Toxicological significance of covalently-bound residues

Bound residues may be defined in terms of the nonextractable radioactivity which persists in tissues after administration of radiolabelled compounds to an organism. This fraction is found to contain natural endogenous compounds resulting from incorporation of degradation products of the administered substance into intermediary metabolites (amino acids, carbohydrates etc.). However, 'new' compounds are also found which arise from covalent binding of the administered substance or its metabolites to endogenous macromolecules. The former fraction is nontoxic, but in the second case the nature of the covalent binding is important from the toxicological point of view. It is unspecific and irreversible, and often involves the action of short-lived and highly reactive intermediates. The covalent bond is usually thermodynamically irreversible. A good example is provided by bromobenzene, which binds to proteins via the 3,4-epoxide, which is the hepatotoxic agent. From the above considerations it is possible to distinguish two types of metabolites that may be found in foodstuffs prepared from drug-treated animals. The first are represented by the drug itself and its primary metabolites. These compounds are potentially more or less toxic to the consumer. The second type are the covalently bound metabolites. These have lost their reactivity in an irreversible manner and may be considered to have low toxicity to the consumer as well as low bioavailability. Some examples (trenbolone acetate, aflatoxin, carbaryl) are discussed to support this contention.