Using DNA and hemoglobin adducts to improve the risk assessment of butadiene

The purpose of this paper is to review what we know about various biomarker s of butadiene in animal, human and in vitro studies, and to draw inference s from these data that impact on the accurate assessment of human risks for cancer. Studies comparing the DNA and hemoglobin adducts of butadiene with exposure, metabolism and genotoxicity have provided a great deal of insigh t that is applicable to biologically based risk assessment. First, the DNA and hemoglobin adduct data strongly support the conclusion that 3,4-epoxy-1 ,2-butanediol is the major electrophile available for binding to these macr omolecules. Biomarker studies have also provided insight into the possibili ty of a sensitive population associated with the GSTT1 null genotype. While it is clear that lymphocytes from GSTT1 null individuals are more sensitiv e for the induction of sister chromatid exchanges (SCE) following in vitro exposure to 1,2,3,4-diepoxybutane, there was no such increase in SCE or oth er biomarkers of genotoxicity in workers exposed to 1-3 p.p.m. butadiene, r egardless of GST genotype. The globin adduct data also demonstrate that the re is roughly a tenfold range for interindividual differences in the metabo lism of butadiene. This type of analysis represents an excellent means for providing scientific data for this critical determinant. Another useful app lication of hemoglobin adducts in risk assessment was demonstrated by regre ssing data for various endpoints for genotoxicity against that individual's biologically effective dose, thereby providing an independent mechanism fo r evaluation that excludes any possible confounding by inappropriate contro ls. Finally, biomarker studies have identified critical gaps in our knowled ge that are needed for the accurate assessment of butadiene. Most notable o f these is the lack of diepoxide-specific biomarkers in mice, rats and huma ns. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.