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qUANTITATIVE RELATIONSHIP BETWEEN MUTAGENIC AND CARCINOGENIC POTENCIES: A FEASIBILITY STUDY Committee on Chemical Environmental Mutagens Board on Toxicology and Environmental Health Hazards Commission on Life Sciences National Research Council National Academy Press Washington, D,C e 1983 #

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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 report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Research Council was established 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 of advis ing the federa ~ government . The Counci 1 operates in accordance with general policies determined by the Academy under the authority of its congressional charter of 1863, which establishes the Academy as a private, nonprofit, self-governing membership corporation. The Council has become the principal operating agency of both the National Academy o f Sciences and the Nat tonal Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. It is administered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Medicine were established in 1964 and 1970, respectively, under the charter of the National Academy of Sciences. The evaluation described in this report has been funded by the U. S. Environmental Protection Agency through Contract 68-01-5873; however, the report has not been subjected to Agency review and therefore does no t ne ces s ar i ly re f lee t the views o f the Agency . Available from NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 Printed in the United States of America

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PREFACE The Committee on Chemical Environmental Mutagens (CCEM) has been asked to determine whether it is feasible at this time to study the relationship between mutagenic and carcinogenic potencies. The problem of studying this relationship begins with the definitions of mutagenic and carcinogenic potencies. Often, mutagenic potency must be described according to the biologic test in which it appears. It is usually defined as the amount of increase in the response of a tes t organism or test system at a particular concentration of the chemical under test. Potency has been variously expressed as other measures that are equivalent or closely related, including the initial slope of the dose-response curve, the lowest effective dose, the doubling dose, the mutation effect at 50: cell death, and the radiation-equivalent dose. 70 The definition of carcino- genic potency 1 ikewise depends on the biologic system that generates the data . A recent def inn' ion of carcinogen) c potency is the dose of ~ chemical carcinogen required to pro- duce tumors in hat f the tumor-free test animals in a normal 1 i fet ime . Several issues arise in the calculation of mutagenic or carcinogenic potency. We need to know whether the data are accurate and whether the results can be extrapolated among different experimental organisms. The success of past attempts to make comparisons can be used to suggest the likely outcome of future efforts that use the same approaches. And, it is important to examine the rationale of any relationship between the processes of carcinogenesis and mutagenesis. It is very important to determine whether algorithms can be created for extrapolating short-term test data to animal models and, ultimately, to human carcinogenesis. Without this, human risk asses sment cannot be approached quanti tat ively through these types of toxicity tests. This report will discuss the critical factors necessary to determine if there is a quanti- tative correlation between mutagenesis and carcinogenesis. After assessing the factors, the Committee offers general recommendations for how such a quantitative study might be done.

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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 report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Research Council was established 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 of advis ing the federa ~ government . The Counci 1 operates in accordance with general policies determined by the Academy under the authority of its congressional charter of 1863, which establishes the Academy as a private, nonprofit, self-governing membership corporation. The Council has become the principal operating agency of both the National Academy o f Sciences and the Nat tonal Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. It is administered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Medicine were established in 1964 and 1970, respectively, under the charter of the National Academy of Sciences. The evaluation described in this report has been funded by the U. S. Environmental Protection Agency through Contract 68-01-5873; however, the report has not been subjected to Agency review and therefore does no t ne ces s ar i ly re f lee t the views o f the Agency . Available from NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, D.C. 20418 Printed in the United States of America

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COMMITTEE ON CHEMICAL ENVIRONMENTAL MUTAGENS James F. Crow, University of Wisconsin, Madison, WI, Chairman Seymour Abrahamson, University of Wisconsin, Madison, WI, Vice-Chairman David G. Hoel, National Institute of Environmental Health Sciences, Research Triangle Park, NC Eliezer Hube~-=an, Argonne National Laboratory, Argonne, IL Peter N. Magee, Fels Research Institute, Philadelphia, PA Joyce McCann, Lawrence Berkeley Laboratory, Berkeley, CA Verne A. Ray, Pfizer Inc., Groton, CT Marvin A. Schneiderman, Clement Associates, Arlington, VA Robert A. Squire, Johns Hopkins University, Baltimore, MD BOTEHH Liaison Representative Liane B. Russell, Oak Ridge National Laboratory, Oak Ridge, TN Staff John Delehanty, Project Director Norman Grossblatt, Editor Shirley Ash, Administrative Secretary

