Toxic effects of benzene and benzene metabolites on granulopoietic stem cells and bone marrow cellularity in mice

Mice were injected subcutaneously with benzene or one of three of its metabolites (phenol, hydroquinone, or 1,2-dihydro-1,2-dihydroxybenzene). The adverse effects on the concentration of granulopoietic stem cells (measured as number of colony-forming units per tibia or per 10⁵ cells) and on the bone marrow cellularity in tibia were measured. Benzene had strong toxic effects. Thus, 0.7 mg benzene/kg body wt injected daily on 6 consecutive days gave detectable effects on stem cell concentration, and 3.5 mg/kg/day affected also cellularity. Six daily injections of 440 mg benzene/kg reduced cellularity and number of colony-forming units per tibia by 86–95%. None of the benzene metabolites tested could reproduce the strong effects of benzene when injected subcutaneously, although phenol slightly but significantly affected stem cell concentration. Toluene, a competitive inhibitor of benzene metabolism, significantly alleviated the effects of benzene. Regeneration of the bone marrow after benzene injections occurred rapidly during the first week, then at a slower rate for the next 4 weeks. At this time cellularity and granulopoietic stem cell concentration were restored, but the fraction of stem cells in S phase was still higher than in controls, indicating a still elevated proliferation rate.