Ulrich Mohr - Böcker

Regulatory authorities worldwide still depend greatly upon and require long-term animal test results. To improve the reliability of interpretation of such results, a standardized nomenclature for the lesions observed in the tests is essential. Scientists from both academia and industry in many countries have closely cooperated to arrive at a consensus on the descriptions of all the types of tumour and pre-neoplastic lesions encountered in laboratory mice. The series of fascicles should provide information and guidelines especially adapted for international use in practical toxicologic pathology. Images showing the typical appearance of the discussed lesions and references to the most recently published papers complete the presented information.

During the years that have intervened since the third volume of the International Life Sciences Institute (ILSI) Monographs on Pathology of Laboratory Animals, Digestive System, was published, new information of interest to pathologists has developed at a rather remarkable pace. Standardized nomenclature has been proposed and gained significant acceptance during the period since the first edition and is being utilized on an international basis. This has resulted in improvement in communi­ cation of pathologic data to regulatory agencies and in scientific publica­ tions worldwide. This monograph series and others sponsored by ILSI have had significant effects on improved communications and the inter­ national acceptance of standardized nomenclature. In this second edition, new formats have been used in some instances where more appropriate for the subjects to be covered. The format introduced in the first edition remains useful as it emphasizes the neces­ sity to recognize the morphologic features of pathologic lesions to iden­ tify them precisely. This identification is an essential first step toward development of new insights into pathogenetic mechanisms and their use in decisions eventually applicable to public health.

Approximately 10 years have elapsed since the first volume of the International Life Sciences Institute (ILSI) Monographs on Pathology of Laboratory Animals, Endocrine System was completed. New information of interest to pathologists has developed at a rather remarkable pace during the intervening years. Exceptional progress has been made in the routine identification of cell products in endo­ crine cells. A better understanding has developed of the mechanisms involved in cell metabolism, particularly involving toxins and car­ cinogens. Clear concepts have developed concerning the significance of some pathologic lesions in the endocrine system and their relation to human health and risk assessment. Standardized nomenclature has developed significantly during the 1O-year period since the first volume and is being utilized on an international basis. This has resulted in significant improvement in communication of pathologic data to regulatory agencies and in scientific publications worldwide. This monograph series and others sponsored by ILSI have produced a significant effect on improved communications and the international acceptance of standardized nomenclature. In this second edition, new formats have been used where more appropriate for the subjects to be covered. In many cases, the format used in the first edition still is useful. It is still necessary to recognize the morphologic features of pathologic lesions in order to identify them precisely, an essential step toward development of new insights into pathogenetic mechanisms and their use in decisions eventually applicable to public health.

Approximately ten years have elapsed since the second volume of the International Life Sciences Institute (ILSI) Monographs on Pathology of Laboratory Animals, Respiratory System, was first completed. New in­ formation of interest to pathologists has developed at a rather remark­ able pace during these years. Exceptional progress has been made in the routine identification of enzymes and cell products in respiratory cells. A better understanding has developed on the functions of cells of the respiratory tract and of the mechanisms involved in cell metabolism, particularly those involving toxins and carcinogens. Clear concepts have developed concerning the significance of pathologic lesions, particularly in the upper respiratory tract and their relation to human health and risk assessment. Standardized nomenclature has developed significantly dur­ ing the lO-year period since the first edition and is being utilized on an international basis. This has resulted in significant improvement in com­ munication of pathologic data to regulatory agencies and in scientific publications worldwide. This monograph series and others sponsored by ILSI have had significant effects on these improved communications and the international acceptance of standardized nomenclature. In this sec­ ond edition, new formats have been used where more appropriate for the subjects to be covered.

