Extrapolation of cellular and molecular level studies to the human situation

Abstract

This presentation deals with aspects of extrapolation in the areas of carcinogenesis and mutagenesis. Although many chemicals are known to induce cancer in experimental animals, relatively few are recognized with certainty as carcinogenic in humans. A large number of N-nitroso compounds are potent carcinogens in animals and are useful models for extrapolation, although they are not proved human carcinogens.Prediction of carcinogenic activity from chemical structure is possible in some cases but is not generally reliable. Most carcinogens require metabolic activation by microsomal mixed-function oxidases, and phenobarbitone, an inducer of these enzymes, produces tumors of mouse liver similar to those produced by some organochlorine pesticides. Epidemiological studies in humans indicate that prolonged phenobarbitone intake does not significantly increase the incidence of any human tumor except in the brain. Liver tumor induction in mice may be markedly influenced by relatively small environmental changes. Several screening tests for carcinogenesis depend on extrapolation from molecular studies, including various in vitro assays and detection of interaction with DNA.Attempts to identify adducts of activated carcinogens with human cellular macromolecues have been made by several groups. Studies of the repair of DNA lesions induced by carcinogens may influence thinking on possible defense mechanisms of the body against cancer induction.

Reaction of DNA with alkylating agents. Quantitation of alkylation by ethylnitrosourea of oxygen and nitrogen sites on poly[dA-dT] including phosphotriester formation

“…Under our reaction conditions this polymer assumes a double-helical conformation closely similar to the average helical conformation of natural DNA (reviewed by Wells & Wartell, 1973). Ethylnitrosourea and methylnitrosourea are potent laboratory carcinogens which are related both chemically and in biological effectiveness to the intensively studied laboratory and suspect human carcinogens diethylnitrosamine and dimethylnitrosamine (Pegg, 1977;Magee, 1977a).…”