Cancer Risk Assessment E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 1784

Veröffentlichungsjahr: 2010

Beschreibung

With a weight-of-the-evidence approach, cancer risk assessment indentifies hazards, determines dose-response relationships, and assesses exposure to characterize the true risk. This book focuses on the quantitative methods for conducting chemical cancer risk assessments for solvents, metals, mixtures, and nanoparticles. It links these to the basic toxicology and biology of cancer, along with the impacts on regulatory guidelines and standards. By providing insightful perspective, Cancer Risk Assessment helps researchers develop a discriminate eye when it comes to interpreting data accurately and separating relevant information from erroneous.

Leseprobe

Table of Contents

Cover

Table of Contents

Half title page

Title page

Copyright page

PREFACE

CONTRIBUTORS

ABBREVIATIONS AND ACRONYMS

Part I: CANCER RISK ASSESSMENT, SCIENCE POLICY, AND REGULATORY FRAMEWORKS

CHAPTER 1 CANCER RISK ASSESSMENT

1.1. CANCER RISK ASSESSMENT

1.2. THE WEIGHT OF EVIDENCE (WOE) FOR DETERMINING CARCINOGENICITY

1.3. RISK ASSESSMENT IN THE 21ST CENTURY

1.4. APPLICATIONS IN RISK MANAGEMENT

CHAPTER 2 SCIENCE POLICY AND CANCER RISK ASSESSMENT

2.1. INTRODUCTION

2.2. USE OF RISK ASSESSMENT IN REGULATORY DECISION-MAKING

2.3. ROLE OF RISK ASSESSMENT GUIDELINES

2.4. DATA QUALITY REQUIREMENTS

2.5. TYPES OF DATA USED IN RISK ASSESSMENT

2.6. APPLICATION OF “CONSERVATIVE” ASSUMPTIONS AND PRECAUTION

2.7. CONCLUSION

CHAPTER 3 HAZARD AND RISK ASSESSMENT OF CHEMICAL CARCINOGENICITY WITHIN A REGULATORY CONTEXT

3.1. OVERVIEW

3.2. RISK ASSESSMENT

3.3. REGULATORY SCHEMES FOR INDUSTRIAL CHEMICALS AND BIOCIDES

3.4. SCIENTIFIC ASPECTS OF CARCINOGENIC RISK ASSESSMENT

3.5. CONCLUSIONS

ACKNOWLEDGMENTS

CHAPTER 4 USE OF CANCER RISK ASSESSMENTS IN DETERMINATION OF REGULATORY STANDARDS

4.1. INTRODUCTION

4.2. AIR STANDARDS

4.3. WATER STANDARDS

4.4. FOOD STANDARDS, PESTICIDE TOLERANCES, ADDITIVES, AND IMPURITIES

4.5. SOIL STANDARDS

4.6. CONSUMER PRODUCT STANDARDS

4.7. RECENT DEVELOPMENTS AND FUTURE DIRECTIONS

Part II: CANCER BIOLOGY AND TOXICOLOGY

CHAPTER 5 THE INTERPLAY OF CANCER AND BIOLOGY

5.1. HISTORICAL ACCOUNT OF SOME IMPORTANT EVENTS IN UNDERSTANDING CANCER

5.2. RECENT FOUNDATIONS OF BIOLOGICAL MECHANISMS OF CANCER

5.3. CELL BIOLOGY OF CANCER

5.4. SOME FINAL THOUGHTS ON BIOLOGY AND CANCER

CHAPTER 6 CHEMICAL CARCINOGENESIS: A BRIEF HISTORY OF ITS CONCEPTS WITH A FOCUS ON POLYCYCLIC AROMATIC HYDROCARBONS

6.1. A BRIEF HISTORY OF CHEMICAL CARCINOGENESIS

6.2. JAMES A. AND ELIZABETH C. MILLER AND THEIR THEORY OF METABOLIC ACTIVATION

6.3. THE CONCEPTS OF INITIATION, PROMOTION, AND PROGRESSION: THE ORIGIN OF MULTISTAGE CARCINOGENESIS

CHAPTER 7 HORMESIS AND CANCER RISKS: ISSUES AND RESOLUTION

7.1. INTRODUCTION

7.2. EVIDENCE FOR REGULATORY CANCER RISK ASSESSMENT

7.3. HORMESIS AND CANCER RISK ASSESSMENT: MODELS

7.4. CONCLUSIONS

ACKNOWLEDGMENTS

CHAPTER 8 THRESHOLDS FOR GENOTOXIC CARCINOGENS: EVIDENCE FROM MECHANISM-BASED CARCINOGENICITY STUDIES

8.1. OVERVIEW

8.2. INTRODUCTION

8.3. LOW-DOSE CARCINOGENICITY OF 2-AMINO-3,8-DIMETHYLIMIDAZO[4,5-F]QUINOXALINE (MEIQx) IN THE RAT LIVER

8.4. LOW-DOSE HEPATOCARCINOGENICITY OF N-NITROSO COMPOUNDS

8.5. LOW-DOSE CARCINOGENICITY OF 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[5,6-B]PYRIDINE (PHIP) IN THE RAT COLON

8.6. LOW-DOSE CARCINOGENICITY OF POTASSIUM BROMATE, KBRO3 IN THE RAT KIDNEY

8.7. CONCLUSION

ACKNOWLEDGMENTS

Part III: GENETIC TOXICOLOGY, TESTING GUIDELINES AND REGULATIONS, AND NOVEL ASSAYS

CHAPTER 9 DEVELOPMENT OF GENETIC TOXICOLOGY TESTING AND ITS INCORPORATION INTO REGULATORY HEALTH EFFECTS TEST REQUIREMENTS

9.1. INTRODUCTION

9.2. DEFINITIONS AND USAGE

9.3. THE HISTORICAL DEVELOPMENT OF GENETIC TOXICITY TESTING

9.4. TYPES OF AVAILABLE TESTS

9.5. TESTING APPROACHES

9.6. WHERE ARE WE NOW?

9.7. SUMMARY

CHAPTER 10 GENETIC TOXICOLOGY TESTING GUIDELINES AND REGULATIONS

10.1. HISTORICAL OVERVIEW OF GENOTOXICITY TESTING GUIDELINES

10.2. ORGANIZATION FOR ECONOMIC COOPERATION AND DEVELOPMENT (OECD) GUIDELINES FOR GENOTOXICITY

10.3. INTERNATIONAL CONFERENCE OF HARMONIZATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE (ICH) GUIDELINES FOR PHARMACEUTICALS

10.4. INTERNATIONAL WORKSHOP ON GENOTOXICITY TESTS (IWGT)

10.5. THE INTERNATIONAL PROGRAM ON CHEMICAL SAFETY (IPCS) UNDER THE AUSPICES OF THE WORLD HEALTH ORGANIZATION (WHO)

10.6. IN VITRO TESTING

10.7. IN VIVO TESTING

10.8. EUROPEAN UNION GUIDELINE FOR TESTING OF CHEMICALS UNDER THE REGISTRATION, EVALUATION, AUTHORIZATION AND RESTRICTION OF CHEMICAL (REACH)

