Introduction: Session on Metabolism

Benzene, discovered by Faraday in 1825, and isolated from coal-tar by Hofmann in 1845, was not obtained pure until 1952 when it was synthesized labeled with 14C. Although at that time exposure to benzene was associated with aplastic anemia, its toxicity was not generally considered to be a serious problem and was loosely associated with probable impurities. The material was used freely as an industrial and laboratory solvent and in several household products, and process workers often used benzene in preference of water to clean up at the end of a shift. The synthesis of [1-'4C] benzene, its partial purification as the nickel ammonium cyanide clathrate complex, and ultimate chemical purification to constant specific radioactivity revealed that many simple derivatives of benzene described by Beilstein and in the chemical literature were impure and even since have not been adequately characterized. The use of '4C-benzene in metabolism studies over 30 years ago established unequivocally that 1,2,4-trihydroxybenzene, L-phenylmercapturic acid, and trans-trans-muconic acid were minor metabolites, a quantitative account was made of the major pathways of metabolism to phenol, catechol and quinol and their conjugates, and its oxidative metabolism to 14C02 and to 2-carbon fragments, which resulted in the incorporation of '4C into tissue proteins and fatty acids, was established. Benzene is radiomimetic, a property probably associated with its causation of aplastic anemia and possibly also with its carcinogenicity as, similar to radiationinduced malignancy, benzene-induced malignancy is characterized by a multiplicity of tissue sites. This contrasts with the monohalobenzenes that are not radiomimetic, probably not carcinogenic, and are metabolized mostly by epoxidation to give the corresponding catechols and phenylmercapturic acids, which are only minor metabolites of benzene. Hence, the unique toxicity of benzene may well be associated with unique aspects of its metabolism such as the ring scission product mucondialdehyde, or one or more of the polymeric polyphenols formed from the primary phenolic metabolites. However,