title: Prediction of substances of weak toxicity from chemical structures. An epidemiological approach.
abstract: 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.
authors.affiliation: Yano Research Laboratory, Inc., 5234-8 Oba, Fujisawa 251, Japan. nicky@ra2.so-net.ne.jp
authors.forename: K
authors.initials: K
authors.lastname: Yano
authors.forename: K
authors.initials: K
authors.lastname: Yano
mesh_terms: D000818:Animals; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D016021:Epidemiologic Studies; D005544:Forecasting; D007928:Lethal Dose 50; D051379:Mice; D008958:Models, Molecular; D013329:Structure-Activity Relationship