10.9. SPECIALTY GUIDELINES FOR GENOTOXICITY: GENOTOXIC IMPURITIES IN PHARMACEUTICALS

10.10. THE QUINTESSENCE FOR REGULATORY ASSESSMENT: IN VIVO TESTING FOR RISK ASSESSMENT

10.11. SUMMARY AND OUTLOOK

CHAPTER 11 IN VITRO GENOTOX ASSAYS

11.1. INTRODUCTION

11.2. IN VITRO METABOLIC ACTIVATION

11.3. IN VITRO TESTS FOR GENE MUTATION IN BACTERIA

11.4. IN VITRO TESTS FOR GENE MUTATION IN MAMMALIAN CELLS

11.5. IN VITRO TESTS FOR CHROMOSOME DAMAGE IN MAMMALIAN CELLS

11.6. THE IN VITRO MICRONUCLEUS TEST

11.7. IN VITRO TEST FOR UNSCHEDULED DNA SYNTHESIS IN RAT HEPATOCYTES

11.8. IN VITRO COMET ASSAY

11.9. STRENGTHS AND LIMITATIONS

CHAPTER 12 IN VIVO GENOTOXICITY ASSAYS

12.1. INTRODUCTION

12.2. PARAMETERS AND CRITERIA FOR VALID IN VIVO GENOTOXICITY ASSAYS AND IMPLICATIONS FOR EXPERIMENTAL DESIGN

12.3. IN VIVO GENOTOXICITY ASSAYS REQUIRED IN THE STANDARD BATTERY OF TESTS

12.4. IN VIVO GENOTOXICITY ASSAYS USED MAINLY AS COMPLEMENTARY OR FOLLOW-UP TESTS

12.5. CONCLUSION AND PERSPECTIVES

Part IV: ASSESSING THE HUMAN RELEVANCE OF CHEMICAL-INDUCED TUMORS

CHAPTER 13 FRAMEWORK ANALYSIS FOR DETERMINING MODE OF ACTION AND HUMAN RELEVANCE

13.1. INTRODUCTION

13.2. FRAMEWORK ANALYSIS: MODE OF ACTION AND KEY EVENTS

13.3. FRAMEWORK ANALYSIS: HUMAN RELEVANCE

13.4. FUTURE DIRECTIONS

CHAPTER 14 EXPERIMENTAL ANIMAL STUDIES AND CARCINOGENICITY

14.1. INTRODUCTION

14.2. CURRENT STATUS OF HAZARD TESTING FOR CANCER FOR REGULATORY RISK ASSESSMENT

14.3. APPLICATION IN RISK ASSESSMENT

14.4. EVOLUTION OF TESTING STRATEGIES

14.5. DISCUSSION: CLOSING THE GAP BETWEEN HAZARD TESTING AND RISK ASSESSMENT

CHAPTER 15 CANCER EPIDEMIOLOGY

15.1. INTRODUCTION

15.2. CONSIDERATIONS FOR THE EPIDEMIOLOGIC STUDY OF CANCER

15.3. EPIDEMIOLOGIC STUDY METHODS

15.4. EVALUATION OF STUDIES AND THEIR RESULTS

15.5. SUBSTANCES CAUSALLY ASSOCIATED WITH CANCER

15.6. FUTURE FOR CANCER EPIDEMIOLOGY

CHAPTER 16 RODENT HEPATOCARCINOGENESIS

16.1. INTRODUCTION

16.2. MECHANISMS OF ACTION OF HEPATIC CARCINOGENS

16.3. HUMAN RELEVANCE FRAMEWORK

16.4. SUMMARY

CHAPTER 17 MODE OF ACTION ANALYSIS AND HUMAN RELEVANCE OF LIVER TUMORS INDUCED BY PPARα ACTIVATION

17.1. OVERVIEW

17.2. INTRODUCTION

17.3. MODE OF ACTION ANALYSIS IN THE U.S. EPA RISK ASSESSMENT FRAMEWORK

17.4. RELEVANCE OF PPARα ACTIVATOR-INDUCED RODENT LIVER TUMOR RESPONSE TO HUMANS

CHAPTER 18 ALPHA2U-GLOBULIN NEPHROPATHY AND CHRONIC PROGRESSIVE NEPHROPATHY AS MODES OF ACTION FOR RENAL TUBULE TUMOR INDUCTION IN RATS, AND THEIR POSSIBLE INTERACTION

18.1. INTRODUCTION

18.2. CHEMICALS THAT INCREASE THE INCIDENCE OF RENAL TUBULE TUMORS IN MALE RATS BY AN α2U-GLOBULIN MODE OF ACTION

18.3. CHEMICALS INCREASING THE INCIDENCE OF RENAL TUMORS THROUGH EXACERBATION OF SPONTANEOUS CHRONIC PROGRESSIVE NEPHROPATHY (CPN)

18.4. CHEMICALS INCREASING RTT INCIDENCE THROUGH A MODE OF ACTION INVOLVING EXACERBATION OF CPN

18.5. EXAMPLES WHERE THE α2U-G AND EXACERBATED CPN MODES OF ACTION MAY BE ACTING IN CONCERT

18.6. RELEVANCE OF RAT A2U-GLOBULIN NEPHROPATHY AND CPN TO HUMANS

CHAPTER 19 URINARY TRACT CALCULI AND BLADDER TUMORS

19.1. INTRODUCTION

19.2. DIRECT AND INDIRECT FORMATION OF URINARY SOLIDS

19.3. URINARY FACTORS INFLUENCING THE FORMATION OF URINARY SOLIDS

19.4. COLLECTION OF URINE FOR DETECTION OF URINARY SOLIDS

19.5. INTERSPECIES COMPARISON OF URINE COMPOSITION

19.6. URINARY SOLID CARCINOGENESIS IN RODENTS

19.7. EPIDEMIOLOGY

19.8. RISK ASSESSMENT

Part V: METHODS FOR INFORMING CANCER RISK QUANTIFICATION

CHAPTER 20 (Q)SAR ANALYSIS OF GENOTOXIC AND NONGENOTOXIC CARCINOGENS: A STATE-OF-THE-ART OVERVIEW

20.1. INTRODUCTION

20.2. OVERVIEW OF (Q)SAR ANALYSIS AND MODELING

20.3. MECHANISM-BASED SAR ANALYSIS OF CHEMICAL CARCINOGENS, FIBERS, AND PARTICLES/NANOPARTICLES

20.4. USES OF (Q)SAR IN CANCER HAZARD/RISK ASSESSMENT AND BRIEF OVERVIEW OF PREDICTIVE SYSTEMS/SOFTWARES

20.5. FUTURE PERSPECTIVES

CHAPTER 21 PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS IN CANCER RISK ASSESSMENT

21.1. INTRODUCTION

21.2. PBPK MODELING: CHARACTERISTICS AND APPROACHES

21.3. PBPK MODELS IN CANCER RISK ASSESSMENT

21.4. PBPK MODELS IN CANCER RISK ASSESSMENT: CASE STUDIES

21.5. CONCLUDING REMARKS

CHAPTER 22 GENOMICS AND ITS ROLE IN CANCER RISK ASSESSMENT

22.1. INTRODUCTION

22.2. “-OMICS” TECHNOLOGIES

22.3. GENOMICS AND THE NEW RISK ASSESSMENT PARADIGM

22.4. CASE STUDIES

22.5. USE OF GENOMICS IN PREDICTIVE TOXICOLOGY

22.6. CONCLUSIONS

CHAPTER 23 COMPUTATIONAL TOXICOLOGY IN CANCER RISK ASSESSMENT

23.1. INTRODUCTION

23.2. RISK ASSESSMENT: HISTORICAL PERSPECTIVE

23.3. ENHANCEMENTS IN QUANTITATIVE RISK ASSESSMENT

23.4. COMPUTATIONAL TOXICOLOGY AND FUTURE RISK ASSESSMENTS

23.5. CONCLUSION

Part VI: GENERAL APPROACHES FOR QUANTIFYING CANCER RISKS

CHAPTER 24 LINEAR LOW-DOSE EXTRAPOLATIONS

24.1. INTRODUCTION

24.2. HISTORICAL

24.3. ISSUES RELATED TO EXTRAPOLATION FROM EXPERIMENTAL DATA

24.4. CONCLUSION

ACKNOWLEDGMENTS

CHAPTER 25 QUANTITATIVE CANCER RISK ASSESSMENT OF NONGENOTOXIC CARCINOGENS

25.1. INTRODUCTION

25.2. SOME EXAMPLES AND APPLICATIONS

25.3. CONCLUDING REMARKS

CHAPTER 26 NONLINEAR LOW-DOSE EXTRAPOLATIONS

26.1. INTRODUCTION

26.2. MECHANISTIC ASPECTS OF NONLINEAR CARCINOGENESIS

26.3. DNA-REACTIVE CARCINOGENS AND NONLINEARITY

26.4. NONMUTAGENIC CARCINOGENS AND NONLINEARITY

26.5. CANCER RISK ASSESSMENT

26.6. NONLINEARITY PRINCIPLES INTO PRACTICE

26.7. SUMMARY AND CONCLUSION

ACKNOWLEDGMENTS

CHAPTER 27 CANCER RISK ASSESSMENT: MORE UNCERTAIN THAN WE THOUGHT

27.1. INTRODUCTION

27.2. SUMMARY OF PREVIOUS ANALYSES

27.3. SELECTION OF CARCINOGENICITY MEASURE—THE CD10

27.4. THE VARIATION OF CD10 WITHIN A SPECIES

27.5. EXTRAPOLATION OF THE MEDIAN CD10 BETWEEN SPECIES

27.6. EXTRAPOLATION OF THE INTRASPECIES VARIATION IN CD10

27.7. CONCLUSIONS

ACKNOWLEDGMENTS

27.8. APPENDIX

CHAPTER 28 COMBINING NEOPLASMS FOR EVALUATION OF RODENT CARCINOGENESIS STUDIES

28.1. INTRODUCTION

28.2. RATIONALE FOR COMBINING NEOPLASMS

28.3. USEFULNESS OF DIFFERENTIATING BENIGN FROM MALIGNANT NEOPLASMS AND OF SUBCLASSIFYING NEOPLASMS

28.4. CRITERIA FOR COMBINING NEOPLASMS

28.5. SUMMARY

CHAPTER 29 CANCER RISK BASED ON AN INDIVIDUAL TUMOR TYPE OR SUMMING OF TUMORS

29.1. INTRODUCTION

29.2. SUMMING OF TUMORS OF RELATED TYPES

29.3. SUMMING OF UNRELATED TUMOR TYPES

29.4. EXAMPLE: 1,3-BUTADIENE

29.5. CONCLUSIONS

CHAPTER 30 EXPOSURE RECONSTRUCTION AND CANCER RISK ESTIMATE DERIVATION

30.1. INTRODUCTION

30.2. EXPOSURE RECONSTRUCTION METHODOLOGY

30.3. APPLICATION OF ESTIMATED HISTORICAL EXPOSURE VALUES TO CANCER RISK ESTIMATES

30.4. SUMMARY

Index

Color Plates

CANCER RISK ASSESSMENT

About the cover: The cover structures are chemicals classified as known human carcinogens in the U.S. National Toxicology Program’s Annual Report on Carcinogens (http://www.ntp.niehs.nih.gov/). The center structure is cyclosporin A (CASRN 59865-13-3). The outer structures going clockwise are benzidine (92-87-5), vinyl chloride (CASRN 75-01-4), tamoxifen (CASRN 10540-29-1), cyclophosphamide (CASRN 50-18-0), benzene (CASRN 71-43-2), and azathioprine (CASRN 446-86-6). These structures were prepared using ACD/ChemSketch (ACD/Labs Release: 11; Product Version: 11.01; http://www.acdlabs.com).

