Predicting Toxicity and Degradability of Quadricyclane, Fluorocarbon Ethers and their Analogs (1996-1997)

Abstract

In a large number of cases, we have to assess the risk of chemicals and predict the toxic potential of molecules in the face of limited experimental data. Structural criteria and functional criteria (if available) are routinely used to estimate the possible hazard posed by a chemical to the environment and ecosystem. Frequently, no biological or relevant physicochemical properties of the chemical species of interest are available to the risk assessor. In the proposed project, we will develop and implement a number of methods of quantifying molecular similarity of chemicals using techniques of computational and mathematical chemistry. Some of the methods are new and will be based on our own research on the theoretical development and implementation of molecular similarity methods. These techniques will be implemented in a user friendly computer environment of the Silicon Graphics workstation. The similarity methods will be used to select analogs of chemicals of interest to the Air Force, viz., QUADRICYCLANE, FLUOROCARBON ETHERS AND THEIR ANALOGS, from databases containing high quality physicochemical data and toxicity endpoints for large number of chemicals. The databases used in the project will come from three sources: a) public domain databases, b) our own in-house databases, and c) databases acquired from commercial vendors. The set of selected analogs, called probe-induced subsets, will be used to: a) develop structure-activity relationships (SAR), and b) carry out ranking of chemicals. Both of these methods will be used to estimate the hazard of the chemicals of interest. A set of chemicals (five to ten) will be chosen for experimental work with the purpose of evaluating and refining computer models. The set will include quadricyclane and fluorocarbon ethers of interest to the Air Force. It will also include a selection of analogs (probe-induced subset) that are readily available, suitable for experimentation, and for which data are lacking. Experiments will be performed to assess the biodegradability and photochemical degradability of the members of the set. Their toxicity will be tested by MicroTox and MutaTox. In cases where significant degradation is observed, the toxicity of the degradation products will also be tested. Direct measurement of the hydrophobicity (octanol-water partition coefficient) will be performed on the members of the set.