The Use of In vivo Hepatic Initiation-Promotion Systems in Understanding the Hepatocarcinogenesis of Technical Grade Dinitrotoluene

Abstract

A 2 year bioassay sponsored by the Chemical Industry Institute of Toxicology demonstrated the potent hepatocarcinogenicity of technical grade dinitrotoluene (DNT) which contains 76% 2,4-DNT, 18% 2,6-DNT and less than 3% of each 2,3; 2,5; 3,4 and 3,5-DNT isomers. In contrast, a 2 year bioassay of 2,4-DNT sponsored by the National Cancer Institute did not result in the appearance of hepatic neoplasms above the spontaneous incidence. Using previously described in vivo hepatic initiation-promotion systems, an evaluation of the initiating and promoting activity of individual DNT isomers was undertaken to provide an understanding for the differences between the two bioassays. Weak hepatocyte initiating activity was identified in technical grade DNT and purified 2,6-DNT. In contrast, 2,3; 2,4; 2,5; 3,4 and 3,5 isomers had no detectable initiating activity. When fed following a diethylnitrosamine initiating regimen, technical grade DNT, purified 2,4 and 2,6-DNT isomers had demonstrable promoting activity. Therefore, the hepatic neoplasms resulting from technical grade DNT feeding apparently resulted from the initiating activity of 2,6-DNT followed by the promoting effect of both the 2,4 and 2,6-DNT isomers. The lack of hepatic neoplasms following chronic feeding of 2,4-DNT was apparently due to the lack of hepatic initiating activity.