Copyright © 2010 John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, [phone], fax [phone], or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, [phone], fax [phone], or online at http://www.wiley.com/go/permission.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at [phone], outside the United States at [phone] or fax [phone].

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging-in-Publication Data:

Cancer risk assessment : chemical carcinogenesis, hazard evaluation, and risk quantification / [edited by] Ching-Hung Hsu, Todd Stedeford.

p. ; cm.

 Includes bibliographical references and index.

 Summary : “With a weight-of-the-evidence approach, cancer risk assessment indentifies hazards, determines dose-response relationships, and assesses exposure to characterize the true risk. This book focuses on the quantitative methods for conducting chemical cancer risk assessments for solvents, metals, mixtures, and nanoparticles. It links these to the basic toxicology and biology of cancer, along with the impacts on regulatory guidelines and standards. By providing insightful perspective, Cancer Risk Assessment helps researchers develop a discriminate eye when it comes to interpreting data accurately and separating relevant information from erroneous”—Provided by publisher.

 ISBN 978-0-470-23822-6 (cloth)

 ISBN 978-1-118-03512-2 (ebk)

 1. Carcinogens. 2. Health risk assessment. I. Hsu, Ching-Hung. II. Stedeford, Todd.

[DNLM: 1. Neoplasms–chemically induced. 2. Risk Assessment–methods. 3. Carcinogens–toxicity. 4. Environmental Exposure. 5. Mutagenicity Tests. QZ 202 C21556 2010]

 RC268.6.C357 2010

 616.99′4071—dc22

2009049268

PREFACE

Cancer risk assessment is an ever-changing discipline with standard regulatory practices and defaults giving way to ever-increasing breakthroughs in scientific discovery. The scientific literature is, however, replete with reports of toxicant-induced changes, but discriminating between those reports that are irrelevant or relevant to humans and those that are compensatory versus truly adverse can be an arduous task. This book aims to inform and to provide interpretive guidance on evaluating toxicological data and understanding the relevance of such data to hazard evaluation and cancer risk estimation.

The topics presented herein begin with Part I, which provides an overview of cancer risk assessment, followed by a discussion on science policy. The regulatory frameworks for industrial chemicals and biocides are presented along with the general approaches for developing standards for chemicals in air, water, food, soil, and consumer products. In Part II, basic concepts in cancer biology, chemical carcinogenesis, hormesis, and experimental evidence of thresholds for genotoxic carcinogens are provided. Thereafter, Part III describes the testing guidelines and regulations for in vitro and in vivo genotoxicity testing, and Part IV offers interpretive guidance on assessing the human relevance of chemical-induced tumors from rodent studies, along with the necessary criteria for evaluating data from epidemiological studies. Commonly observed modes of action from experimental animal studies, including PPAR-α, α2u-globulin, and so on, are then discussed. In Part V, methods for informing cancer risk quantification, including quantitative structure–activity relationships (QSAR), physiologically based pharmacokinetic (PBPK) modeling, “-omics”, and computational toxicology are discussed. Finally, Part VI addresses general approaches for quantifying cancer risks including linear and nonlinear low-dose extrapolations, summing tumors, and exposure reconstruction for cancer risk estimation.

The foregoing topics are critical for keeping abreast of changes that are taking place in cancer risk assessment, as well as in the fields of toxicology and risk assessment in general. For example, with the increased emphasis on describing a chemical’s mode of action for both cancer and noncancer endpoints, an understanding of the human relevance framework is essential, as is the role of rapidly developing technologies (e.g., “-omics”) for informing mode(s) of action. Therefore, readers of this text will take away knowledge that is applicable to cancer risk assessment and more broadly to toxicology and risk assessment. The resources that formed the bases for this text include: peer-reviewed scientific articles, regulatory guidance documents, validated test guidelines, and the many years of experience conveyed throughout by the contributing authors.

The editors are truly grateful to the contributing authors of this text, who provided their expertise on a gratis basis. If it were not for their dedication and commitment to advancing the knowledge and understanding of cancer risk assessment, the extensive coverage provided herein would not have been possible.

CHING-HUNG HSU

Taipei, Taiwan

TODD STEDEFORD

Baton Rouge, Louisiana

April 2010

CONTRIBUTORS

Elizabeth L. Anderson, Ph.D., FATS Group Vice President and Principal Scientist, Exponent, Inc., Alexandria, Virginia

Lora L. Arnold, M.S. Assistant Professor, University of Nebraska Medical Center, Omaha, Nebraska

Barbara D. Beck, Ph.D., DABT, FATS Principal, Gradient, Cambridge, Massachusetts

Jerry N. Blancato, M.S., Ph.D. Acting Director, Office of Administrative and Research Support, Office of Research and Development (ORD), United States Environmental Protection Agency, Research Triangle Park, North Carolina

Amy Brix, D.V.M., Ph.D., DACVP Veterinary Pathologist and Contractor for NTP QA, Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina

Jessie P. Buckley, M.P.H. Ph.D. Candidate, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina

Edward J. Calabrese, Ph.D., FATS Professor of Toxicology, Department of Public Health, University of Massachusetts, Amherst, Massachusetts

Samuel M. Cohen, M.D., Ph.D. Havlik–Wall Professor of Oncology, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska

J. Christopher Corton, Ph.D. Senior Research Biologist, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), United States Environmental Protection Agency, Research Triangle Park, North Carolina

Edmund A. C. Crouch, Ph.D. Senior Scientist, Cambridge Environmental, Inc., Cambridge, Massachusetts

Vicki Dellarco, Ph.D. Science Advisor, Office of Pesticide Programs, United States Environmental Protection Agency, Washington, D.C.

Kathryn D. Devlin, M.S. Health Scientist, ChemRisk, LLC, Boulder, Colorado

Michael Dourson, Ph.D., DABT, FATS President, Toxicology Excellence for Risk Assessment (TERA), Cincinnati, Ohio

Anna M. Fan, Ph.D., DABT Chief, Pesticide and Environmental Toxicology Branch, Office of Environmental Health Hazard Assessment (OEHHA), California Environmental Protection Agency, Oakland, California

Shoji Fukushima, M.D., Ph.D. Director, Japan Bioassay Research Center, Japan Industrial Safety & Health Association, Hadano, Kanagawa, Japan

Shannon H. Gaffney, Ph.D., M.H.S., CIH Managing Health Scientist, ChemRisk, LLC, San Francisco, California

David Gatehouse, Ph.D., FRCPath Consultant, Buntingford, Hertfordshire, United Kingdom

Herman J. Gibb, Ph.D., M.P.H. President, Tetra Tech Sciences, Arlington, Virginia

Virginia A. Gretton Regulatory Advisor, SafePharm Laboratories Ltd., Derbyshire, United Kingdom

Lynne Haber, Ph.D., DABT Associate Director, Toxicology Excellence for Risk Assessment (TERA), Cincinnati, Ohio

Gordon C. Hard, BVSc, Ph.D., DSc, DACVP, FRCPath, FRCVS, FAToxSci Independent Consultant, Tairua, New Zealand

Jerry F. Hardisty, D.V.M., DACVP, IATP President and Veterinary Pathologist, Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina

James W. Holder, Ph.D. Toxicologist/Cancer, National Center for Environmental Assessment, Office of Research and Development, United States Environmental Protection Agency (Retired), Washington, D.C.

Robert A. Howd, Ph.D. Chief, Water Toxicology Section, Office of Environmental Health Hazard Assessment (OEHHA), California Environmental Protection Agency, Oakland, California

Jihyoun Jeon, M.S., Ph.D. Staff Scientist, Program in Biostatistics and Biomathematics, Fred Hutchinson Cancer Research Center, Seatte, Washington

Anna Kakehashi, Ph.D. Lecturer, Department of Pathology, Osaka City University Medical School, Osaka, Japan

David J. Kirkland, Ph.D. Consultant and Professor (University of Wales, Swansea, United Kingdom), Tadcaster, North Yorkshire, United Kingdom

James E. Klaunig, Ph.D. Professor and Chair, Environmental Health, Indiana University, Bloomington, Indiana

Kannan Krishnan, Ph.D., DABT, FATS Professor, Department of Environmental Health and Health at Work, University of Montréal, Montreal, Quebéc, Canada

David Y. Lai, Ph.D., DABT Senior Toxicologist, Risk Assessment Division, Office of Pollution Prevention and Toxics (OPPTS), United States Environmental Protection Agency, Washington, D.C.

