Lung tumorigenicity of benzene oxide, benzene dihydrobiols and benzene diolepoxides in the BUL:Ha newborn mouse assay

Abstract

Metabolic activation of benzene may occur by a pathway analogous to that accepted for polynuclear aromatic hydrocarbons (PAHs) involving ring epoxidation, enzymatic hydrolysis to the dihydrodiol, and further epoxidation to the diolepoxide. This hypothesis was explored by testing benzene oxide (BzO) and enantiomers and racemates of benzene dihydrodiols and diolepoxides for their capacity to induce lung tumors in a newborn mouse assay. Although benzene and benzene diolepoxide-1 [(+/-)-BzDE-1] were inactive, BzO and racemates of benzene dihydrodiol [(+/-)-BzDh] and benzene diolepoxide-2 [(+/-)-BzDE-2] induced dose-dependent increases in lung tumor incidence and multiplicity. (+/-)-BzDE-2 may be an ultimate tumorigenic metabolite of benzene since it was the most active compound tested on a molar basis with an estimated ED50 (dose inducing lung tumors in 50% of mice) of 12.0 mumol and an estimated TM1.0 (total dose inducing 1.0 lung tumor/mouse) of 16.2 mumol. No stereoselectivity was apparent in the tumorigenic activity of dihydrodiol and diolepoxide enantiomers since at equimolar doses the resolved (+)-BzDh was equally tumorigenic as the (+/-)-BzDh racemate and the resolved (+)- and (-)-BzDE-2 were both equally active as (+/-)-BzDE-2.