Environmental Sciences and Engineering

KULBIR BAKSHI, Senior Program Officer for Toxicology

EILEEN N. ABT, Senior Program Officer for Risk Analysis

KARL E. GUSTAVSON, Senior Program Officer

K. JOHN HOLMES, Senior Program Officer

ELLEN K. MANTUS, Senior Program Officer

SUSAN N.J. MARTEL, Senior Program Officer

STEVEN K. GIBB, Program Officer for Strategic Communications

RUTH E. CROSSGROVE, Senior Editor

Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
×

INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL

Members

STEPHEN W. BARTHOLD (Chair),

University of California, Davis

KATHRYN A. BAYNE,

Association for Assessment and Accreditation of Laboratory Animal Care International, Waikoloa, HI

MYRTLE A. DAVIS,

Lilly Research Laboratories, Greenfield, IN

JEFFREY I. EVERITT,

GlaxoSmithKline Research and Development, Research Triangle Park, NC

JAMES G. FOX,

Massachusetts Institute of Technology, Cambridge

NELSON L. GARNETT, (formerly)

Johns Hopkins University, Baltimore, MD

ESTELLE B. GAUDA,

Johns Hopkins University, Baltimore, MD

COENRAAD F.M. HENDRIKSEN,

Netherlands Vaccine Institute, Bilthoven

JON H. KAAS,

Vanderbilt University, Nashville, TN

JOSEPH W. KEMNITZ,

University of Wisconsin, Madison

JUDY A. MCARTHUR CLARK, (formerly)

Pfizer Global R&D, Groton, CT

LETICIA V. MEDINA,

Abbott Laboratories, Abbott Park, IL

BERNARD E. ROLLIN,

Colorado State University, Fort Collins

ABIGAIL L. SMITH,

University of Pennsylvania, Philadelphia

STEPHEN A. SMITH,

Virginia Polytechnic Institute and State University, Blacksburg

Staff

JOANNE ZURLO, Director

LIDA ANESTIDOU, Program Officer

KATHLEEN BEIL, Administrative Coordinator

RHONDA HAYCRAFT, Senior Project Assistant

SUSAN VAUPEL, Managing Editor,

ILAR Journal

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OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY

Models in Environmental Regulatory Decision Making (2007)

Sediment Dredging at Superfund Megasites: Assessing the Effectiveness (2007)

Environmental Impacts of Wind-Energy Projects (2007)

Scientific Review of the Proposed Risk Assessment Bulletin from the Office of Management and Budget (2007)

Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006)

New Source Review for Stationary Sources of Air Pollution (2006)

Human Biomonitoring for Environmental Chemicals (2006)

Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006)

Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006)

State and Federal Standards for Mobile-Source Emissions (2006)

Superfund and Mining Megasites—Lessons from the Coeur d’Alene River Basin (2005)

Health Implications of Perchlorate Ingestion (2005)

Air Quality Management in the United States (2004)

Endangered and Threatened Species of the Platte River (2004)

Atlantic Salmon in Maine (2004)

Endangered and Threatened Fishes in the Klamath River Basin (2004)

Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003)

Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002)

Biosolids Applied to Land: Advancing Standards and Practices (2002)

The Airliner Cabin Environment and Health of Passengers and Crew (2002)

Arsenic in Drinking Water: 2001 Update (2001)

Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001)

Compensating for Wetland Losses Under the Clean Water Act (2001)

A Risk-Management Strategy for PCB-Contaminated Sediments (2001)

Acute Exposure Guideline Levels for Selected Airborne Chemicals (five volumes, 2000-2007)

Toxicological Effects of Methylmercury (2000)

Strengthening Science at the U.S. Environmental Protection Agency (2000)

Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000)

Ecological Indicators for the Nation (2000)

Waste Incineration and Public Health (2000)

Hormonally Active Agents in the Environment (1999)

Research Priorities for Airborne Particulate Matter (four volumes, 1998-2004)

The National Research Council’s Committee on Toxicology: The First 50 Years (1997)

Carcinogens and Anticarcinogens in the Human Diet (1996)

Upstream: Salmon and Society in the Pacific Northwest (1996)

Science and the Endangered Species Act (1995)

Wetlands: Characteristics and Boundaries (1995)

Biologic Markers (five volumes, 1989-1995)

Review of EPA's Environmental Monitoring and Assessment Program (three volumes, 1994-1995)

Science and Judgment in Risk Assessment (1994)

Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
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Pesticides in the Diets of Infants and Children (1993)

Dolphins and the Tuna Industry (1992)

Science and the National Parks (1992)