Ari S. Lewis, M.S. Senior Scientist, Gradient, Cambridge, Massachusetts

Edward A. Lock, MIBiol, Ph.D., FRCPath, FBTS, FATS Professor, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom

Kimberly Lowe, Ph.D., M.H.S. Senior Scientist, Exponent, Inc., Seattle, Washington

Gary E. Marchant, Ph.D., J.D. Lincoln Professor, College of Law, Arizona State University, Tempe, Arizona

Hans-Jörg Martus, Ph.D. Head, Genetic Toxicology, Preclinical Safety, Novartis Institutes for BioMedical Research, Basel, Switzerland

Ernest E. McConnell, D.V.M., M.S., DACVP, DABT President, Tox Path, Inc., Raleigh, North Carolina

Mary Elizabeth (Bette) Meek, M.Sc., Ph.D. Associate Director, Chemical Risk Assessment, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, Ontario, Canada

Rafael Meza, Ph.D. Research Scientist, Division of Mathematical Modeling, University of British Columbia Centre for Disease Control, Vancouver, British Columia, Canada

Suresh H. Moolgavkar, M.D., Ph.D. Corporate Vice President and Director, Center for Epidemiology, Biostatistics, and Computational Biology, Exponent, Inc., Bellevue, Washington

Lutz Müller, Ph.D. Head Full Development Projects, Non-Clinical Drug Safety, F. Hoffmann-La Roche Ltd., Basel, Switzerland

Stephen Nesnow, Ph.D. Senior Research Scientist, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), United States Environmental Protection Agency, Research Triangle Park, North Carolina

Dennis J. Paustenbach, Ph.D., CIH, DABT President and Founder, ChemRisk, LLC, San Francisco, California

R. Julian Preston, Ph.D. Associate Director for Health, National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), United States Environmental Protection Agency, Research Triangle Park, North Carolina

Paolo F. Ricci, Ph.D., LL.M., M.P.A. Professor, Holy Names University, Oakland, California, and University of Massachusetts, Amherst, Massachusetts

Lindsey A. Roth, M.A. Research Scientist II, Safer Alternatives Assessment and Biomonitoring Section, Office of Environmental Health Hazard Assessment (OEHHA), California Environmental Protection Agency, Oakland, California

Jennifer Sahmel, M.P.H., CIH, CSP Supervising Health Scientist, ChemRisk, LLC, Boulder, Colorado

Banalata Sen, Ph.D. Science Education and Outreach Program Manager, Environmental Health Perspectives, DHHS, NIH, NIEHS, Durham, North Carolina

Andrew G. Salmon, M.A., D.Phil. Chief, Toxicology and Risk Assessment Section, Office of Environmental Health Hazard Assessment (OEHHA), California Environmental Protection Agency, Oakland, California

Todd Stedeford, Ph.D., J.D., DABT Toxicology Advisor & In-House Counsel, Health, Safety & Environment, Albemarle Corporation, Baton Rouge, Louisiana

Shugo Suzuki, M.D., Ph.D. Postdoctoral Research Associate, University of Nebraska Medical Center, Omaha, Nebraska

Henk Tennekes, M.Sc., Ph.D., RT Consultant in Toxicology, Experimental Toxicology Services, Zutphen, The Netherlands

Véronique Thybaud, Ph.D. Scientific Advisor, Disposition-Safety and Animal Research, Preclinical Safety, Sanofi Aventis, Vitry sur Seine, France

Paul Turnham, B. Eng., M.S., P.E. Senior Managing Scientist, Exponent, Inc., Alexandria, Virginia

Mathieu Valcke, M.Sc. Scientific Advisor, National Institute of Public Health of Québec, Montreal, Quebec, Canada

Hideki Wanibuchi, M.D., Ph.D. Professor, Department of Pathology, Osaka City University Medical School, Osaka, Japan

Min Wei, M.D., Ph.D. Assistant Professor, Department of Pathology, Osaka City University Medical School, Osaka, Japan

Douglas C. Wolf, D.V.M., Ph.D., FIATP, ATS Assistant Laboratory Director, National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development (ORD), United States Environmental Protection Agency, Research Triangle Park, North Carolina

Yin-tak Woo, Ph.D., DABT Senior Toxicologist, Risk Assessment Division, Office of Pollution Prevention and Toxics (OPPTS), United States Environmental Protection Agency, Washington, D.C.

Errol Zeiger, Ph.D., J.D. Principal, Errol Zeiger Consulting, Chapel Hill, North Carolina

ABBREVIATIONS AND ACRONYMS

AAF

2-Acetylaminofluorene

4-ABP

4-Aminobiphenyl

ACF

Aberrant crypts foci

ACO

Acyl-CoA oxidase

ACToR

Aggregated chemical toxicity resource

ADAF

Age-dependent adjustment factor

Ade

Adenine

ADI

Allowable daily intake

ADME

Absorption, distribution, metabolism, and excretion

AFC

Altered foci cells

AHF

Altered hepatic foci

AhR

Aryl hydrocarbon receptor

AI

Artificial intelligence

AMS

Accelerator mass spectrometry

ANOVA

Analysis of variance

AOM

Azoxymethane

apo

Apolipoprotein

ARB

Air Resources Board, California EPA

ARNT

Ah receptor nuclear translocator

ATSDR

U.S. Agency for Toxic Substances and Disease Registry

AUC

Area under the curve

B[a]A

Benz[a]anthracene

BBDR

Biologically based dose–response

BDA

Bayesian data analysis

BE

Biomonitoring equivalents

BEEL

Biological environmental exposure limit

BEIs

Biological exposure indices

BMD

Benchmark dose

BMDL

Benchmark dose lower bound

BMR

Benchmark response

B[a]P

Benzo[a]pyrene

BPD

Biocidal products directive

BPDE

Benzo[a]pyrene diol epoxides

BrDU

5-Bromo-2-deoxyuridine

b.w.

