Occupational exposure to butadiene is associated with the occurrence of lymphohaematopoietic cancers. The mutagenicity of butadiene is thought to be mediated by its mono- and diepoxide metabolites, which are capable of binding to DNA. Diepoxybutane is the most potent genotoxic metabolite and is known to produce interstrand DNA cross-links. In order to study individual differences in response to the genotoxicity of diepoxybutane, we devised a human lymphocyte culture system that involves short-term culture of T lymphocytes and measurement of sister chromatid exchange (SCE) and chromosomal aberration frequency as genotoxic end-points. We observed that when lymphocytes from healthy individuals are exposed in vitro to 6 microM of diepoxybutane, the number of SCEs induced is distributed bimodally: about 20% of 173 healthy workers studied were twice as sensitive to the induction of SCEs as the remaining 80%. Cells from sensitive individuals also contain four times more diepoxybutane-induced chromosomal deletions and exchanges. Of particular interest is the observation that diepoxybutane-sensitive individuals have higher frequencies of baseline (i.e., uninduced) SCEs. We have now examined the sensitivity of individual lymphocytes to SCE induction by another DNA cross-linking agent (nitrogen mustard) and to monoepoxybutene. The results indicate that lymphocytes sensitive to diepoxybutane-induced SCEs have normal sensitivity to nitrogen mustard and a moderately increased response to the monofunctional agent monoepoxybutene. Measurement of diepoxybutane-induced SCEs is a potential biomarker of sensitivity to the genotoxic effects of butadiene and may be useful in occupational epidemiological studies. Such studies, in combination with measures of butadiene metabolism, could be useful in ascertaining whether the sensitivity is mediated by enzyme polymorphisms.