Human Exposure Assessment for Airborne Pollutants (1991)

Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991)

Decline of the Sea Turtles (1990)


Copies of these reports may be ordered from the National Academies Press

(800) 624-6242 or (202) 334-3313

www.nap.edu

Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
×

INSTITUTE FOR LABORATORY ANIMAL RESEARCH PUBLICATIONS

Science, Medicine, and Animals: A Circle of Discovery (2004)

The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop (2004)

National Need and Priorities for Veterinarians in Biomedical Research (2004)

Occupational Health and Safety in the Care and Use of Nonhuman Primates (2003)

International Perspectives—The Future of Nonhuman Primate Resources: Proceedings of the Workshop Held April 17-19, 2002 (2003)

Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003)

Principles and Guidelines for the Use of Animals in Precollege Education (2001)

Strategies That Influence Cost Containment in Animal Research (2000)

Definition of Pain and Distress and Reporting Requirements for Laboratory Animals: Proceedings of the Workshop Held June 22, 2000 (2000)

Monoclonal Antibody Production (1999)

Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1999 US/Japan Conference (1999)

The Psychological Well-Being of Nonhuman Primates (1998)

Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1998 US/Japan Conference (1998)

Biomedical Models and Resources: Current Needs and Future Opportunities (1998)

Approaches to Cost Recovery for Animal Research: Implications for Science, Animals, Research Competitiveness, and Regulatory Compliance (1998)

Occupational Health and Safety in the Care and Use of Research Animals (1997)

Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use (1997)

Guide for the Care and Use of Laboratory Animals, 7th ed. (1996)

Nutrient Requirements of Laboratory Animals, 4th ed. (1995)

Laboratory Animal Management: Dogs (1994)

Recognition and Alleviation of Pain and Distress in Laboratory Animals (1992)

Infectious Diseases of Mice and Rats (1991)

Companion Guide to Infectious Diseases of Mice and Rats (1991)

Laboratory Animal Management: Rodents (1990)

Immunodeficient Rodents: A Guide to Their Immunobiology, Husbandry, and Use (1989)

Use of Laboratory Animals in Biomedical and Behavioral Research (1988)


Copies of these reports may be ordered from the National Academies Press

(800) 624-6242 or (202) 334-3313

www.nap.edu

Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
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Preface

Over the past few decades, several toxicity-testing strategies have emerged for evaluating the hazards or risks associated with exposure to drugs, food additives, pesticides, and industrial and other chemicals. New testing technologies, methods, and approaches also have emerged in recent years. The U.S. Environmental Protection Agency (EPA) recognized the need to conduct a comprehensive review of toxicity-testing methods and strategies and requested that the National Research Council (NRC) conduct such a review and propose a long-range vision and strategy for toxicity testing.

In its 2006 interim report, the NRC Committee on Toxicity Testing and Assessment of Environmental Agents reviewed current toxicity-testing methods and strategies and selected aspects of several reports by EPA and others that described initiatives or proposals to improve current methods or strategies. The committee now presents its long-range vision and strategic plan to advance toxicity testing and considers its vision within the current regulatory framework. Although the committee was not charged to review government programs related to toxicity testing, some federal programs that are relevant to the subject of this report may be of interest to readers. For example, EPA has established a National Center for Computational Toxicology (http://www.epa.gov/comptox/index.html) that is developing new software and methods for predictive toxicology. The National Institute of Environmental Health Sciences, through the National Toxicology Program's Roadmap for the Future (http://ntp.niehs.nih.gov/files/NTPrdmp.pdf), has initiated a partnership with the Chemical Genomics Center of the National Institutes of Health to develop and carry out high- and medium-throughput screening assays to test more chemicals in less time and at less cost.

Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
×

This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the NRC’s Report Review Committee. The purposes of this independent review are to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following for their review of this report: Cynthia Afshari (Amgen, Inc.), Frederic Bois (INERIS), James Bus (Dow Chemical), Vincent James Cogliano (International Agency for Research on Cancer), David Dorman (The Hamner Institutes for Health Sciences), Alan Goldberg (Johns Hopkins University), Carole Kimmel (consultant), Gilbert Omenn (University of Michigan), Lorenz Rhomberg (Gradient Corporation), Joseph Rodricks (ENVIRON), Leslie Stayner (University of Illinois), and Helmut Zarbl (Fred Hutchinson Cancer Research Center).

Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by the review coordinator, Rogene Henderson (Lovelace Respiratory Research Institute), and the review monitor, Donald Mattison (National Institutes of Health). Appointed by the NRC, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the committee and the institution.