Body weight

CAA

U.S. Clean Air Act

CAF

Cancer-associated fibroblast

CAG

Carcinogens Assessment Group

CAM

Cellular adhesion molecule

CAR

Constitutive androstane receptor

CCA

Chromated copper arsenate

CCl4

Carbon tetrachloride

CD10

10% of Cancer dose

CDC

Center for Disease Control

CDC

U.S. Centers for Disease Control and Prevention

CDK

Cyclin-dependent kinase

CEBS

Chemical effects in biological systems

CEO

Chloroethylene oxide

CEO

Cyanoethylene oxide

CEPA

Canadian Environmental Protection Act

CERCLA

Comprehensive Environmental Response, Compensation and Liability Act

cGys

Centigrays

ChAMP

Chemical Assessment and Management Program

CHMP

Committee of Human Medicinal Products

CIIT

Chemical Industries Institute of Toxicology

CMRs

Carcinogens, mutagens, or reproductive toxicants

CNDR

Canadian National Dose Registry

CoA

Acyl coenzyme A

COPC

Contaminants of Potential Concern

CPDB

Carcinogenic potency database

CPN

Chronic progressive nephropathy

CPSC

Consumer Product Safety Commission

CPT-I

Carnitine palmitoyl transferase-I

CPUM

Colorado Plateau Uranium Miners

CSA

Chemical Safety Assessment

CSF

Cancer slope factor

CSR

Chemical Safety Report

CTM

Chinese tin miners

Cx

Connexon

CYP

Cytochrome P450

2-D

Two-dimensional

3-D

Three-dimensional

4-DAB

4-Dimethylaminoazobenzene

DAG

Directed acyclic graph

DAPI

4′,6-Diamidino-2-phenylindole

4-DAST

4-Dimethylaminostilbene

DB[a,l]P

Dibenzo[a,l]pyrene

DC

Dendritic cells

DCB

1,4-Dichlorobenzene

DCC

Deleted in colorectal cancer

DCM

Dichloromethane or methylene chloride

1,3-DCP

1,3-Dichloropropene

DDT

Dichlorodiphenyltrichloroethane

DEEM

Dietary Exposure Evaluation Model

DEHA

Di-(2-ethylhexyl)adipate

DEHP

Di-(2-ethylhexyl)phthalate

DEN

N-Nitrosodiethylamine

DEN, DENA

N,N-Diethylnitrosamine

DEPM

Dietary Exposure Potential Model

dGua

Deoxyguanosine

DHEW

U.S. Department of Health Education and Welfare

DINP

Di-(2-isononyl) phthalate

DINP

Diisononyl phthalate

DMA

Dimethylarsenic acid

DMBA

7,12-Dimethylbenz[a]anthracene or 9,10-Dimethyl-1,2-benz[a] anthracene

DMN

Dimethylnitrosamine

DMN

N-Nitrosodimethylamine

DQA

Data Quality Act

DSS

Dextran sulfate sodium

DSSTox

Distributed structure-searchable toxicity

Dt

Dose metrics

EAF

Enzyme-altered foci

ECHA

European Chemicals Agency

ECM

Extracellular matrix

ECVAM

European Centre for the Validation of Alternative Methods

ED

Effective dose

EFSA

European Food Safety Authority

2-EH

2-Ethylhexanol

EHEN

Ethyl hydroxyethylnitrosamine

ELISA

Enzyme-linked immunosorbant assays

EMSA

Electrophoretic mobility shift assay

ENNG

N-Ethyl-N′-nitro-N-nitrosoguanidine

ENU

Ethylnitrosourea

ENU

N-Nitroso-N-ethylurea

EPA

U.S. Environmental Protection Agency

EPI

Exposure potency index

EPIC

European Prospective Investigation into Cancer and Nutrition

ER

Estrogen receptor

ERK

Extracellular signal-regulated kinases

ESR

Electron spin resonance

ESTR

Expanded Simple Tandem Repeat

EU

European Union

FDA

U.S. Food and Drug Administration

FDCA

Food, Drug and Cosmetic Act

FFDCA

Federal Food, Drug and Cosmetic Act

FGF

Fibroblast growth factor

FGFR3

Fibroblast growth factor receptor 3

FIFRA

Federal Insecticide, Fungicide and Rodenticide Act

FISH

Fluorescent in situ hybridization

FPG

Formamido pyrimidine glycosylase

FQPA

Food Quality Protection Act

GAC

Genetic alterations in cancer

γ-GGT

Gamma-glutamyltransferase

GI

Gastrointestinal

GJIC

Gap junction intercellular communication

GJs

Gap junction connections

GLP

Good laboratory practice

G6PD

Glucose-6-phosphate dehydrogenase

GSSG

Glutathione disulfide

GSH

Glutathione

GST

Glutathione S-transferases

GST-P

Glutathione S-transferase placental form

Gua

Guanine

HaSDR

Health and Safety Data Reporting

HCA

Hydrocyanic acid

HCA

High content analysis

HC

Health Canada

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

HEAA

β-Hydroxyacetic acid

HGP

Human Genome Project

HIV

Human immunodeficiency virus

HMG-CoA

3-Hydroxy-3-methylglutaryl-CoA

Hmgcr

Hydroxymethylglutaryl-CoA reductase

hPPARα

Human PPARα

HPLC

High-performance liquid chromatography

hprt

Hypoxanthine-guanine phosphoribosyl transferase

HPV

Human papilloma viruses

HPV

High production volume

HPVIS

High Production Volume Information System

HRF

Human relevance framework

HSC

Hemocytoblasts

HTLV

Human T-cell lymphotropic virus

HTS

High-throughput screening

IAEMS

International Association of Environmental Mutagen Societies

IARC

International Agency for Research on Cancer

ICEM

International Conferences on Environmental Mutagens

ICCVAM

Interagency Coordinating Committee on the Validation of Alternative Methods

ICH

International Conference on Harmonisation

IDS

Immunodefense system

IKK

IκB kinase

IL1α

Interleukin-1alpha

IL1β

Interleukin-1beta

ILSI

International Life Science Institute

ILSI RSI

International Life Sciences Risk Sciences Institute

IND

Exploratory investigational new drug applications

IPCS

International Programme on Chemical Safety

IR

Ionizing radiation

IRIS

Integrated Risk Information System

IRIS

U.S. EPA Integrated Risk Information System

ITER

International Toxicity Estimates for Risk

ITC

TSCA Interagency Testing Committee

IUR

Inhalation unit risk

IUR

Inventory update reporting

IWGT

International Workshop(s) on Genotoxicity Tests

IWR

Interaction weighting ratio

JaCVAM

Japanese Center for the Validation of Alternative Methods

JECFA

Joint FAO/WHO Expert Committee on Food Additives

JEM

Job exposure matrix

JNK

c-Jun N-terminal kinases

Kdis

Dissolution rate constants

LBD

Ligand binding domains

LED01

Lower limit on effective dose01

LED10

Lower 95% confidence limit for the dose giving the animals an increased tumor incidence of 10%

LET

Linear-energy-transfer

LFC

Lowest feasible concentration

LMS

Linearized multistage

LMW

Low-molecular-weight protein

ln(GSD)

Logarithm of the geometric standard deviation

LNT

Linear no-threshold

LOAEL

Lowest observed adverse effect level

LSC

Lymphoblast

LSS

Life-stage study

LTA

Local tissue array

MAC

Apoptosis-induced channel

MACT

Maximum achievable control technology

MAP

Mitogen-activated protein

MC

Mast cell

MCL

Maximum contaminant level

MCMC

Markov chain Monte Carlo

MDA

Malondialdehyde

MEHP

Mono-2-ethylhexyl phthalate

MeIQx

2-Amino-3,8-Dimethylimidazo[4,5-f] quinoxaline

MIBK

Methyl isobutyl ketone

miRNA

MicroRNAs

MLA

Mouse lymphoma tk+/− assay

MLE

Maximum likelihood estimate

MMP

Matrix metalloprotease

MMS

Methyl methanesulfonate

MN

Micronuclei

MNU

Methylnitrosourea

MOA

Mode of action

MOE

Margin of exposure

MPV

Medium-production volume

MS

Mass spectrometric

MSCE

Multistage clonal expansion

MTBE

Methyl-tert-butyl ether

MTD

Maximum tolerable dose

MUP

Mouse urinary protein

MVK

Moolgavkar–Venzon–Knudson

NAS

National Academy of Sciences

NAS

U.S. National Academies of Science

NBR

NCI Black–Reiter

NCEA

U.S. EPA National Center for Environmental Assessment

NCEs

Normochromatic erythrocytes

NCEH

National Center for Environmental Health

NCoR

Nuclear receptor corepressor

NDI

National death index

NF-kB

Nuclear factor kappa B

NHANES

National Health and Nutrition Examination Survey

NIOSH

U.S. National Institute for Occupational Safety and Health

NIOSH-IREP

Interactive RadioEpidemiological Program

NNG

Net nuclear grain

NNM

N-Nitrosomorpholine

NOAEL

No observed adverse effect level

NOEL

No observed effect level

NPCs

Nonparenchymal cells

NRC

National Research Council

NRC

U.S. National Research Council

NSRLs

No significant risk levels

NTP

National Toxicology Program

NTP

U.S. National Toxicology Program

Cmax

Maximum or peak concentration

OECD

Organisation for Economic Co-operation and Development

OEHHA

Office of Environmental Health Hazard Assessment, California EPA

8-OH-dG

8-Hydroxy-2′-deoxyguanosine

2-OH-TMP

2,2,4-Trimethyl 2-pentanol

OMB

U.S. Office of Management and Budget

OPP

U.S. EPA Office of Pesticide Programs

OPPTS

Office of Prevention, Pesticides and Toxic Substances

ORD

U.S. EPA Office of Research and Development

OSHA

U.S. Occupational Safety and Health Administration

OSH Act

U.S. Occupational Safety and Health Act of 1970

OSOR

One substance, one registration

OSTP

U.S. Office of Science and Technology Policy

OSWER

U.S. EPA Office of Solid Waste and Emergency Response

PAHs

Polycyclic aromatic hydrocarbons

PAIR

Preliminary assessment and information reporting

PAPS

3′-Phosphoadenosine 5′-phosphosulfate

PBBs

Polybrominated biphenyls

PBPK

Physiologically based pharmacokinetic

PBTs

Persistent, bioaccumulative, and toxic substances

PCBs

Polychlorinated biphenyls

PCDD

Polychlorinated dibenzo dioxin

PCE

Polychromatic erythrocyte

pCi

Picocuries

PCNA

Proliferating cell nuclear antigen

PD

Cell population growth over time

PDF

Probability density function

PDGF

Platelet-derived growth factor

PEI

Polyethyleneimine

PELs

Permissible exposure limits

PFAA

Perfluoroalkyl acid

PFOA

Perfluorooctanoic acid

PFOS

Perfluorooctanesulfonic acid

PGMBE

Propylene glycol monobutyl ether

Pgp

P-glycoprotein

PHGs

Public health goals

PhIP

2-Amino-1-methyl- 6-phenylimidazo[4,5-b] pyridine

PIR

Proportionate incidence ratio

PMR

Proportionate mortality ratio

POD

Point of departure

PPAR

Peroxisome proliferator-activated receptor

PPAR-α

Peroxisome proliferation activating receptor-alpha

PPL

32P-Postlabeling

PPREs

PPARα responsive elements

pRb

Inactivated retinoblastoma gene product

PRGs

Preliminary remediation goals

PSP

Poorly soluble particles

PTEN

Phosphatase and tension

PTL

Priority testing list

PXR

Pregnane X receptor

q1*

Upper 95% confidence limit on the cancer potency slope

qPCR

Quantitative polymerase chain reaction

(Q)SAR

Quantitative structure–activity relationships

RAGS

Risk assessment guidance for Superfund

RBC

Red blood cell

RBP

Risk-based prioritizations

RCF

Refractory ceramic fibers

R&D

Research and development

REACH

Registration, evaluation, authorization, and restriction of chemicals

REDs

Reregistration eligibility documents

RELs

Recommended exposure limits

RfD

Reference dose

RFLP

Restriction fragment length polymorphism

RIVM

The Netherlands National Institute for Public Health and

RMM

Risk management measures

RNS

Reactive nitrogen species

R.O.C.

