Prediction of substances of weak toxicity from chemical structures. An epidemiological approach

A global structure set of acute toxicity (LD50, mouse, i.v.) was constructed from databases. The common structural features of low toxicity substances were obtained from 1495 structure-toxicity data by applying the substructural balance method (SBM). This set contained 111 low toxicity (> ca. 1000 mg/kg) and 817 high toxicity substances (< ca. 30 mg/kg). The result was expressed by a control chart which is made to control the structural causes to obtain the desired effect (low toxicity). Within the control limits, 100% of low toxic and 20% of high toxic substances were found. The control chart was tested with another set of 81 structures of low toxicity selected among 718 structures retrieved from RTECS. Seventy-eight structures were found within the control limits and the predictability was 96.3% (78/81). SBM employs a new paradigm of descriptors, the ratios of numbers of substructures, which were selected through a descriptor-screening process. The results confirm that the new paradigm is applicable for structure-based toxicity prediction. This "epidemiological" approach suggests key structural criteria where no reliable mechanism of toxicity is available and serves to reduce the search space of organic structures. A theory supporting SBM was discussed.