Progress Report of the Air Force Project Covering research period 7/1/94 to 6/30/95 Agency No: DOD/F49620-94-1-0401 U of M No: 0756-5140 (1613-189-6090) NRRI Technical Report Number: NRRI/TR-95/35 Center for Water and the Environment Contribution Number 161 Predicting T oxicity and D egradability of Q uadricyclane , Fluorocarbon Ethers and T heir Analogs Submitted By: Subhash C. Basak, Ph.D. Principal Investigator Natural Resources Research Institute and 5013 Miller Trunk Highway Duluth, MN 55811 Phone: (218)7200-4230 Fax: (218)720-9412 Email: [email protected] Keith B. Lodge, Ph.D. Co-principal Investigator Department of Chemical Engineering University of Minnesota, Duluth Duluth, MN 55812 Joseph Schubauer-Berigan, Ph.D. Principal Investigator University of South Carolina Subcontract NIWB NERR Baruch Marine Laboratory P.O. Box 1630 Georgetown, SC 29442 The University of Minnesota is an equal opportunity educator and employer. T a b l e o f C o n t e n t s Acknowledgments........................................................................................................ 2 Objectives ................................................................................................................... 3 Status of E ffo rt............................................................................................................. 4 Accomplishments/New Findings.................................................................................. 4 A. Background .................................................................................................. 4 B. Progress of Tasks of the Project ................................................................ 6 TASK 1: Development of data bases ................................................. 6 TASK 2: Development of methods to quantify molecular similarity .... 6 TASK 3: Selection of analogs ................................................................ 8 TASK 4 Estimation of properties of the target chemical from the probe- induced subset ......................................................................... 23 TASK 5: Measurement of hydrophobicity .......................................... 24 TASK 6: Microbial degradation studies ................................... 24 TASK 7: Photochemical transformations ............................................ 27 Publications ............................................................................................................... 27 Interactions/Transitions ............................................................................................. 28 A. Participation/Presentations at Meetings, Seminars, e t c ...................... .. 28 I. Presentations at Scientific Conferences .......................................... 28 II. Invited seminars/lectures ................................................................ 29 B. Consultative and Advisory Function.......................................................... 30 C. Transitions .............................................. 30 New Discoveries........................................................................................................ 30 Honors/Awards 31 A cknowledgments During the first year of the Air Force grant I have benefited considerably through interaction with numerous colleagues. I would like to specially mention Drs. William Fisanick (Research Department, Chemical Abstracts Service, Columbus, OH), Mic Lajiness (Computer-Aided Drug Discovery, The Upjohn Company, Kalamazoo, Ml), Dr. Douglas Bristol (NIH/NIEHS, RTP, NC), Don Gieschen (PSI International, Towson, MD), Professor A. T. Balaban (Polytechnic Institute, Bucharest, Roumania), Professor K. Balasubramanian (Department of Chemistry and Biochemistry, Arizona State University Tempe, AZ), Professor Timothy Colburn (Department of Computer Science, University of Minnesota, Duluth), Dr. Axel Drefahl (Department of Civil Engineering, Stanford University, Palo Alto, CA), Dr. Mark Johnson (Computer-Aided Drug Discovery, The Upjohn Company, Kalamazoo, Ml), Professor Milan Randic (Department of Mathematics and Computer Science, Drake University, IA), Dr. Romualdo Benigni (Director, Unit of Structure-Activity Relationships, Institute Superiore di Sanita, Rome) and Professor Rainer Bruggemann (GSF-Forschungszentrum fur Umselt und Gesundheit PUC, Germany) for very many fruitful discussions on topics related to quantification of molecular structure, molecular similarity and structure- activity relationships (SAR) pertaining to environmental toxicology. I would like to acknowledge the help of Dr. William Fisanick for generating for us the 75 analogs of Quadricyclane from a 120,000 Chemical Abstracts Service database and Dr. Mic Lajiness for generating for us a subset of 6,836 seven carbon compounds from Available Chemicals Directory (ACD) and generating for us analogs of Quadricyclane from the ACD. I am thankful to Mr. Greg Grunwald, Applications Programmer of NRRI, for his excellent and sustained efforts in developing databases and carrying out computations resulting in many publications supported by the Air Force. I would like to thank my graduate students, David Axtell (Computer Science, UMD), and Brian Gute (Toxicology Ph.D. program, U of Minnesota) for collaborating with me in developing neural net and similarity methods in estimating toxicological properties of chemicals. Finally I would like to thank AFOSR for providing us financial support for carrying out the research reported here. Subhash C. Basak, Ph.D. Principal Investigator Predicting toxicity and degradability of quadricyclane, fluorocarbon ethers and their analogs 2 Principal Investigator: Subhash C. Basak OBJECTIVES ( The same as in the original proposal) 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. Predicting toxicity and degradability of quadricyclane, fluorocarbon ethers and their analogs 3 Principal Investigator: Subhash C. Basak Status of Effort A number of novel molecular similarity methods have been developed using nonempirical parameters which can be computed directly from molecular structure. These parameters include topological indices (TIs), atom pairs (APs) and semiempirical quantum chemical parameters. The relative effectiveness of these similarity techniques in selecting analogs and estimating properties of toxicological importance have been tested on a selected set of properties like lipophilicity (logP, the logarithm of its octanol water portion coefficient, octanol/water), normal boiling point, mutagenicity, etc. The K nearest neighbor (KNN) method, K=1, 2, ------ , 25, has been used in generating probe-induced subsets from different databases for each probe. Results show that the KNN method gives the best estimate of properties at K = 5-10 for a diverse range of properties studied. Seventy-five probe-induced subsets have been generated for Quadricyclane from three different databases: a) STARLIST logP database of Daylight, Inc., containing more than 4,000 high quality logP values, b) Available Chemicals Directory (ACD), containing over 180,000 chemicals which are currently available from suppliers worldwide, and c) a Chemical Abstracts Service database containing about 120,000 diverse chemicals. Both water solubility