TOXICOLOGICAL SIGNIFICANCE OF ALKYLBENZENE METABOLISM

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The long term objective of this project is to supply information that will aid in the identification of conditions under which individuals might be susceptible to alkylbenzene-induced toxicity. Monocyclic aromatic hydrocarbons are compounds that are produced in enormous quantities throughout the world. The compounds to ,e examined in this proposal, toluene, the xylenes, ethylbenzene and n-propylbenzene are major components of gasoline comprising up to 40% of the product. United States production of toluene, the xylenes and ethylbenzene are about 6 billion, 5 billion and 8 billion pounds, respectively, ranking each of these compounds among the top 10 chemicals. These compounds are widely used as solvents particularly toluene and xylene which are used as "safe" substitutes for benzene. These compounds are released into the environment primarily through automobile exhausts and losses from refineries, leading to frequent exposure in the form of photochemical smog. Alkylbenzene losses to the environment have been estimated at 12.2 million tons with over half of the release from toluene. The toxic effects of these compounds include narcosis, liver, kidney and heart damage which are evident from both acute and chronic exposure to these compounds. Detoxification of the alkylbenzenes involves the microsomal electron transport system, where the terminal oxidase cytochrome P-450 catalyzes both the aliphatic and aromatic oxidations of these compounds. The specific aims to be addressed in this project include: (1) Identification of changes in the metabolic fate of the alkylbenzenes due to their prior administration. These studies will focus on the metabolites produced, whether prior administration affects the relative amounts of side chain versus aromatic hydroxylation, and whether each alkylbenzene induces a unique cytochrome P-450 isozyme which catalyzes its oxidation. (2) The effects of age, sex and strain differences as well as the effects of exposure time and exposure to hydrocarbon mixtures will be examined. (3) The effect of hydrocarbon induction of cytochrome P-450 on the association of the alkylbenzenes with the enzyme will be determined by measuring spectral binding to cytochrome P-450, substrate effects on first electron input, and the ability of hydrocarbons to inhibit cytochrome P-450 dependent reactions. These studies will not only be useful in the safety assessment of this important class if compounds, but will also contribute to a fundamental knowledge of the enzyme system involved in their metabolism.