PubMed1976
The growing challenge to secure wholesome food of animal origin in quantities sufficient to feed the ever increasing world population leads to the compelling need of search for new means to enhance animal production. Such an endeavor often involves the use of pharmacologically active agents. As new substances are continuously introduced into agriculture, the necessity clearly arises to reassess the requirements for the approval of compounds likely to appear in the food of man via the edible tissues of animals. Since a number of animal drugs and feed additives have been recently found to show carcinogenic potency, using examples from their own research, the authors discuss problems encountered while planning animal studies for the safety evaluation of chemicals. Among the most important factors to be reckoned with is the metabolism of the test substance. Most carcinogens require metabolic transformation in order to react with macromolecules and, thus, exert their biological action. Similarly, residues of many drugs in animal tissues appear to be various metabolites rather than the parent compounds themselves. At present, it is not known whether many chemical residues are simply stored in different compartments of the carcass as a result of their physico-chemical properties or whether they are covalently bound to vital macromolecules (e.g., nucleic acids). Hence, their biological significance is not quite clear. The enzyme system which metabolizes numerous drugs, pesticides, as well as other endogenous and exogenous substrates is responsible for both the activation and detoxification of carcinogenic chemicals. The delicate balance between these two processes of opposing toxicological consequence is determined by genetic and environmental factors. Depending upon the metabolic profile of chemicals, certain compounds are carcinogenic in one animal species while not in others. The manipulation of their metabolism by physiological (e.g., stress) or pharmacological (e.g., inducers or inhibitors of microsomal enzymes) means can result in a profound change of various biological actions of chemicals (e.g., cytotoxicity, carcinogenicity, mutagenicity). To ascertain that potential toxicological hazards to human health by animal drugs and feed additives will be recognized during the phase of testing, appropriate test animals have to be selected with great care. It is indispensible that the metabolic break-down of the investigational substance proceeds via similar pathways in both test animals and the target species. This will assure that the same metabolites which, in the form of residues in food, man might be exposed to will have ample opportunity to exert their possible adverse effects to the experimental animals during a life-long feeding of the test substance. Therefore, it can, with a reasonable certainty, be assumed that, in experiments performed under such precautionary measures, toxico-pharmacological properties relevant to human safety evaluation will not remain undetected.
9,10-Dimethyl-1,2-benzanthracene↗