The hematopoietic and carcinogenic effects of
benzene may result from an interaction of various
benzene metabolites. Following the co-administration of
phenol and
hydroquinone, a synergistic increase in myelotoxicity and genotoxicity has been observed in the bone marrow of mice. To understand the mechanisms underlying these synergistic genotoxic effects we have studied the origin of micronuclei (MN) formed in bone marrow erythrocytes following the co-administration of these two metabolites.
Phenol and
hydroquinone were administered to male CD-1 mice by i.p. injection three times at 24 h intervals. The frequency of MN was evaluated in bone marrow cells harvested 24 h following the final dose. A marked increase in MN was observed in mice co-administered
phenol and
hydroquinone, which was significantly greater than that observed with the individual metabolites. Labeling with the CREST antibody and multicolor fluorescence in situ hybridization with the mouse major and minor satellite probes indicated that both chromosomal loss and breakage and occurred. The major increase in MN induced by the
phenol and
hydroquinone combination originated from breakage in the euchromatic region of the mouse chromosomes. The origin of MN in mice co-administered
phenol and
hydroquinone differed substantially from that induced by
hydroquinone alone, but was almost identical to that seen in MN from
benzene-treated mice. These results strongly support the hypothesis that interactive effects among
benzene metabolites play an important role in the genotoxic and carcinogenic effects of
benzene.