Receiver operating characteristic

RoC

Report on carcinogens

ROS

Reactive oxygen species

RSD

Risk–specific dose

RTG

Relative total growth

RT-PCR

Reverse transcription polymerase chain reaction

RTT

Renal tubule tumors

RXRα

Retinoid X receptor-alpha

SA

Structural alert

SAB

U.S. EPA Science Advisory Board

SAR

Structure–activity relationship

SARA

Superfund Amendments and Reauthorization Act

SCE

Sister chromatid exchange

SDWA

U.S. Safe Drinking Water Act

S9 fraction

9000 g Supernatant

SDS

Safety data sheet

SEER

Surveillance epidemiology and end results

SHEDS

Stochastic human exposure and dose simulation

SIEF

Substance information exchange forum

SIR

Standardized incidence ratio

SMR

Standardized mortality ratio

SOT

U.S. Society of Toxicology

SPP

Security and prosperity partnership

SPS

Sanitary and phytosanitary

SS IIC

Stoddard solvent IIC

STN

Stochastic transition network

SV

Simian virus

SWCNT

Single-walled carbon nanotubes

SWP

Safety working party

T-90

90% Clearance time

t/a

Tonnes per annum

TAA

Thioacetamide

TBA

Tert-butyl alcohol

TBARS

Thiobarbituric reactive substances

TCA

Trichloroacetate

TCDD, dioxin

2,3,7,8-Tetrachlorodibenzo-p-dioxin

TCE

Trichloroethylene

TD

Tolerable dose

TD50

The dose inducing a tumor incidence of 50% in rodents

TDI

Tolerable daily intake

TERA

Toxicology Excellence for Risk Assessment

TF

Transcription factor

TGD

Technical guidance document

TGF

Transforming growth factor

TGFβ1

Transforming growth factor beta 1

tk

Thymidine kinase

TLC

Thin-layer chromatography

TMP

2,2,4-Trimethylpentane

TNF

Tumor necrosis factor

TNFα

Tumor necrosis factor alpha

ToxRefDB

Toxicology reference database

TPA

Tetradecanoyl phorbol acetate

the Environment

TRAIL

TNF-related apoptosis-inducing ligand

TRI

Toxics release inventory

TSCE

Two-stage clonal expansion

TTC

Threshold of toxicological concern

TWA

Time-weighted average

UCL

Upper confidence limit

UDS

Unscheduled DNA synthesis

UF

Uncertainty factor

USDA

U.S. Department of Agriculture

UVR

Ultraviolet radiation

VC

Vinyl chloride

VLDL

Very low density lipoproteins

VOC

Volatile organic compound

WOE

Weight of evidence

vPvBs

Very persistent and very bioaccumulative substances

VSD

Virtually safe dose

WHO

World Health Organization

Wnt

Wingless type

WT1/2

Weighted clearance half-time

WTO

World Trade Organization

Part I: CANCER RISK ASSESSMENT, SCIENCE POLICY, AND REGULATORY FRAMEWORKS

CHAPTER 1

CANCER RISK ASSESSMENT

Elizabeth L. Anderson, Kimberly Lowe and Paul Turnham

1.1. CANCER RISK ASSESSMENT

1.1.1. Cancer in the United States

Cancer is a group of diseases that result from abnormal and prolific cellular division. Based on current U.S. National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) of cancer prevalence, it is estimated that more than 10 million people were living with cancer in the United States in 2005 (NCI 2008). The American Cancer Society predicts that 1 in 2 males and 1 in 3 females will develop some type of cancer in their lifetime, and that 1 in 4 males and 1 in 5 females is at risk of dying from this disease (NCI 2007a,b). Cancer is undoubtedly a substantial threat to public health.

Understanding the etiology of cancer, identifying methods of prevention or treatment, and determining the carcinogenicity of the chemicals we use in our everyday lives are the objectives of many of our government divisions, academic institutions, and health-care industries. However, for public health agencies charged with quantifying safe levels of exposure to protect public health, these tasks are not simple matters of using biology to inform the standard-setting process; instead, gaps in science must be filled using a number of assumptions that are based both on scientific inferences and policy judgments.

Under Congressional delegation, the broad mission of public health agencies is disease prevention. This includes a wide range of activities from providing education about healthy living to regulating the use and dispersion of agents that are known, or suspected, to cause cancer or other diseases. The basic principle of cancer risk assessment is to characterize both the weight of evidence (WOE) that the agent might be capable of causing cancer and the magnitude of risk, given past, current, or future exposure levels. The fundamental objective is to determine the threshold at which exposure to the agent poses no appreciable risk to humans or, in the absence of mechanistic knowledge, to define an acceptable risk for suspect carcinogens.

1.1.2. Historical Perspectives of Cancer Risk Assessment

Imagine a time when there was no exposure assessment, no evaluation of dose–response relationships (potency), and no particular attention paid to mechanisms of action to define the relevance of responses in animals to diseases in humans, as well as a time when the science of risk assessment to address environmental carcinogens was not developed. This time existed when the U.S. Environmental Protection Agency (EPA) was created in 1970, and it existed until the first Federal policy to adopt the use of risk assessment and risk management was announced by the Agency in 1976 (Albert et al. 1977; USEPA 1976). This policy was accompanied by the first guidelines for carcinogen risk assessment (USEPA 1976) and the establishment of an Agency group to carry out these assessments (named the Carcinogens Assessment Group, or CAG). The approach was novel at the time; however, it borrowed from the experience of radiation risk assessment, where a common mechanism of action was known and dose–response relationships in humans had been reasonably well characterized. Of course, large knowledge gaps existed. For most agents suspected of causing cancer, evidence was from high-dose studies in animals that relied on two dose levels to define cancer potential for humans who experienced much lower environmental exposures. Although controversial at the time, the science of risk assessment has developed into the internationally accepted approach to evaluate carcinogen risk associated with of exposure to environmental agents, food contaminants, and occupational contaminants. These approaches also have dictated close scrutiny of the scientific principles that lead to improved methods of addressing potency, mechanisms of action, test methods, exposure, and internal dose relationships. This section describes the landmarks and key events in the evolution of this science.

Not long after the EPA was established, it began evaluating carcinogenesis data and translating its findings into public policy. These early decisions spawned the necessity to depart from simple qualitative characterization of tumors in humans or animals to incorporate the reality of exposures at low doses, far below those in the studies, and the potential for harm associated with these low-dose exposures. Because the Agency was newly developed, there was no precedent for regulating carcinogens in the environment.

The early years of the EPA were a time of enormous zeal to cleanse the environment, especially of carcinogens that were thought to be the principal cause of a “cancer epidemic.” The Food, Drug, and Cosmetic Act (FDCA) had a provision for regulating intentional food additives to a zero-tolerance level, meaning that evidence of cancer by tumor formation in animals or humans was sufficient cause for banning the agent. The same zero-tolerance policy was attempted for a wide range of environmental agents thought to be potential carcinogens, including three major pesticides: dichlorodiphenyltrichloroethane (DDT), aldrin/dieldrin, and chlordane/heptachlor, although the cancellation of DDT was probably more compelled by ecologic harm (USEPA 1972, 1975). Between 1970 and 1975, the EPA moved to suspend their use. The cancellation of these three pesticides set the zero-tolerance policy in motion and became what was judged to be the Agency’s cancer policy. However, it quickly became evident that a zero-tolerance policy was impractical. For many economically important products, it was impossible to remove all exposure to agents suspected of having the ability to cause cancer (e.g., low-level exposure to benzene, a known human carcinogen, in gasoline). The policy was also highly controversial. Using the qualitative evidence of tumors in animals or humans, attorneys at the EPA had summarized the scientific information needed to characterize an agent as carcinogenic in legal briefs at the conclusions of the hearings to cancel the pesticides listed above. These summary statements were referred to in legal motions as “Cancer Principles.” The intent of these statements was to establish the foundation for the EPA’s authority to protect public health from exposure to environmental carcinogens. This approach received substantial criticism from the scientific community, parts of the private sector, and the Congress (Anonymous 1976). The criticism was largely based on the fact that the complex field of carcinogenesis could not be reduced to simple summary statements (USEPA 1976). In addition, there was concern that the Agency would take a broad approach to cancer regulation by labeling agents as carcinogenic in humans if they were carcinogenic in animals, treating all agents as if they had equal potency, or regulating without information about exposure and the specific threat of a particular agent.

Given the large number of chemicals to which people are exposed in their everyday lives, there was a substantial need to establish a basis for setting priorities and balancing the risks associated with their use in terms of social and economic factors, as called for by the specific statutes under which public health agencies operated, including the EPA, which had inherited very broad authorities (Anderson 1983). Ultimately, the failure of the zero-tolerance policy led to the development of the risk assessment framework at the EPA. It was not until 1979 that other federal agencies joined the EPA in an effort to establish interagency guidance for conducting carcinogen risk assessments (Albert et al. 1977; IRLG 1979c; USEPA 1976). This initial risk assessment approach was developed to answer two questions (Anderson 1983):

1. How likely is the agent to be a human carcinogen? This step involves evaluating all of the relevant biomedical data to determine the total weight of evidence (WOE). At that time, the WOE was ranked from strongest to weakest in a scientific context. The strongest evidence was obtained from human data that were supported by animal bioassay results. Substantial evidence of carcinogenicity could be obtained from laboratory animal bioassay results showing replication of effects across species related to dose levels, and suggestive evidence could be obtained from weaker associations in animal studies. Other evidence from in vivo or in vitro studies was also considered.

