Comparative hepatocarcinogenicity of hexachlorobenzene, pentachlorobenzene, 1,2,4,5-tetrachlorobenzene, and 1,4-dichlorobenzene: Application of a medium-term liver focus bioassay and molecular and cellular indices

Of the twelve different chlorobenzene isomers, a thorough evaluation of car cinogenicity has only been assessed on monochlorobenzene, 1,2-, and 1,4-dic hlorobenzene, and hexachlorobenzene. In the studies presented here, we meas ured the ability of 1,4-dichlorobenzene (DCB), 1,2,4,5-tetrachlorobenzene ( TeCB), pentachlorobenzene (PeCB), and hexachlorobenzene (HCB) to promote gl utathione S-transferase pi (GSTP1-1) positive preneoplastic foci formation in rat liver, following diethylnitrosamine (DEN) initiation. The results fr om these studies show that TeCB, PeCB, and HCB all promote the formation of GSTP1-1 positive foci and that DCB does not. The numbers and area of foci were greatest following HCB promotion, and TeCB and PeCB were approximately equal in their promoting ability. Levels of hepatic CYP1A2, CYP2B1/2, non- focal GSTP1-1, and c-fos were measured in response to treatment with the 4 chlorobenzene isomers, as were reduced glutathione (GSH) and oxidized gluta thione (GSSG) levels. Results from these studies show that induction of CYP 1A2 and CYP2B1/2 have correlation with both the presence and degree of GSTP 1-1 foci promotion by the 4 chlorobenzenes. Alterations in GSH and GSSG lev els were similar in PeCB- and TeCB-treated animals in that GSSG levels were significantly decreased, whereas HCB and DCB did not have this effect, alt hough HCB treatment led to a significant increase in GSH levels. We conclud e that induction of CYP1A2 or CYP2B1/2 by chlorobenzene isomers may indicat e promotional ability, and that this property might be exploited to predict the hepatocarcinogenicity of other chlorobenzene isomers.