The International Life Sciences Institute (ILSI), a nonprofit, public foundation, was established in 1978 to advance the sciences of nutrition, toxicology, and food safety. ILSI promotes the resolution of health and safety issues in these areas by sponsoring research, conferences, publications, and educational programs. Through ILSI's programs, scientists from government, academia, and industry unite their efforts to resolve issues of critical importance to the public. As part of its commitment to understanding and resolving health and safety issues, ILSI is pleased to sponsor this series of monographs that consolidates new scientific knowledge, defines research needs, and provides a background for the effective application of scientific advances in toxicology and food safety. Alex Malaspina President International Life Sciences Institute Contents Series Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Part I. Approaches to Assessing the Toxicity of Airborne Toxicants Chapter 1. Standard-Setting as an Integrative Exercise: Alchemy, Juggling, or Science? . . . . . . . . . . . . . . . . . . . . . . . 1 D. v. Bates Chapter 2. Species Differences in Inhalation Toxicology: Variations in Exposure-Dose Relationships and Macrophage Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 J. D. Brain Chapter 3. Cell Populations of the Respiratory System: Interspecies Diversity in Composition, Distribution, and Morphology . . . . . . . . . . . . . . . . . . . . . . . . 25 e. G. Plopper, A. Mir, J. St. George, N. Tyler, A. Mariassy, D. Wilson, S. Nishio, D. Cranz, J. Heidsiek, and D. Hyde Chapter 4. Comparative Metabolic Basis for the Disposition and Toxic Effects of Inhaled Materials . . . . . . . . . . . . . . . . . 41 A. R. Dahl Part II. Methodological Issues in Designing and Conducting Studies with Laboratory Animals Chapter 5. Exposure Facilities and Aerosol Generation and Characterization for Inhalation Experiments. . . . . . . . . .

The International Life Sciences Institute (ILSI) was estab­ lished to stimulate and support scientific research and edu­ cational programs in nutrition, toxicology, and food safe­ ty; and to encourage cooperation in these programs among scientists from universities, industry, and government in order to facilitate the resolution of health and safety issues. The officers and trustees of ILSI believe that questions re­ garding health and safety are best resolved when govern­ ment and industry rely on scientific investigations, analy­ ses, and reviews by independent experts. This process is furthered by the examination and discussion of issues on an international basis. ILSI is pleased to sponsor this set of monographs on the pathology of laboratory animals. This project collectively brings together the most comprehensive information on non-neoplastic and neoplastic lesions that occur in com­ monly used laboratory animals. The international compo­ sition of the authors, editors, and editorial board who have contributed to these monographs strengthens our expecta­ tions that understanding and cooperation will be strength­ ened worldwide through this series.

This is the ninth volume in a series dealing with induced lesions in laboratory animals. The information on pathology and toxicology documented in the series is an aid to scientific institutions, industry and government agencies charged with the safety testing of food, drugs and chemicals.

The International Life Sciences Institute (ILSI) was established in 1978 to stimulate and support scientific research and educational programs related to nutrition, toxicology, and food safety, and to encourage cooper­ ation in these programs among scientists in universities, industry, and government agencies to assist in the resolu­ tion of health and safety issues. To supplement and enhance these efforts, ILSI has made a major commitment to supporting programs to har­ monize toxicologic testing, to advance a more uniform in­ terpretation of bioassay results worldwide, to promote a common understanding of lesion classifications, and to encourage wide discussion of these topics among scien­ tists. The Monographs on the Pathology of Laboratory Animals are designed to facilitate communication among those involved in the safety testing of foods, drugs, and chemicals. The complete set will cover all organ systems and is intended for use by pathologists, toxicologists, and others concerned with evaluating toxicity and carcinogen­ icity studies. The international nature of the project - as reflected in the composition of the editorial board and the diversity of the authors and editors - strengthens our ex­ pectations that understanding and cooperation will be im­ proved worldwide through the series. Alex Malaspina President International Life Sciences Institute Preface This book, on the eye and ear, is the tenth volume of a set prepared under the sponsorship of the International Life Sciences Institute (ILSI).

