We use the topological sub-structural molecular design (TOPS-MODE) approach to formulate structural alert rules for chromosome aberration (CA) of organic compounds. First, a classification model was developed to group chemicals as active/inactive respect to CA. A procedure for extracting structural information from orthogonalized TOPS-MODE descriptors was then implemented. The contributions of bonds to CA in all the molecules studied were then generated using the orthogonalized classification model. Using this information we propose 22 structural alert rules which are ready to be implemented in expert systems for the automatic prediction of CA. They include, among others, structural alerts for N-nitroso compounds (ureas, urethanes, guanidines, triazines), nitro compounds (aromatic and heteroaromatic), alkyl esters or phosphoric acids, alkyl methanesulfonates, sulphonic acids and sulphonamides, epoxides, aromatic amines, azaphenanthrene hydrocarbons, etc. The chemico-biological analysis of some of the structural alerts found is also carried out showing the potential of TOPS-MODE as a knowledge generator.