Mouse Liver Tumors: Relevance to Human Cancer Risk Symposium of the European Society of Toxicology Held in Rome, February 2–5, 1986 PDF
Preview Mouse Liver Tumors: Relevance to Human Cancer Risk Symposium of the European Society of Toxicology Held in Rome, February 2–5, 1986
Archives of Toxicology, Supplement 10 Mouse Liver Tumors Relevance to Human Cancer Risk Symposium of the European Society of Toxicology Held in Rome, February 2-5, 1986 Edited by P. L. Chambers, D. Henschler and ROesch With 64 Figures Springer-Verlag Berlin Heidelberg New York London Paris Tokyo PInuP L. CHAMBERS University of Dublin, Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland DIETRICH RENSCHLER Institut fiir Toxikologie und Pharmakologie der Universitat Wiirzburg, Versbacher LandstraBe 9,8700 Wiirzburg FRANZ OESCH Institut fUr Toxikologie der Universitat Mainz, Obere Zahlbacher StraBe 67,6500 Mainz ISBN-13 :978-3-540-17124-9 e-ISBN-13 :978-3-642-71617-1 DOl: 10.1007/978-3-642-71617-1 Library of Congress Cataloging in Publication Data. European Society of Toxicology. Meeting (1986: Rome, Italy) Mouse liver tumors. (Archives of toxicology. Supplement, 10) Includes index. 1. Liver-Tumors-Animal Models-Congresses. 2. Mice-Diseases-Congresses. I. Chambers, P. L. (philip L.), 1931. II. Henschler, Dietrich. III. Oesch, Franz, 1938. [DNLM: 1. Liver Neoplasms-congresses. 2. Mice-congresses. 3. Neoplasms, Experimental-congresses. Wi AR49GA v. 10/ WI 735 E89m 1986] RA1190.E8 Suppl. vol. 10 615.9s 86-26133 [RC280.L5] [616.99'436] ISBN-13:978-3-540-17124-9 (U.S.) This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law, where copies are made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich. © Springer-Verlag Berlin Heidelberg 1987 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence ofa specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book, in every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. 2127/3020-543210 Contents Introduction The Mouse in Safety Evaluation J.DOULL ......... . 3 Liver Lesions in B6C3F1 Mice: The National Toxicology Program, Experience and Position R. R. MARONPOT, J. K. HASEMAN, G. A. BOORMAN, S. E. EUSTIs, G. N. RAo, and J. E. HUFF. 10 Biology and Functional Properties of Mouse Liver Nodules Invasiveness, Metastasis, and Transplantability of Mouse Liver Nodules S. D. VESSEUNOVITCH . . . . . . . . . . . . . . . . . . . . . . . 29 Xenobiotic-Induced Peroxisome Proliferation: Role of Tissue Specificity and Species Differences in Response in the Evaluation of the Implications for Human Health J. K. REDDY and M. S. RAo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 The Role of Necrosis in Hepatocellular Proliferation and Liver Tumors P. M. NEWBERNE, P. PuNYARIT, J. DE CAMARGO, and V. SUPHAKARN . . 54 Biological Markers Characterizing the Development of Preneoplastic and Neoplastic Lesions in Rodent Liver D. G. BEER and H. C. PrroT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Relationship Among the Histochemically Distinguishable Early Lesions in Multistep-Multistage Hepatocarcinogenesis E. SCHERER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 The Histopathology and Biochemistry of Phenobarbitone-Induced Liver Nodules in C3H Mice S. D. GANGOLU, B. G. LAKE, and J. G. EVANS. . . . . . . . . . . . . . . . . . . . . . 95 Molecular Basis Species Differences in Enzymes Controlling Reactive Epoxides H. R. GLATT and F. OESCH. . . . . . . . . . . . . . . . .. 111 Species Differences of Glucuronidation and Sulfation in Relation to Hepatocarcinogenesis K. W. BOCK and G. SCHIRMER . . . . . . . . . . . . . . . . . . . . . . . . .. 125 Glutathione S-Transferase Subunits in the Mouse and Their Catalytic Activities Towards Reactive Electrophiles J. D. HAYES, R. E. COULTHWAITE, P. K. STOCKMAN, A. J. HuSSEY, T. J. MANTLE, and C. R. WOLF 136 Species Differences in Biotransformation of and Peroxisome Proliferation due to Trichloro ethylene C. R. ELCOMBE, I. S. PRATT, and T. GREEN ....................... 147 The Distribution of Carcinogen Metabolizing Enzymes in the Mouse Liver: Comparison of Parenchymal and Non-Parenchymal Cell Populations P. STEINBERG, W. M. LAFRANCONI, and F. OESCH . . . . . . . . . . . . . . . . .. 148 Investigations on the Mechanism of Liver Tumour Induction by Peroxisome Proliferators P. BENTLEY, F. BIERI, F. MITCHELL, F. WAECHTER, and W. STAUBLI ............ 157 DNA Damage and Repair in Mouse Liver J. A. SWENBERG and T. R. FENNELL . . . . ................ 162 Individual Differences in DNA Repair Capacities in Man F. OESCH, W. AULMANN, K. L. PLATT, and G. DOERJER. . ............... 172 Variables Influencing DNA-Binding in Mouse Liver H.-G. NEUMANN . . . • . . • • . . • • • . • . 180 Pharmacokinetic Factors and Their Implication in the Induction of Mouse Liver Tumors by Halogenated Hydrocarbons H. M. BOLT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 Comparative Study on the Indirect Methylation of Liver DNA Guanine by the 1-Carbon Pool in Hepatotoxicity R. C. SHANK. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 Activation of a Cellular Proto-Oncogene in Spontaneous Liver Tumor Tissue of B6C3F1 Mouse T. R. Fox, A. M. SCHUMANN, and P. G. WATANABE . . . . . . . . . . . . . . . . . . . 