Several compounds are associated with experimentally induced neoplasms in the urinary systems, and especially the kidneys, of laboratory animals. Many of these neoplasms are succintly described and illustrated in detail in this volume, and some are compared with spontaneously occurring lesions. Pragmatic aspects of disease which are of particular interest to pathologists are emphasized, such as classification and differential diagnosis of neoplasms that occur in the urinary system; comparison and significance of toxic effects of substances in animals and humans; and similarities and differences in disease manifestations between animals and humans.

The International Life Sciences Institute (ILSI) was estab­ lished in 1978 to stimulate and support scientific research and educational programs related to nutrition, toxicology, and food safety, and to encourage cooperation in these programs among scientists in universities, industry, and government agencies to assist in the resolution of health and safety issues. To supplement and enhance these efforts, ILSI has made a major commitment to supporting programs to harmon­ ize toxicological testing, to advance a more uniform inter­ pretation of bioassay results worldwide, to promote a common understanding of lesion classifications, and to encourage wide discussion of these topics among scien­ tists. The Monographs on the Pathology of Laboratory Ani­ mals are designed to facilitate communication among those involved in the safety testing of foods, drugs, and chemicals. The complete set will cover all organ systems and is intended for use by pathologists, toxicologists, and others concerned with evaluating toxicity and carcinogen­ icity studies. The international nature of the project - as reflected in the composition of the editorial board and the diversity of the authors and editors - strengthens our ex­ pectations that understanding and cooperation will be im­ proved worldwide through the series. Alex Malaspina President International Life Sciences Institute Preface This book, on the nervous system, is the sixth volume of a set pre­ pared under the sponsorship of the International Life Sciences Insti­ tute (ILSI).

The International Life Sciences Institute (ILSI) was estab­ lished in 1978 to stimulate and support scientific research and educational programs related to nutrition, toxicology, and food safety, and to encourage cooperation in these programs among scientists in universities, industry, and government agencies to assist in the resolution of health and safety issues. To supplement and enhance these efforts, ILSI has made a major commitment to supporting programs to harmon­ ize toxicologic testing, to advance a more uniform inter­ pretation of bioassay results worldwide, to promote a common understanding of lesion classifications, and to encourage wide discussion of these topics among scien­ tists. The Monographs on the Pathology of Laboratory Ani­ mals are designed to facilitate communication among those involved in the safety testing of foods, drugs, and chemicals. The complete set will cover all organ systems and is intended for use by pathologists, toxicologists, and others concerned with evaluating toxicity and carcinogen­ icity studies. The international nature of the project - as reflected in the composition of the editorial board and the diversity of the authors and editors - strengthens our ex­ pectations that understanding and cooperation will be im­ proved worldwide through the series. Alex Malaspina President International Life Sciences Institute Preface This book, on the integumentary system, is the seventh volume of a set prepared under the sponsorship of the International Life Sciences Institute (ILSI).

The International Life Sciences Institute (ILSI) was estab­ lished in 1978 to stimulate and support scientific research and educational programs related to nutrition, toxicology, and food safety, and to encourage cooperation in these programs among scientists in universities, industry, and government agencies to assist in the resolution of health and safety issues. To supplement and enhance these efforts, ILSI has made a major commitment to supporting programs to harmon­ ize toxicologic testing, to advance a more uniform inter­ pretation of bioassay results worldwide, to promote a common understanding of lesion classifications, and to encourage wide discussion of these topics among scien­ tists. The Monographs on the Pathology of Laboratory Ani­ mals are designed to facilitate communication among those involved in the safety testing of foods, drugs, and chemicals. The complete set will cover all organ systems and is intended for use by pathologists, toxicologists, and others concerned with evaluating toxicity and carcinogen­ icity studies. The international nature of the project - as reflected in the composition of the editorial board and the diversity of the authors and editors - strengthens our ex­ pectations that understanding and cooperation will be im­ proved worldwide through the series. Alex Malaspina President International Life Sciences Institute Preface This book, on the hemopoietic system, is the eighth volume of a set prepared under the sponsorship of the International Life Sciences In­ stitute (ILSI).

