USING DEREK TO PREDICT THE ACTIVITY OF SOME CARCINOGENS MUTAGENS FOUND IN FOODS

The knowledge-based expert computer system DEREK (Deductive Estimation of Risk from Existing Knowledge) has been assessed for its potential as a screen for predicting genotoxicity and carcinogenicity of some ch emicals found in foods. This was achieved by establishing databases, s ummarizing published activities of several chemical classes, including aflatoxins, flavonols, hydroxylated anthraquinones and polycyclic aro matic hydrocarbons (PAHs), to construct draft rules to identify struct urally alerting toxicophores. This information was used, together with other data (e.g. physicochemical properties, steric effects and molec ular modelling), to produce a set of simplified, non-specific rules wh ere possible to cover a wide spectrum of structures within each chemic al class. Examples of toxicophores identified include: a bisfuranoid s ubstructure centred around the 2,3-vinyl ether bond for aflatoxins and a 6-bond substructure, based on the 'bay' region of phenanthrene, for PAHs. The effects of various substituents and the presence of extra r ings were considered. Operation of the rules is illustrated by referen ce to these chemical groups, and to the favonols for which there are f our on-screen messages, depending on hydroxylation at positions 3 and 5 on the fused ring system and on the phenyl appendage, and whether fu rther hydroxylation can occur, for example by mixed function oxidase a ctivity and/or chemical or metabolic release of masked hydroxyls. Rule s were tested by processing a wide range of structurally related chemi cals in each class, with known and unknown activities. In some cases, key candidate structures for synthesis and toxicity testing were ident ified. The results from such studies should facilitate rule improvemen t. Whereas predictivity of a set of rules depends on the availability of reliable, experimental toxicity data for as many potential molecule s in a group as possible, utility for identifying toxic untested, nove l structures may be enhanced by using physicochemical information. Exa mples of this approach, as well as the advantages and current limitati ons of DEREK, are presented and discussed. It is concluded that DEREK has potential as a screen for genotoxicity and the approach adopted he re for rule development may be useful for predicting other toxicity en dpoints.