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AQUATIC TOXICITY MODE OF ACTION STUDIES APPLIED TO QSAR DEVELOPMENT
Citation:
Schmieder, P. K., S P. Bradbury, C L. Russom, AND S J. Broderius. AQUATIC TOXICITY MODE OF ACTION STUDIES APPLIED TO QSAR DEVELOPMENT. Presented at Chemical Society Meeting, Divisions of Computers in Chemistry, Quantative Structural-Activity Relationship in vivo Session, Washington, D.C, August 20-24, 2000.
Description:
A series of QSAR models for predicting fish acute lethality were developed using systematically collected data on more than 600 chemicals. These models were developed based on the assumption that chemicals producing toxicity through a common mechanism will have commonality in their physical-chemical or stereoelectronic properties. The establishment of robust predictive models thus required a fundamental understanding of toxic mechanisms. Various techniques were employed to elucidate toxic mode of action (MOA) to assign chemicals to MOA groupings, including: critical analysis of dose-response curves and behavioral data from single chemical tests; application of joint toxic action models; and, an assessment of physiological responses associated with intoxication. This MOA approach also identified numerous reactive (electrophile/pro-electrophile) chemicals. Recent studies have focused on discriminating among mechanisms of reactive chemical toxicity (redox cycling and arylation) and receptor-based MOAs. Assays at multiple levels of biological organization are used to determine in vivo MOA for receptor-based processes.