The International Life Sciences Institute (ILSI) was estab­ lished in 1978 to stimulate and support scientific research and educational programs related to nutrition, toxicology, and food safety, and to encourage cooperation in these programs among scientists in universities, industry, and government agencies to assist in the resolution of health and safety issues. To supplement and enhance these efforts, ILSI has made a major commitment to supporting programs to harmonize toxicologic testing, to advance a more uniform interpreta­ tion of bioassay results worldwide, to promote a common understanding of lesion classifications, and to encourage wide discussion of these topics among scientists. The Mo­ nographs on the Pathology of Laboratory Animals are de­ signed to facilitate communication among those involved in the safety testing of foods, drugs, and chemicals. The complete set will cover all organ systems and is intended for use by pathologists, toxicologists, and others con­ cerned with evaluating toxicity and carcinogenicity stu­ dies. The international nature of the project - as reflected in the composition of the editorial board and the diversity of the authors and editors -strengthens our expectations that understanding and cooperation will be improved worldwide through the series. Alex Malaspina President International Life Sciences Institute Preface This book, on Nonhuman Primates, is the eleventh volume of a set pre­ pared under the sponsorship of the International Life Sciences Institute (ILSI).

The International Life Sciences Institute (ILSI) was estab­ lished in 1978 to stimulate and support scientific research and educational programs related to nutrition, toxicology, and food safety, and to encourage cooperation in these programs among scientists in universities, industry, and government agencies to assist in the resolution of health and safety issues. To supplement and enhance these efforts, ILSI has made a major commitment to supporting programs to harmonize toxicologic testing, to advance a more uniform interpreta­ tion of bioassay results worldwide, to promote a common understanding of lesion classifications, and to encourage wide discussion of these topics among scientists. The M on­ ographs on the Pathology of Laboratory Animals are de­ signed to facilitate communication among those involved in the safety testing of foods, drugs, and chemicals. The complete set will cover all organ systems and is intended for use by pathologists, toxicologists, and others con­ cerned with evaluating toxicity and carcinogenicity stud­ ies. The international nature of the project - as reflected in the composition of the editorial board and the diversity of the authors and editors - strengthens our expectations that understanding and cooperation will be improved worldwide through the series. Alex Malaspina President International Life Sciences Institute Preface This book on nonhuman primate pathology is the 12th volume of a set of monographs prepared under the sponsorship of the International Life Sciences Institute (ILSI).

The International Life Sciences Institute (ILSI) was creat­ ed to promote cooperative efforts toward solving critical health and safety questions involving foods, drugs, cosmet­ ics, chemicals, and other aspects of the environment. The Officers and Trustees believe that questions regarding health and safety are best resolved when government and industry rely on scientific investigations, analyses, and re­ views by independent experts. Further, the scientific aspects of an issue should be examined and discussed on an international basis, separate from the political concerns of individual companies. ILSI is pleased to sponsor this set of monographs on the pathology of laboratory animals. This project will be use­ ful in improving the scientific basis for the application of pathologic techniques to health and safety evaluation of substances in our environment. The world wide distribu­ tion of the authors, editors, and Editorial Board who are creating these monographs strengthens the expectation that international communication and cooperation will al­ so be strengthened.

The International Life Sciences Institute (ILSI) was creat­ ed to promote cooperative efforts toward solving critical health and safety questions involving foods, drugs, cosmet­ ics, chemicals, and other aspects of the environment. The Officers and Trustees believe that questions regarding health and safety are best resolved when government and industry rely on scientific investigations, analyses, and reviews by independent experts. Further, the scientific aspects of an issue should be examined and discussed on an international basis, separate from the political concerns of individual companies. ILSI is pleased to sponsor this set of monographs on the pathology of laboratory animals. This project will be use­ ful in improving the scientific basis for the application of pathologic techniques to health and safety evaluation of substances in our environment. The world wide distribu­ tion of the authors, editors, and Editorial Board who are creating these monographs strengthens the expectation that international communication and cooperation will al­ so be strengthened.