STRUCTURE-ACTIVITY MODEL OF CHEMICALS THAT CAUSE HUMAN RESPIRATORY SENSITIZATION

We report a structure-activity model of chemicals with the potential t o cause respiratory allergy developed through the CASE/MultiCASE syste ms. Chemicals documented to elicit a decrease in FEV1 of greater than or equal to 20% within 24 h of inhalation provocation challenge were u sed to form a learning set. Additional requirements for inclusion in t he learning set were that chemicals had at least two contiguous nonhyd rogen atoms and were nonmetallic. Forty chemicals met these criteria. The model identified several ''structural alerts'' including the isocy anate functionality (N=C=O), primary and secondary amines, substituted aromatic moieties, and distance descriptors. An external data-withhol ding exercise used to validate the model yielded a sensitivity of 0.95 and a specificity of 0.95. This model is applicable to initial predic tion of the sensitizing ability of untested chemicals and may provide mechanistic insight into the process(es) of respiratory sensitization. (C) 1997 Academic Press.