Organ And Species Specificity In Chemical Carcinogenesis

The Symposium on Organ and Species Specificity in Chemical Carcinogenesis was held March 1981 in Raleigh, North Carolina. Dr. James Miller concluded this Symposium with these remarks: "Without a doubt all of us would agree this has been a very successful symposium in illustrating a very wide range of chemical, stereochemical, biochemical, metabolic, molecular, and biological factors in chemical carcinogenesis. I think it is noteworthy that many of the discussions have dealt with pharmacodynamic, or toxicodynamic, factors that can influence the biological activities of the extremely wide range of structures that we choose to call chemical carcinogens. I sincerely hope that after this symposium everyone here will realize the very great need we have for further information on these agents in the species we profess to be working for, the human species. We badly need an adequate data base on human organs, human tissues, human cells, human subcellular preparations, and human body fluids. I don't think we can rely on extrapolations of data on chemical carcinogenesis from experimental animals to humans, no matter how sophisticated or plausible these extrapolations may seem, until we know far more about chemical carcinogenesis in humans. Now, I'd like to add a somewhat personal note. As many of you know, my wife and I have shared a joint career of some 40 years in this field, and I'd like to emphasize in these closing remarks the factor of youth.

Carcinogens, like chemicals with other toxic hazards, often produce adverse effects only in specific organs or tissues. The factors determining whether a chemical induces cancer in an organ range from simple toxicokinetics to complex phenomena such as expression or lack of expression of specific genes.; This volume examines the site-specific factor

This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.

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.

Despite increasing knowledge of human nutrition, the dietary contribution to cancer remains a troubling question. Carcinogens and Anticarcinogens assembles the best available information on the magnitude of potential cancer riskâ€"and potential anticarcinogenic effectâ€"from naturally occurring chemicals compared with risk from synthetic chemical constituents. The committee draws important conclusions about diet and cancer, including the carcinogenic role of excess calories and fat, the anticarcinogenic benefit of fiber and other substances, and the impact of food additive regulation. The book offers recommendations for epidemiological and diet research. Carcinogens and Anticarcinogens provides a readable overview of issues and addresses critical questions: Does diet contribute to an appreciable proportion of human cancer? Are there significant interactions between carcinogens and anticarcinogens in the diet? The volume discusses the mechanisms of carcinogenic and anticarcinogenic properties and considers whether techniques used to evaluate the carcinogenic potential of synthetics can be used with naturally occurring chemicals. The committee provides criteria for prioritizing the vast number of substances that need to be tested. Carcinogens and Anticarcinogens clarifies the issues and sets the direction for further investigations into diet and cancer. This volume will be of interest to anyone involved in food and health issues: policymakers, regulators, researchers, nutrition professionals, and health advocates.

This Scientific Publication reviews the information on cancer sites and mechanistic events for the more than 100 agents classified in Group 1 (carcinogenic to humans) by the IARC Monographs Program. This category of agents is diverse and includes chemicals and chemical mixtures; occupations; metals, dusts, and fibres; radiation; viruses and other biological agents; personal habits; and pharmaceuticals. For the Group 1 agents, there were cross-cutting questions about the relevance to humans of certain cancer sites or mechanistic pathways in animals. This publication is based on a systematic identification and comparison of the cancer sites observed in humans and those observed in experimental animals, and a compilation of mechanistic events for agents known to cause cancer in humans. Relevant information was analyzed on all the agents classified in Group 1 in Monographs up to and including Volume 109, most of which are reviewed in Volume 100A-F. A database of tumor sites seen in humans and animals was used to examine the degree of concordance by use of an anatomically based tumor classification scheme. The analysis of mechanistic aspects of the IARC Group 1 agents focused on 10 key characteristics of human carcinogens developed during the course of this work. Genotoxicity was the most prevalent mechanistic characteristic, consistent with the process of carcinogenesis necessarily involving genomic changes. The IARC concordance database represents a useful source of information for comparing animal and human data with respect to the tumors caused in different species. The results of the mechanistic analysis can provide a basis for future efforts to categorize mechanistic data for carcinogens through a systematic review process. These reviews and analyses were discussed during a two-part Workshop on Tumour Site Concordance and Mechanisms of Carcinogenesis convened by IARC. This Scientific Publication is the report of that Workshop and of subsequent work by the participants, both individually and collectively. This publication also presents a statement of consensus among the Workshop participants, which summarizes the main findings and their implications for human cancer risk assessment.