title: Effect of repeated benzene inhalation exposures on benzene metabolism, binding to hemoglobin, and induction of micronuclei.
abstract: Metabolism of benzene is thought to be necessary to produce the toxic effects, including carcinogenicity, associated with benzene exposure. To extrapolate from the results of rodent studies to potential health risks in man, one must know how benzene metabolism is affected by species, dose, dose rate, and repeated versus single exposures. The purpose of our studies was to determine the effect of repeated inhalation exposures on the metabolism of [14C]benzene by rodents. Benzene metabolism was assessed by characterizing and quantitating urinary metabolites, and by quantitating 14C bound to hemoglobin and micronuclei induction. F344/N rats and B6C3F1 mice were exposed, nose-only, to 600 ppm benzene or to air (control) for 6 hr/day, 5 days/week for 3 weeks. On the last day, both benzene-pretreated and control animals were exposed to 600 ppm, 14C-labeled benzene for 6 hr. Individual benzene metabolites in urine collected for 24 hr after the exposure were analyzed. There was a significant decrease in the respiratory rate of mice (but not rats) pretreated with benzene which resulted in lower levels of urinary [14C]benzene metabolites. The analyses indicated that the only effects of benzene pretreatment on the metabolite profile in rat or mouse urine were a slight shift from glucuronidation to sulfation in mice and a shift from sulfation to glucuronidation in rats. Benzene pretreatment also had no effect, in either species, on formation of [14C]benzene-derived hemoglobin adducts. Mice and rats had similar levels of hemoglobin adduct binding, despite the higher metabolism of benzene by mice. This indicates that hemoglobin adduct formation occurs with higher efficiency in rats. After 1 week of exposure to 600 ppm benzene, the frequency of micronucleated, polychromatic erythrocytes (PCEs) in mice was significantly increased. Exposure to the same level of benzene for an additional 2 weeks did not further increase the frequency of micronuclei in PCEs. These results indicate that repeated exposures to benzene, such as might be encountered by humans as a result of occupational or environmental exposures, are not likely to change or increase benzene metabolism.
authors.affiliation: Inhalation Toxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico 87185.
authors.forename: P J
authors.initials: PJ
authors.lastname: Sabourin
authors.forename: J D
authors.initials: JD
authors.lastname: Sun
authors.forename: J T
authors.initials: JT
authors.lastname: MacGregor
authors.forename: C M
authors.initials: CM
authors.lastname: Wehr
authors.forename: L S
authors.initials: LS
authors.lastname: Birnbaum
authors.forename: G
authors.initials: G
authors.lastname: Lucier
authors.forename: R F
authors.initials: RF
authors.lastname: Henderson
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001554:Benzene / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D002250:Carbon Radioisotopes; D004334:Drug Administration Schedule; D004781:Environmental Exposure; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology; D005796:Genes / Q000187:drug effects; D005965:Glucuronates / Q000652:urine; D006454:Hemoglobins / Q000378:metabolism*; D006873:Hydroquinones / Q000652:urine; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects*; D051381:Rats; D013997:Time Factors
chemical_list: D002250:Carbon Radioisotopes; D005965:Glucuronates; D006454:Hemoglobins; D006873:Hydroquinones; D001554:Benzene