Benzene is an established human leukemogen. Workers occupationally exposed to
benzene exhibit increased frequencies of both structural and numerical
chromosomal aberrations in their peripheral blood lymphocytes. The metabolite(s) responsible for these
chromosomal aberrations has not yet been identified. Using a modified micronucleus assay, we have examined the ability of the metabolites of
benzene to induce chromosomal damage in human lymphocytes. An antikinetochore antibody was used to distinguish micronuclei that have a high probability of containing a whole chromosome (kinetochore positive) from those containing acentric fragments (kinetochore negative). In vitro treatments with the
benzene metabolites
hydroquinone,
1,4-benzoquinone,
phenol, and
catechol resulted in significant increases in micronuclei formation.
Phenol,
catechol, and
1,4-benzoquinone treatments resulted in moderate (2- to 5-fold) increases in micronuclei, whereas
hydroquinone treatments resulted in a larger (11-fold) increase in micronuclei. Significant dose-related increases in kinetochore-positive micronucleated cells were not observed following
1,4-benzoquinone treatment but were observed following treatment with
phenol,
catechol, and
hydroquinone. The higher efficacy of
hydroquinone in inducing both total micronuclei and kinetochore-positive micronucleated cells when compared with
catechol,
phenol, and
1,4-benzoquinone suggests that
hydroquinone is a major contributor to the clastogenicity and
aneuploidy observed in the lymphocytes of
benzene-exposed workers. Other metabolites may also contribute, however, to the genotoxic effects of
benzene. Since consistent
chromosomal aberrations are often observed in human
leukemias, the ability of the phenolic metabolites of
benzene to induce chromosomal damage in human cells also implicates them in
benzene-induced
leukemia.