EPOXYBUTENE-HEMOGLOBIN ADDUCTS IN RATS AND MICE - DOSE-RESPONSE FOR FORMATION AND PERSISTENCE DURING AND FOLLOWING LONG-TERM LOW-LEVEL EXPOSURE TO BUTADIENE

Measurement of specific adducts to hemoglobin can be used to establish the dosimetry of electrophilic compounds and metabolites in experimen tal animals and in humans. The purpose of this study was to investigat e the dose response for adduct formation and persistence in rats and m ice during long-term low-level exposure to butadiene by inhalation. Ad ducts of 3,4-epoxy-1-butene, the primary metabolite of butadiene, with N-terminal valine in hemoglobin were determined in male B6C3F1 mice a nd male Sprague-Dawley rats following exposure to 0, 2, 10, or 100 ppm of 1,3-butadiene, 6 h/day, 5 days/week for 1, 2, 3, or 4 weeks. Blood samples were collected from groups of five mice and three rats at the end of each week during the 4 weeks of exposure and weekly for 3 week s following the end of the 4-week exposure period. The increase and de crease, respectively, of the adduct levels during and following the en d of the 4-week exposure followed closely the theoretical curve for ad duct accumulation and removal for rats and mice, thereby demonstrating that the adducts are chemically stable in vivo and that the eliminati on follows the turnover of the red blood cells. The adduct level incre ased linearly with butadiene exposure concentration in the mice, where as a deviation from linearity was observed in the rats. For example, a fter exposure to 100 ppm butadiene, the epoxybutene-hemoglobin adduct levels were about four times higher in mice than in rats; at lower con centrations of butadiene, the species difference was less pronounced. Blood concentrations of epoxybutene, estimated from hemoglobin adduct levels, were in general agreement with reported concentrations in mice and rats exposed by inhalation to 62.5 ppm. These studies show that a dducts of epoxybutene with N-terminal valine in hemoglobin can be used to predict blood concentration of epoxybutene in experimental animals . (C) 1998 Academic Press.