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BOARD ON TOXICOLOGY AND END IRONME:NTAL HEALTH RAZARDS Ronald Estabrook, University of Texas Medical School, Southwestern, Dallas, TX, Chairman Philip Landrigan, National Institute for Occupational Safety and Health, Robert Taft Laboratories, Cincinnati, OH, Vice-Chairman Edward Bresnick, Eppley Institute for Research in Cancer and Allied Disease, Omaha, NE David G. Hoel, National Institute of Environmental Health Sciences, Research Triangle Park, NC Michael Lieberman, Washington University School of Medi MO Richard Merrill, University of Virginia, Charlottesville, VA Vaun A. Newill, Exxon Corporation, New York, NY John Peters, University of Southern California School of Medicine Angeles, CA Joseph V. Rodricks, Environ Corporation, Washington, D.C. Liane B. Russel 1, Oak Ridge National Laboratory, Oak Ridge, TN cine, St. Louis, Robert G. Tardiff, Executive Director (until June 24, 1983) Jacqueline K. Prince, Staff Assistant , Los

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CONTENTS THE SOMATIC-MUTATION THEORY OF CANCER Chromosomal Aberration Most Ultimate Carcinogens Are Mutagens Ultimate Care inogens That Are Not Mutagens Genetics of Cancer THE MUTAGENICITY OF CARC INOGENIC COMPOUNDS The Salmonel la/Microsome Test Re cent Comparat ive S t udies Ear 1 ier Qua 1 itst ive Studies QUANTITATIVE CORRELATION BETWEEN MUTAGENICITY AND CARCINOGENICITY Quantitative Potential of Mutagenicity Data Quantitative Potential of Carcinogenicity Data Direct Quantitative Correlation of Mutagenic and Carcinogenic Potencies 4 SUMMARY AND CONCLUSIONS REFERENCES 1 2 3 4 8 8 10 1J 17 17 20 24 27 29

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BOARD ON TOXICOLOGY AND END IRONME:NTAL HEALTH RAZARDS Ronald Estabrook, University of Texas Medical School, Southwestern, Dallas, TX, Chairman Philip Landrigan, National Institute for Occupational Safety and Health, Robert Taft Laboratories, Cincinnati, OH, Vice-Chairman Edward Bresnick, Eppley Institute for Research in Cancer and Allied Disease, Omaha, NE David G. Hoel, National Institute of Environmental Health Sciences, Research Triangle Park, NC Michael Lieberman, Washington University School of Medi MO Richard Merrill, University of Virginia, Charlottesville, VA Vaun A. Newill, Exxon Corporation, New York, NY John Peters, University of Southern California School of Medicine Angeles, CA Joseph V. Rodricks, Environ Corporation, Washington, D.C. Liane B. Russel 1, Oak Ridge National Laboratory, Oak Ridge, TN cine, St. Louis, Robert G. Tardiff, Executive Director (until June 24, 1983) Jacqueline K. Prince, Staff Assistant , Los

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CONTENTS THE SOMATIC-MUTATION THEORY OF CANCER Chromosomal Aberration Most Ultimate Carcinogens Are Mutagens Ultimate Care inogens That Are Not Mutagens Genetics of Cancer THE MUTAGENICITY OF CARC INOGENIC COMPOUNDS The Salmonel la/Microsome Test Re cent Comparat ive S t udies Ear 1 ier Qua 1 itst ive Studies QUANTITATIVE CORRELATION BETWEEN MUTAGENICITY AND CARCINOGENICITY Quantitative Potential of Mutagenicity Data Quantitative Potential of Carcinogenicity Data Direct Quantitative Correlation of Mutagenic and Carcinogenic Potencies 4 SUMMARY AND CONCLUSIONS REFERENCES 1 2 3 4 8 8 10 1J 17 17 20 24 27 29

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