HYDROCARBONS 337 



isomers were recovered from the urine. These investigators therefore 

 postulate that /rans-^raws-muconic acid is formed directly in the course 

 of oxidation of benzene, and does not result from the isomerization of the 

 cis-cis form in vivo. 



The quantities of muconic acid recovered have shown marked variations. 

 Jaffe-"^ was able to isolate only 0.3% of the benzene administered as 

 muconic acid, compared with figures of 3.7% cited by Thierfelder and 

 Klenk,2i'' 0.4% by Drummond and Finar,!^^ 0.5% by Bernhard and 

 Gressly,^" and practically zero by Neumaerker^i^ and by Mori.^* Fuchs 

 and Soos-'^ reported the presence of 0.11% of this unsaturated hexadienoic 

 acid in the urine of patients treated with benzene for leukemia. 



Although Jaffe^"^ was able to recover only about 0.3% of the benzene 

 administered as benzoic acid, he postulated that 25 to 30% of the benzene 

 is metabolized by this route. This hypothesis was based upon the fact 

 that, when muconic acid itself was injected, only approximately 1% 

 could be isolated from the urine; presumably the remaining muconic acid, 

 which is unaccounted for, is oxidized, demonstrating that it is a readily 

 oxidizable metabolite. However, there is some controversy as to how 

 readily muconic acid is metabolized when it is given to rabbits. In con- 

 trast to the positive results of Jaffe,-"^ Bernhard and Gressly-^' w^ere unable 

 to detect any of the administered muconic acid in the urine. However, 

 Neumaerker,2i2 Mori,^^ and Drummond and Finar^'^^ obtained recoveries of 

 53, 73, and 56%, respectively, of administered muconic acid in the urine. 

 These varying results led Williams ^^^ to question whether or not muconic 

 acid may arise normally as a direct metabolite of benzene; he suggested 

 that it may originate because of an abnormal metabolism brought about by 

 benzene. 



HoAvever, the fact that trans-trans-muGomc acid is a normal product 

 seems to have been confirmed by the use of labeled benzene. Thus, 

 Bernhard and Gressly^^^ showed that, when deuteriobenzene was injected 

 into rabbits, deuteriomuconic acid was excreted in the urine. It was later 

 proved by Parke and Williams^^^ that C^''-labeled trans-trans-muconic acid 

 could be recovered from the urine of rabbits fed C^ ''-containing benzene to 

 the extent of 1.3% of the benzene fed. 



Although a considerable proportion of benzene is eliminated as the 

 mono- or diphenolic compounds, definite amounts of the benzene disap- 

 pear, presumably by the rupture of the phenyl residue, with the formation 

 of muconic acid and its ultimate oxidation to carbon dioxide and water. 

 According to Williams,"" on the basis of the findings of Drummond and 

 Finar,"^ the course of the oxidation of benzene may proceed as follows: 



