Quantitative Aspects of Risk Assessment in Chemical Carcinogenesis: Symposium Held in Rome/Italy, April 3-6, 1979

ISBN-13: 9783540095842 / Angielski / Miękka / 1980 / 338 str.

J. Clemmesen; D. M. Conning; D. Henschler

Opis

N-nitroso-compounds form an important class of carcinogenic chemicals which may be of environmental importance (Druckrey et al. , 1967; Magee et al. , 1976; IARC, 1978). The mechanism by which these carcinogens initiate neoplastic growth is not well understood but there is substantial evidence favoring the hypothesis that the simple dialkylnitrosamines and alkylnitrosamides act by means of their conversion to al- kylating agents. Alkylating species are generated from the nitrosamines by metabolic activation and from the nitrosamides by chemical decomposition at physiological pH. It is widely believed that DNA is the critical alkylation target. Alkylation takes place at at least 12 sites within the DNA molecule (Lawley, 1976; Singer, 1976; Pegg, 1977a). Al- though alkylation at the 7-position of guanine is the most extensive reaction with the DNA bases and provides a reliable measurement of the degree of interaction with the carcinogen (Swann and Magee, 1968, 1971), recent experiments have suggested that alkylation of oxygen atoms may be the critical reaction (Goth and Rajewsky, 1974; Margison and Kleihues, 1975; Nicoll et aI. , 1975; Pegg, 1977a). These laboratories have observed a correlation between the production and persistence of 06-alkyl- guanine and the occurrence oftumors in a variety of organs of rodents exposed to N-ni- troso-carcinogens. It has, therefore, been suggested that the ability of tissues to catalyze the removal of 06-alkylguanine from DNA may provide a protective mechanism against carcinogenesis.

Spis treści

Dose Response Relationship in Long-Term Exposure to Low Levels of Carcinogens in Animals.- Epidemiological Studies of Occupational Carcinogens.- Incidence of Hepato-Carcinoma in Relation to Aflatoxin Intake.- Epidemiological Studies of Medically Used Drugs.- Estimation of the Risks of Ionising Radiation.- Discussion.- Dose Response Relationship of Carcinogenic Effects on Target Organs or Tissues.- Formation and Subsequent Repair of Alkylation Lesions in Tissues of Rodents Treated with Nitrosamines.- Dose-Response Relationship in the Primary Lesion of Strong Electrophilic Carcinogens.- Non Linear Pharmacokinetic Parameters Need to be Considered in High Dose/Low Dose Extrapolation.- Glutathione Thresholds in Reactive Metabolite Toxicity.- Dose Dependence of Early Cellular Changes During Liver Carcinogenesis.- Binding Kinetics of Vinyl Chloride and Vinyl Bromide at Very Low Doses.- Discussion.- Dose Response Relationship of Biochemical Mechanisms Affecting Species Differences in Response.- Enzymes Controlling Tissues Levels of Reactive Metabolites Including Irreversible Inactivations.- Activating Enzymes: Multiple Monooxygenase Forms with Different Substrate Preferences as Related to Toxic Effects.- Glucuronic Acid Conjugation in the Metabolism of Chemical Carcinogens by Rodent Cells.- Species Differences in Activating and Inactivating Enzymes Related to in Vitro Mutagenicity Mediated by Tissue Preparations from these Species.- The Ah Locus. A Gene with Possible Importance in Cancer Predictability.- Dose-Response Relationship of Rat Aryl Hydrocarbon Hydroxylase and Epoxide Hydratase Induction.- Repair.- Different Basic Mechanisms in DNA Repair.- Possible Determinants for the Differential Susceptibility of Mammalian Cells and Tissues to Chemical Carcinogens.- Reaction of Benzo(a)pyrene and 7,12-Dimethylbenz(a)anthracene with DNA of Various Rat Tissues in Vivo.- Discussion.- Risk Assessment.- Epidemiological and Animal Data as a Basis for Risk Assessment.- An Approach to the Assessment of the Risk to Man from DNA Damaging Agents.- Range of Experimental Evidence in Assessing Potential Human Carcinogenicity.- Procedures for Assessing Risk at Low Levels of Exposure.- Limited Usefulness of Mathematical Models for Assessing the Carcinogenic Risk of Minute Doses.- Discussion.- Summaries of the Chairmen.- Author Index.