Toxicological Sciences 68, 498-507 (2002)
Copyright © 2002 by the Society of Toxicology
RISK ASSESSMENT |
Risk Assessment of High-Energy Chemicals by in Vitro Toxicity Screening and Quantitative Structure-Activity Relationships
* Technical Management Concepts, Inc., P.O. Box 340345, Beavercreek, Ohio 45434-0345;
Air Force Research Laboratory, Materials and Manufacturing Directorate, Wright-Patterson Air Force Base, Ohio 45433-7702;
ManTech Environmental Technology, Inc., Dayton, Ohio 45437-0009; and
Air Force Research Laboratory, Human Effectiveness Directorate, Wright-Patterson Air Force Base, Ohio 45433-7400
ABSTRACT
Hydrazine propellants pose a substantial operational concern to the U.S. Air Force and to the aerospace industry because of their toxicity. In our continuing efforts to develop methods for the prediction of the toxicological response to such materials, we have measured in vitro toxicity endpoints for a series of high-energy chemicals (HECs) that were recently proposed as propellants. The HECs considered are structurally diverse and can be classified into four chemical types (hydrazine-based, amino-based, triazoles, and a quaternary ammonium salt), although most are hydrazine derivatives. We measured the following endpoints in primary cultures of isolated rat hepatocytes: mitochondrial function (MTT), lactate dehydrogenase leakage (LDH), generation of reactive oxygen species (ROS), and total glutathione content (GSH). In several instances, effective concentrations (EC) were indeterminate, and only lower limits to the measured endpoints could be ascertained. Using molecular descriptors calculated with a semiempirical molecular orbital method, quantitative structure-activity relationships (QSARs) were derived for MTT (EC25) and for GSH (EC50). Correlation coefficients for 2- and 3-parameter QSARs of about 0.9 enable us to predict the toxicity for similar compounds. Furthermore, except in one case, predicted EC values for the uncertain endpoints were consistent with experiment. Descriptors comprising the QSARs for MTT were consistent with the biophysical mechanism of toxic response found experimentally for hydrazine derivatives. Application of our derived QSARs will assist in predicting toxicity for newly proposed propellants.
Key Words: high-energy chemicals; risk assessment; in vitro toxicity; QSAR; hydrazine.
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