This volume will provide a contemporary account of advances in chemical carcinogenesis. It will promote the view that it is chemical alteration of the DNA that is a route cause of many cancers. The multi-stage model of chemical carcinogenesis, exposure to major classes of human carcinogens and their mode-of-action will be a focal point. The balance between metabolic activation to form biological reactive intermediates and their detoxification, ensuing DNA-lesions and their repair will be profiled. It will describe the chemical changes that occur in DNA that result from endogenous insults including epigenetic changes that lead to gene silencing. It will describe major mechanisms of mutagenesis, affects on tumor suppressor genes and proto-oncogenes, and how cell-cycle check points can be by-passed by the "stealth-like" properties of chemical carcinogens. Environmental agents that can promote tumor formation will be discussed. The monograph will have wide appeal as a knowledge base for graduate students, post-doctoral fellows and faculty interested in this aspect of cancer causation and research.

but also the possibility of intervention in specific stages. In Human behavior, including stress and other factors, plays an important role in neoplasia, although too little is known addition, variables which affect cancer development as well on the reasons for such development. Carcinogens, which as some endogenous factors can be better delineated help initiate the neoplastic process, may be either synthetic through such investigations. The topics of this volume encompass premalignant non or naturally-occurring. Cancer causation may be ascribed to invasive lesions, species-specific aspects of carcinogenicity, certain chemicals, physical agents, radioactive materials, viruses, parasites, the genetic make-up of the organism, and radiation, viruses, a quantum theory of carinogenesis, onco bacteria. Humans, eumetazoan animals and vascular plants genes, and selected environmental carcinogens. are susceptible to the first six groups of cancer causes, whe reas the last group, bacteria, seems to affect only vascular plants. Neoplastic development may begin with impairment ofJmdy defenses by a toxic material (carcinogen) which acts as an initiator, followed by promotion and progression to an overt neoplastic state. Investigation of these processes Series Editor Volume Editor allows not only a better insight into the mechanism of action Hans E. Kaiser Elizabeth K. Weisburger vii ACKNOWLEDGEMENT Inspiration and encouragement for this wide ranging project on cancer distribution and dissemination from a comparative biological and clinical point of view, was given by my late friend E. H. Krokowski.

The scientific basis, inference assumptions, regulatory uses, and research needs in risk assessment are considered in this two-part volume. The first part, Use of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity, focuses on whether the maximum tolerated dose should continue to be used in carcinogenesis bioassays. The committee considers several options for modifying current bioassay procedures. The second part, Two-Stage Models of Carcinogenesis, stems from efforts to identify improved means of cancer risk assessment that have resulted in the development of a mathematical dose-response model based on a paradigm for the biologic phenomena thought to be associated with carcinogenesis.

The use of exocyclic adducts as biomarkers offers a promising tool in studies of cancer etiology and prevention, particularly for human neoplasias in which the causative factors and mechanisms are still poorly understood. Presentations at an international conference, which resulted in this volume, comprise a comprehensive treatise on the current state of the art and scientific information on exocyclic DNA adducts. The volume includes sections on ultra sensitive detection methods, formation from exogenous and endogenous sources, DNA repair, physical chemical approaches to structural elucidation, and use as biomarkers and their role in mutagenesis and carcinogenesis.

In November 1997, an expert group was convened to discuss available knowledge on the epidemiology, pathology and mechanisms related to certain tumors that are commonly seen in essays for carcinogenicity in rodents in order that their importance in human hazard evaluation might be assessed. The tumors of interest were urinary bladder carcinomas associated with urolithiasis, microcrystalluria and certain urinary precipitates; renal corticol tumors in male rats associated with alpha-2 urinary globulin nephropathy; and thyroid follicular cell tumors associated with imbalances in thyroid stimulating hormone. Included in the book are a series of individually authored papers on these various topics, as well as a Concensus Report including consideration of how such data may be used within the evalation process in the IARC Monographs on the Evaluation of Carcinogenic risks to Humans.