The TOPological Sub-Structural MOlecular DEsign (TOPS-MODE) approach (Estrada, E. SAR QSAR Environ. Res. 2000, 11, 55-73) has been introduced to the study of toxicological properties. The toxicity of 42 nitrobenzenes was studied with this approach obtaining a good quantitative structure--toxicity model. For the first time we compare the use of eight different weights in the diagonal entries of the bond matrix for selecting the best TOPS-MODE model. TOPS-MODE was used to derive the contribution of different fragments to the toxicity of studied compounds. These contributions were applied to calculate toxicity substituent constants for the groups present in the nitrobenzenes studied.