217 Modifying Factors Nutritional and Dietary Influences on Liver Tumorigenesis in Mice and Rats A. E. ROGERS, H. M. NIELDs, and P. M. NEWBERNE . . . . . . . . . . . . . . . . . . . 231 Anatomy, Function and Aging in the Mouse Liver C. F. HOLLANDER, C. F. A. VAN BEZOOIJEN, and H. A. SOLLEVELD . . . . . . . . . . . . . 244 Sex Hormones and Neoplasia: Liver Tumors in Rodents M. METZLER and G. H. DEGEN . . . . . . . . . . . . .......... 251 Sex Hormones and Neoplasia: Genotoxic Effects in Short Term Assays G. H. DEGEN and M. METZLER ................. . ......... 264 Mouse and Human Liver Tumors Pathogenesis of Experimental Liver Cancer Comparison with Humans E. FARBER ..................................... 281 Author Index 289 Subject Index 291 Introduction Mouse Liver Tumors Arch. Toxico!. Supp!. 10, 3-9 (1987) © Springer-Verlag 1987 The Mouse in Safety Evaluation J. Doull Department of Pharmacology, Toxicology and Therapeutics, University of Kansas, Medical Center, Kansas City, Kansas, 66103 USA Abstract. Several recent publications have reviewed the history, rationale and experience concerning the use of mice as a test species in oncogenicity bioassay programs. Conclusions from three of these publications will be discussed: The Report of the International Expert Advisory Committee on the Relevance of Mouse Liver Hepatoma to Human Carcinogenic Risk (from the Nutrition Foundation), the Report of the NTP Ad Hoc Panel on Chemical Carcinogen esis Testing and Evaluation (from the Board of Scientific Counselors of the National Toxicology Program), and Chemical Carcinogens: Review of the Science and its Associated Principles (from the Office of Science and Technol ogy Policy). Using the recommendations from these and other groups regard ing modification of the current testing protocols and alternative approaches to evaluating the adverse health effects oflong-term, low-level exposure to en vironmental chemicals, an effort will be made to predict some future develop ments in this area of toxicology. Key words: Nutrition Foundation Expert Panel - 'Ad hoc' Panel National Toxicology Program - Office of Science Technology Policy - Chemical carci nogens The entire Western world and the majority of the developing countries rely heavily on the results of animal tests to make decisions regarding the registration and use of drugs, pesticides and other chemicals to which human populations may be exposed. This is a difficult and demanding responsibility and the regulatory authorities need the advice and support of a broad segment of society, including the scientific community and the lay public. Epidemiologic data cannot be avail able on new substances and, even for those compounds which have been in use for some time, the data are often imprecise and of variable utility in decision mak ing. Abbreviations: FDA: Food and Drug Administration. EPA: Environmental Protection Agency. NCI: National Cancer Institute. NCTR: National Center for Toxicologic Research. NTP: National Toxicology Program. NIEHS: National Institute of Environmental Health Science. OSHA: Occupa tional Safety and Health Administration. 4 J. Doul1 The use of experimental animals in risk evaluation has been widely accepted since, when properly used, they serve as satisfactory surrogates for humans. The appropriate management of risk, however, depends on the critical assessment and a balanced interpretation of the available data. Some of the data obtained from mice in recent years have been questioned by the regulatory authorities, industry and the scientific community. Much of the controversy has arisen around the mouse liver nodule which is sometimes the sole indicator of a compound's poten tial risk. With the increasing concern among those responsible for using risk as sessment and management in protecting public health and a desire to explore in depth and sort out what is fact and what is fiction about the biology of mouse liver, this conference included: the historical development of animal bioassays in cluding the mouse, particularly the B6C3F1 hybrid, the biology and function of mouse liver nodules, factors that influence proliferative lesions, the enzymatic control of reactive control of reactive chemical species, oncogenes and DNA re pair. The participants included scientists from government, industry and aca demia who represent a cross-section of the best expertise available in Europe and America and are working at the cutting edge of research in hepatology. The first goal of this conference was to enable these experts to interact both formally and informally in an atmosphere conducive to a frank and perceptive exchange of ideas and data. This exchange between those who are involved in morphologic and histochemical investigations and the biochemists and molecular biologists should further the understanding about the nature and mechanisms of hepatocellular cancer. The second goal of this conference was to focus on the question of whether the mouse liver is or is not a useful tool for assessing risk and protecting the public's health without penalizing industry incorrectly in its effort to continue to provide useful drugs and chemicals essential to the continued de velopment and maintenance of a high standard of living. Those who must regu late the drugs and chemicals to