Dose-related clastogenic effects induced by benzene in bone marrow cells and in differentiating sopermatogonia of Swiss CD1 mice

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Abstract
Cancer hazard is due to genotoxic events in somatic cells and genetic hazard in the strict sense is due to mutagenic events in germ cells. The investigation of sensitivity differences between somatic and germinal cells is pertinent to the question whether a genotoxic carcinogen is also a germ cell mutagen. Cytogenetic damage induced by benzene in mice was evaluated by determining the frequencies of chromosomal aberrations in bone marrow and spermatogonial cells of male Swiss CD1 mice. First, the analysis was performed by administering 1 ml/kg (880 mg/kg) of benzene as a single oral dose and sampling either cell type after a wide range of times (6, 12, 18, 24, 30, 36, 42 and 48 h) to determine the time of maximum response. At this dose benzene showed high clastogenic activity in bone marrow cells with a peak between 24 and 30 h. In differentiating spermatogonia the frequency of aberrant cells was highest 24 h after treatment. The overall effect in spermatogonia was lower than in bone marrow cells. Second, the dose response was determined 24 h after treatment with two additional doses of benzene: 0.1 ml/kg (88 mg/kg) and 0.5 ml/kg (440 mg/kg) for bone marrow cells; 0.25 ml/kg (220 mg/kg) and 0.5 ml/kg (440 mg/kg) for differentiating spermatogonia. The clastogenic effect was dose dependent in both cell types. Hie frequencies of aberrant cells increased in a linear-quadratic manner in bone marrow and linearly in differentiating spermatogonia. Furthermore, the per cell damage was higher in bone marrow than in spermatogonial cells. The doubling dose was calculated for the lower part of the dose-response curve in bone marrow cells and for the whole dose range in spermatogonia. These two doubling doses are similar (bone marrow 0.25 ml/kg; spermatogonia 0.33 ml/kg), however, this comparison does not take into account the severity of damage per affected cell or the deviation from linearity in the upper part of the dose-response curve for bone marrow cells. It is concluded that benzene is a dastogen in male germ cells. Its clastogenic effect is similar in both cell types up to 0.5 ml/kg and is weaker in spermatogonia than in bone marrow cells at the highest dose tested (1 ml/kg).

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