2. On the assumption that an agent is a human carcinogen, what is the magnitude of its public health impact given current and projected exposures? This step is quantitative in nature and involves establishing a dose–response relationship to extrapolate to low levels of exposure, where environmental exposures generally occur, and evaluating the magnitude of the exposures of interest. Its purpose was to provide regulators a sense of the cancer potency of the agent, and some information about the public health impacts associated with exposures. In this step, risks were bracketed between an upper and lower bound approaching zero. The upper bounds were expressed both in terms of the individual increased cancer risks in the exposed population and the nationwide impact in terms of the annual increase in cases.

Of particular note: (1) These first guidelines called for revising each risk assessment as better information became available, a goal that has been rarely realized. (2) Gaps in scientific knowledge were to be filled with public health protective assumptions to err on the side of safety, an early application of the precautionary principle.

Over the last several decades, the Agency has sought to extend guidelines for carcinogens to incorporate improvements in our understanding of the cancer process. Because risk assessment necessarily relies on both science and policy judgments, these guidelines are essential to ensure that a consistent approach to risk assessment is taken. The effort to bring consistency to risk assessment is evolving and has produced revisions of guidelines and standard practices (examples of which are shown in Table 1.1). The most fundamental endorsement of the risk assessments that had been practiced at EPA since 1976, where approximately 150 carcinogen risk assessments had been completed in the first eight years, occurred in 1983 when the National Research Council (NRC) of the U.S. National Academies of Science (NAS) endorsed risk assessment as a proper process and defined specific steps for hazard identification, dose–response assessment, exposure assessment, and risk characterization as the risk assessment paradigm (NRC 1983). This endorsement created wider applications of risk assessment, which rapidly expanded across all federal regulatory agencies and beyond to state agencies and inter­national communities. The specifics of this process are described in the following section.

TABLE 1.1. Historical Perspectives of the Development of the Risk Assessment Process

YearDocumentDetails1975Quantitative Risk Assessment for Community Exposure to Vinyl Chloride (Kuzmack and McGaughy 1975)This was the first risk assessment document to be completed by the EPA.1976Interim Procedures and Guidelines for Health Risks and Economic Impact Assessments of Suspected Carcinogens (USEPA 1976)This document communicated the EPA’s intent to include “rigorous assessments of health risk and economic impacts” in the regulatory process.1978Hazardous substances summary and full development plan. United States. Interagency Regulatory Liaison Group (IRLG 1979a)This document describes laws and legislation regarding hazardous substances and chemicals.1979Publications on toxic substances. United States. Interagency Regulatory Liaison Group (IRLG 1979b)This document reports basic facts about toxic substances and describes the publications that are available from many federal agencies.1980Integrated Risk Information System (IRIS)This database reports human health effects that may be related to chemicals found in the environment.1983Risk Assessment in the Federal Government: Managing the Process (NRC 1983)Commonly referred to as the “Red Book,” this document was published by the National Academy of Sciences and described methods for risk assessment in the federal government. The EPA adopted and implemented the risk assessment methods that were outlined in this book.1984Risk Assessment and Management: Framework for Decisionmaking (USEPA 1984)Published by the EPA, this document illustrated the strengths and weaknesses of the risk assessment process and emphasized the need to make the process as transparent as possible.1985Chemical Carcinogens: A Review of the Science and Its Associated Principles (OSTP 1985)Published by the U.S. Office of Science and Technology Policy (OSTP), this document provides a complete review of the application of epidemiology in carcinogen risk assessment.1986The Risk Assessment Guidelines of 1986a (USEPA 1986b)This EPA document provided guidelines for evaluating the human and animal evidence of carcinogenicity, as well as a classification scheme for categorizing the level of risk associated with a particular agent (i.e., limited, inadequate, no data, or no evidence).1986Guidelines for Carcinogen Risk Assessment (USEPA 1986a)The purpose of these guidelines was to outline a procedure that EPA scientists could use to assess the cancer risk associated with exposure to chemicals in the environment. This document was also used to inform the public about the process of cancer risk assessment.1989Risk Assessment Guidance for Superfund, Vol. I: Human Health Evaluation Manual (Part A) (USEPA 1989)Published by the EPA Office of Solid Waste and Emergency Response (OSWER), this is the first of a series of guidance documents on risk assessment for the Superfund.1996Proposed Guidelines for Carcinogen Risk Assessment (USEPA 1996)Because limitations were identified in the 1986 carcinogen risk assessment guidelines, new cancer risk assessment guidelines were set forth that allowed scientists the flexibility to incorporate relevant biological information into the assessment process. The new guidelines were reviewed by the EPA Science Advisory Board (SAB) in 1997. The guidelines were made available for public comment in 2001 and then were reviewed again by the SAB in 2003.1997Exposure Factors Handbook. U.S. EPA (USEPA 1997)Published by the EPA National Center for Environmental Assessment (NCEA) within the EPA’s Office of Research and Development (ORD), this document provides data on exposure activities and other parameters for assessing exposure to contaminants in the environment. The 1997 handbook updates the 1989 original.2002OSWER Draft Guidance for Evaluating the Vapor Intrusion to Indoor Air Pathway from Groundwater and Soils (Subsurface Vapor Intrusion Guidance) (USEPA 2002)Published by the EPA Office of Solid Waste and Emergency Response (OSWER), this document provides guidance for the evaluation of the vapor intrusion exposure pathway.2003World Trade Center Indoor Environment Assessment: Selecting Contaminants of Potential Concern and Setting Health-Based Benchmarks (USEPA 2003)This document, published by the Contaminants of Potential Concern (COPC) Committee of the World Trade Center Indoor Air Task Force Working Group, provides guidelines and methodologies for setting health based standards for chemicals in settled indoor dust.2005Guidelines for Cancer Risk Assessment (USEPA 2005)The formal guidelines for cancer risk assessment were initially developed in 1986 and were finalized in 2005. After almost two decades of scientific input and progress, the final guidelines were designed to be flexible, with the ability to evolve as scientific advancement occurs.2008Child-Specific Exposure Factors Handbook (USEPA 2008a)Published by the National Center for Environmental Assessment (NCEA) within the EPA’s Office of Research and Development (ORD), this document supplements the 1997 Exposure Factors Handbook with child-specific data on exposure activities and other parameters for assessing exposure to contaminants in the environment.2009The U.S. Environmental Protection Agency’s Strategic Plan for Evaluating the Toxicity of Chemicals (USEPA 2009)In response to modern advances in computational and molecular biology, the EPA developed a strategic plan in 2009 to outline an approach for transforming and improving toxicity testing and risk assessment over the next 10 years. The premise of the proposed new plan is that risk assessors should consider how genes, proteins, and small molecules interact in the molecular pathways to maintain cellular function and how exposure to agents in the environment could disrupt these pathways. The strategic plan is built upon three components: (1) toxicity pathway identification and chemical screening prioritization, (2) toxicity pathway-based risk assessment, (3) institutional transition.

Present-day risk assessment methodologies have an increasing emphasis on physiologically based pharmacokinetics (PBPK) or toxicokinetic models and mode of action (MOA). Such models have been developed to predict exposure levels in target tissues for a large number of agents. PBPK models are especially useful in the risk assessment context because they allow data to be extrapolated across species, dose levels, and routes of exposure.

1.1.3. The Defining Steps in Cancer Risk Assessment

The NAS has developed risk assessment strategies and guidelines that are used by many agencies in cancer risk assessment to answer four fundamental questions: (1) Is the agent a carcinogenic hazard? (2) At what dose does the agent become a carcinogenetic hazard? (3) What is the current and expected extent of human exposure to the agent? (4) What is the estimated disease burden expected from exposure to the agent? The strategies used to answer these questions are divided into four actions (NRC 1983):

Hazard Identification. The total weight of the evidence from epidemiologic, animal, and toxicological studies is evaluated to determine the toxicity and carcinogenicity of an agent. In addition, as scientists begin to understand the process by which healthy cells transform into malignant cells, the use of mechanistic information is becoming more common in risk assessment. This may involve identifying the precursor events that may lead to increased cancer risk, as well as the specific genetic or cellular processes that occur during carcinogenesis.Dose–Response Assessment. The toxic effect of an agent is dependent upon many factors, including the amount of agent that is ingested, the route of exposure, and the specific endpoint under evaluation. Dose–response assessments are primarily focused on determining the safe dose for human exposure for noncarcinogens or acceptable risk levels for carcinogens. Because thresholds for carcinogen activity could not be defined as had traditionally been the case for noncarcinogens, the first risk assessment guidelines at the EPA relied on a linear, nonthreshold, dose extrapolation model for placing plau­sible upper bounds on risk; the real risks at low doses were thought to be lower, even approaching zero. Dose–response assessments are generally conducted in animals and use empirical, physiologically based toxicokinetic, or mechanism-based dose–response modeling techniques. In contrast, safety assessments for noncarcinogens historically relied on (a) establishing a no observed effect level (NOEL) or a lowest observed adverse effect level (LOAEL) in animals and (b) reducing this level by application of various safety or uncertainty factors to arrive at a safe dose for humans. Today, there is a convergence of methods for carcinogens and noncarcinogens, at least academically, to utilize understandings of toxicokinetics and toxicodynamics to arrive at safe exposure levels.Exposure Assessment. The fate of an agent in the environment and the extent to which humans will be exposed to the agent is determined through exposure assessment. The primary interests in exposure assessments are to determine the magnitude, frequency, and duration of the exposure. This assessment involves determining the environmental fate and transport of the agent, as well as evaluating the routes of potential exposure (i.e., inhalation in the air, ingestion in food or water, and through dermal contact). The most detailed guidance for exposure assessment is found in the EPA’s Risk Assessment Guidance for Superfund, Volume I (USEPA 1989) and the EPA’s Exposure Factors Handbook (USEPA 1997).Risk Characterization. Using both (a) the results of the qualitative hazard identification to express the WOE that an agent poses a cancer risk and (b) the quantitative information obtained from the dose–response modeling together with the results of the exposure assessment, the risk characterization step fundamentally describes the risk associated with exposure to an agent at various levels of exposure for the circumstances of concern.