which man is or may be exposed must do so in the absence of complete information; hopefully, the results of this conference should make a job a bit easier and more acceptable to all. There have been several groups in the past few years that have examined the validity of predicting human cancer risks on the basis of rodent studies, and in most cases these groups have also considered the more specific issue of the mouse liver tumor. In organizing this conference on the relevance of mouse liver tumors to human risk, it was felt that a review of the recommendations and conclusions of some of these groups would provide useful background information and a fo cus for some of the problems areas. During the summer of 1982, the Nutrition Foundation established an Interna tional Expert Advisory Committee on the Relevance of Mouse Liver Hepatoma to Human Carcinogenic Risk. The members of this committee included Dr. Bridges from England, Dr. Munro from Canada, Dr. Kroes from The Nether lands and Drs. Darby, Doull, Golberg, Paynter, Pitot, Squire and Williams from the U.S. The report of this committee, which was issued in the fall of 1983, con sisted of major sections describing the pathology of mouse liver neoplasms, the factors which modify the spontaneous and induced incidence of this lesion, the natural course of mouse hepatoma and a final section dealing with the regulatory aspects and interpretation of mouse hepatoma data. Included in the report are The Mouse in Safety Evaluation 5 discussions of the nomenclature, morphology and both the functional and bio logic characteristics of mouse hepatomas. Data is also presented on the incidence of mouse hepatoma in different strains, the interlaboratory variation in incidence within a single strain (B6C3Fl) and a summary ofNCI and NTP data comparing chemical induction of liver and other tumors in rats and mice. With regard to the nomenclature of mouse liver hepatomas, the report distin guishes between nodular hyperplasia, adenoma and hepatocellular carcinoma in terms of morphology and both functional and biological characteristics. Al though there are conflicting results and discordant conclusions in this area, the committee felt that there is now fairly general agreement that some types of mouse liver neoplasms are capable of metastasizing either spontaneously or ar tificially by transplantation. The committee concluded that some nodular mouse liver lesions with the morphological abnormalities associated with malignancy in other organ systems also display functional and biological abnormalities indica tive of a malignant character and that such lesions are appropriately diagnosed as hepatocellular carcinomas. Other well-differentiated nodular lesions have been shown to possess functional abnormalities and in some cases to be progressively growing and transplantable. The bulk of evidence suggests that these lesions are neoplasms, albeit less aggressive than the type that is morphologically more ab normal, and the committee agreed that these lesions may be benign neoplasms and that the designation of adenoma is appropriate. Whether or not the type A hepatoma or adenoma is a precursor of hepatocellular carcinoma is less clear. The report points out, however, that although the neoplastic nature of such nodules may be equivocal, they are indicative of a neoplastic process in the liver. The com mittee recognized that most of the current problems associated with the diagno sis, interpretation and biological significance of mouse liver neoplasms stem from the fact that the various steps in the carcinogenic process are not well understood. However, they point out that since some of the newer approaches, such as the use of recombinant DNA techniques, appear to be feasible for mouse hepatoma, it is likely that many of these problems could be clarified in a reasonably short time if such approaches were to be vigorously pursued. During the initial meetings of this committee, a series of questions were devel oped which it was felt should be addressed by toxicologists and those who use the results of toxicologic bioassays. Several of these questions, such as those involv ing the resolution of conflicting data sets and the appropriate use of negative bioassay data, were beyond the scope of the charge to this committee, but two of these questions were addressed. The first of these is "How reliable are rodent tests in predicting carcinogenicity in man?", and the second is "What is the basis for the use of sensitive strains exhibiting high natural incidence of liver and/or lung tumors, for example, in carcinogenic bioassays?" In responding to the first question, the committee pointed out that the concept of dose-response and the argument that tests in animals, when properly qualified, are applicable to man constitute well-established principles not only of toxicology but of biology in gen eral. Another approach to this question is to ask "How reliable are mouse bioas say tests in predicting carcinogenicity in the rat?". Using NCI data on 85 chemi cals which produced neoplasia in at least 1 tissue of rats and/or mice, the commit tee noted that the B6C3Fl mouse exhibited only liver tumors in 37 of these bioas-
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