The proposed research herein represents a unique interdisciplinary collaboration between biologist/toxicologists and chemical engineers - an endeavor which goes beyond normal disciplinary boundaries. At the heart of this proposal is the integration of mechanistic toxicology, molecular and cellular biology related to mutagenicity and carcinogenicity, and the petroleum engineering concept and technique of structure oriented lumping (SOL) plus QSAR modeling. The long term goal of this proposed project is to develop an interdisciplinary approach based on mechanistic toxicology and chemical engineering concepts (structure oriented lumping) for the prediction of mutagenic and carcinogenic potential of petroleum hydrocarbons and mixtures. We anticipate synergistic creativity and productivity with this collaboration. In this grant period of five years, we plan to accomplish the first step of the long-term goal stated above, namely, the development of a predictive approach for mutagenic and carcinogenic potentials, in two cell culture systems (A sub L cells and human keratinocytes), for the following selected groups of chemicals and chemical mixtures: (1) benzo[a]pyrene, benzo[b]thiophene, isoquinoline, and carbazole as """"""""parent compounds""""""""; (2) selected alkylated derivatives for the four parent compounds; and (3) the four chemical mixtures resulting from the alkylation reaction of the parent compounds. Quantitative data on cell growth characteristics, expression of defined cell cycle regulators, and cell growth factors will be used in the SOL and OSAR modeling for the development of a predictive tool. Since all hydrocarbon mixtures from nature or industry (i.e., petroleum, petroleum refined products, pitch, coal tar, smoke, soot, solvents, etc.) are made up of alkylated components and the above four classes of chemicals represent some of the most common constituents in these hydrocarbon mixtures, our proposed research project will mark the beginning of a systematic endeavor to ultimately predict the mutagenic and carcinogenic potentials for petroleum products. The proposed research will be a close and integrated collaboration between the Center of Environmental Toxicology and Technology at Colorado State University and the Department of Chemical Engineering, University of Delaware. Hands-on cross training of graduate students between the two campuses on biology/toxicology and chemical engineering research techniques are proposed as well.