The fact that there are scientific uncertainties in these steps has long been recognized. While there are no formal methods to fully characterize the uncertainties in the hazard assessment and dose–response stages (USEPA 2005), methodology and mathematical techniques exist for accounting for uncertainty (and variability) in the exposure assessment stages. Monte Carlo risk analysis modeling, for example, is a mathematical tool that can be used to describe the impact of uncertainty in a specific exposure scenario. It provides a probability distribution for each uncertainty parameter in the model and then can calculate thousands of probability scenarios. This tool allows risk assessors to model the unavoidable uncertainties that are inherent in the risk assessment process, including the occasion when conflicting expert opinions needs to be combined (Vose 1997).

The NAS also defined a separate step, Risk Management, where the level of acceptable risk is established. For suspected carcinogens, an acceptable risk range of one in a million to one in ten thousand has been chosen by the EPA and most other public health agencies as the acceptable risk range for regulatory purposes, with risk becoming less acceptable as it rises above the presumptively safe level of one in ten thousand (40_CFR_Part_61 1989). In addition, the results of any necessary risk–benefit analyses and scientific uncertainty analyses, as well as other social and economic issues as defined by the enabling statute, may be considered at this stage in the process.

1.1.4. The Mode of Action (MOA)

As described in the Guidelines for Cancer Risk Assessment (USEPA 2005, pp. 1–10), the MOA is defined as “a sequence of key events and processes, starting with interaction of an agent with a cell, proceeding through operational and anatomical changes, and resulting in cancer formation.” In fact, the severity of effect associated with exposure to an agent largely depends on the interaction between the biology of the organism and the chemical properties of the specific agent (USEPA 2005). In terms of cancer risk assessment, theoretically the potential carcinogen effect of an agent can be identified through modes of action that influence mutagenicity, mitogenesis, inhibition of cell death, cytoxicology, and immune function (USEPA 2005). Conclusions about the MOA for a particular agent are based on the following questions (USEPA 2005): (1) Do animal tests sufficiently support the hypothesized MOA? (2) If the MOA is supported by animal models, is the same action relevant to humans? (3) Are there specific populations or life stages in which humans are more vulnerable to the MOA? This information is included in the final risk assessment narrative that summarizes the total weight of the evidence regarding the potential carcinogenicity of an agent.

Because the MOA is based on physical, chemical, and biological processes, it is possible for an agent to have more than one MOA at different sites within the body. This makes it impossible to generalize the results obtained for one endpoint to other sites within the body. Information on the MOA often includes tumor data in humans, tumor data in animals and observations from in vitro test systems, and the structural analogue of the agent (USEPA 2005). As with all components of risk assessment, establishing the MOA of an agent can only be defined with confidence where complete data packages, rather than generic assessments or general knowledge of the agent, provide the foundations. When determining if the MOA observed in animal models is relevant to humans, risk assessors must rely on many sources of information including consideration of the tumor type, the number of studies conducted at each site, and the subgroups evaluated (gender, species, etc.), the metabolic activation and detoxification process observed in the animal model and in humans, the route of exposure, the dose, and the effect of dose and time on the progression of the tumor (see Chapter 13) (USEPA 2005). Only rarely are complete data sets available for defining the MOA. Most often the available information can provide only partial certainty about the MOA and its contribution to the WOE evaluation.

1.1.5. Accounting for Scientific Uncertainty

One of the greatest challenges of risk assessment is to account for and manage the scientific uncertainty associated with each step in the assessment process. Uncertainty is an unavoidable consequence of evaluating the fate of an agent in our dynamic environment and complex human systems. Sources of uncertainty in assessing the carcinogenicity of an agent include: (1) the parameter values resulting from data that are limited or inadequate, (2) the parameter modeling caused by inherent limitation in the models that are used to evaluate exposures and outcomes, and (3) the completeness of the assessment because of the often infeasible task of exhaustively evaluating all possible components of risk (USEPA 1997). In addition, there is uncertainty associated with applying the results of laboratory animal studies to humans (i.e., interspecies extrapolation), estimating the risk of low-dose ambient exposures from high-dose animal studies (i.e., dose extrapolation), and accounting for the needs of susceptible populations (i.e., intraspecies extrapolation). Given these intrinsic challenges, it may be impossible to guarantee that the best outcome identified in the risk assessment process will actually occur; however, it is imperative that public health decisions are made despite these uncertainties. The consequence of not doing so would be paralysis of the public health and regulatory systems (Bean 1988).

1.2. THE WEIGHT OF EVIDENCE (WOE) FOR DETERMINING CARCINOGENICITY

1.2.1. Epidemiologic Studies

Results from well-conducted epidemiologic studies provide the strongest weight of evidence (WOE) in cancer risk assessment. Epidemiology is the science of understanding the distribution of disease among humans and the factors that increase or decrease the risk of disease incidence (see Chapter 15). Because epidemiologic studies always measure an exposure (i.e., to a toxic agent) and an outcome (i.e., a specific cancer type), they are of great value to the cancer risk assessment process. Nevertheless, most observations in human populations have occurred when populations have been inadvertently exposed at high levels, above those commonly experienced in the environment. Epidemiologic studies are conducted in humans; therefore there are no issues related to species-to-species variation; however, other factors must be considered when estimating how the carcinogen potential of an agent may change when exposures are far lower or when population circumstances are at issue—for example, when lifestyle factors of the individual or population are concurrently assessed. The best evidence comes from well-conducted epidemiologic studies that are sufficiently powered to test a specific hypothesis and are backed up by confirmatory animal studies. However, well-conducted epidemiology studies are available for only a limited number of substances and often have limited uses because of difficulties involved in interpretation.

Unlike animal studies that are conducted in a controlled setting within the laboratory, epidemiologic studies seek to evaluate humans in their natural environments. This is both advantageous and challenging for the risk assessment process. Well-conducted epidemiologic studies will often have many of the following attributes (USEPA 2005): The objectives and the hypothesis are clearly stated, the people included in the study have been properly selected, the exposure has been characterized, the length of the study is long enough to ensure adequate time for the disease to occur, design flaws that may bias the results have been identified and minimized, factors that may confound the relationship between the exposure and the outcome have been properly accounted for, enough people have been enrolled in the study to detect the desired measure of effect, the data have been collected and analyzed using appropriate methods, and the results have been clearly documented. Because it is possible for one or more of these factors to be inadequate, epidemiologic studies that show no association between exposure to an agent and a cancer outcome do not prove that an agent has no carcinogenic potential. Therefore, the limitations of epidemiologic studies that are used in the risk assessment process must be identified and considered.

The types of epidemiologic studies used by risk assessors include case–control studies, cohort studies, descriptive epidemiologic studies, and case reports:

Case–control studies enroll people who have the disease (i.e., cases) and people who do not have the disease (i.e., controls) and then look retrospectively to assess the differences in exposure between the two groups. It is possible to determine causality from a well-conducted case–control study; overall evidence of causality is judged as a WOE that takes account of all qualified epidemiologic studies.Cohort studies enroll people who have been exposed to the agent of interest and people who have not been exposed to the agent, and then they follow the two groups through time to see which group (if either) has a higher incidence of disease. It is possible to determine causality from a well-conducted cohort study; overall evidence of causality is judged as a WOE that takes account of all qualified epidemiologic studies.Descriptive epidemiologic studies do not have a temporal component like case–control or cohort studies. Rather, this type of study evaluates factors that may influence the incidence of a disease, such as demographic or socioeconomic characteristics. It is not possible to determine causality from a descriptive epidemiologic study. Rather, this type of study is often used to generate a hypothesis that can be tested in case–control or cohort studies.Case reports are used to describe specific events or outcomes that occurred in a small number of people. It is not possible to determine causality from case reports, but they are useful for identifying unique events, such as the effects of a unique exposure or the incidence of an unusual tumor and for generating hypotheses that may be tested in follow-up, appropriately designed studies.

The premise of epidemiology is to determine if there is an association