The committee gratefully acknowledges the following for making presentations to the committee: Thomas Hartung (ECVAM), William Greenlee (The Hamner Institutes for Health Sciences), Carl Barrett (Novartis Institute for BioMedical Development), Robert Chapin (Pfizer, Inc.), Michael Festing (private consultant), William Stokes (National Institute of Environmental Health Sciences), Edward Calabrese (University of Massachusetts-Amherst), John Doull (University of Kansas Medical Center), Bette Meek (Health Canada), Michael Firestone (EPA), Clifford Gabriel (EPA), Lee Hoffman (EPA), Jim Jones (EPA), Deidre Murphy (EPA), Rita Schoeny (EPA), and Charles Auer (EPA). The committee especially thanks Dorothy Patton (retired from EPA) for her contributions to the report and consultation on toxicity testing in regulatory contexts.

The committee is also grateful for the assistance of the NRC staff in preparing this report. Staff members who contributed to the effort are Ellen Mantus, project director; Joanne Zurlo, director of the Institute for Laboratory Animal Research; James Reisa, director of the Board on Environmental Studies and Toxicology; Jennifer Obernier, program officer; Ruth Crossgrove, senior editor; Norman Grossblatt, senior editor; Mirsada Karalic-Loncarevic, manager of the Tech-

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nical Information Center; Jordan Crago, senior project assistant; and Radiah Rose, senior editorial assistant.

I would especially like to thank all the members of the committee for their efforts throughout the development of this report.


Daniel Krewski, Chair

Committee on Toxicity Testing and Assessment of Environmental Agents

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BOXES

S-1

 

Key Questions to Address in Implementation

 

13

2-1

 

Key Terms Used in the Report

 

38

3-1

 

Example of Components of Signaling Pathway That Could Be Modeled

 

73

5-1

 

Key Research Questions in Developing Knowledge to Support Pathway Testing

 

124

5-2

 

Main Questions in Developing Tests and Methods

 

128

5-3

 

Some Science and Technology Milestones in Developing Toxicity-Pathway Tests As the Cornerstone of Future Toxicity-Testing Strategies

 

134

FIGURES

S-1

 

The committee’s vision for toxicity testing is a process that includes chemical characterization, toxicity testing, and dose-response and extrapolation modeling

 

5

S-2

 

Biologic responses viewed as results of an intersection of exposure and biologic function

 

7

2-1

 

The exposure-response continuum underlying the current paradigm for toxicity testing

 

39

2-2

 

Biologic responses viewed as results of an intersection of exposure and biologic function

 

49

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Suggested Citation:"Front Matter." National Research Council. 2007. Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC: The National Academies Press. doi: 10.17226/11970.
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2-3

 

The committee’s vision is a process that includes chemical characterization, toxicity testing, and dose-response and extrapolation modeling

 

50

3-1

 

Overview of chemical characterization component

 

58

3-2

 

Toxicity-testing component, which includes toxicity-pathway testing in cells and cell lines and targeted testing in whole animals

 

61

3-3

 

Overview of dose-response and extrapolation modeling component

 

69

3-4

 

Nrf2 antioxidant-response pathway schematic

 

73

3-5

 

Overview of population-based and human exposure data component

 

76

3-6

 

Overview of risk contexts component

 

81

3-7

 

Risk-assessment components

 

91

5-1

 

Progression of some important science and technology activities during assay development

 

136

5-2

 

Screening of chemicals that would not otherwise be tested or be subject to only limited testing

 

149

TABLES

2-1

 

Options for Future Toxicity-Testing Strategies

 

44

6-1

 

Definitions of Adverse Effect

 

178

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TOXICITY TESTING IN THE 21ST CENTURY

A VISION AND A STRATEGY

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Toxicity Testing in the 21st Century: A Vision and a Strategy Get This Book
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Advances in molecular biology and toxicology are paving the way for major improvements in the evaluation of the hazards posed by the large number of chemicals found at low levels in the environment. The National Research Council was asked by the U.S. Environmental Protection Agency to review the state of the science and create a far-reaching vision for the future of toxicity testing. The book finds that developing, improving, and validating new laboratory tools based on recent scientific advances could significantly improve our ability to understand the hazards and risks posed by chemicals. This new knowledge would lead to much more informed environmental regulations and dramatically reduce the need for animal testing because the new tests would be based on human cells and cell components. Substantial scientific efforts and resources will be required to leverage these new technologies to realize the vision, but the result will be a more efficient, informative and less costly system for assessing the hazards posed by industrial chemicals and pesticides.

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