Haemoglobin adducts of epoxybutanediol from exposure to 1,3-butadiene or butadiene epoxides

Pérez, Hermes Licea; Lähdetie, Jaana; Landin, Helena Hindsø; Kilpeläinen, Ilkka; Koivisto, Pertti; Peltonen, Kimmo; Osterman-Golkar, Siv

doi:10.1016/s0009-2797(97)00049-5

Cited by 63 publications

(28 citation statements)

References 24 publications

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“…The data on adduct levels of EB-Val and EBdiol-Val in Hb from mice and rats in the study of Boysen and colleagues (12) were in agreement with the earlier studies in rodents on Hb-adduct levels after treatment with BD (20,25,30). The study of Boysen and colleagues (12), however, is the first to report data on DEB-Val adduct levels after treatment with BD, and the Hb-adduct data from this study was therefore used for the calculations in the present study.…”

Section: Doses In Blood Of Epoxide Metabolites Of Bdsupporting

confidence: 88%

“…The AUC of EBdiol increased with exposure dose, however, not linearly, probably due to saturation of metabolizing enzymes. This has also been observed through measurements of Hb adducts in earlier studies with exposure to BD or to its epoxide metabolites (20,30), and recently through measurement of steady-state concentrations of epoxide metabolites in blood after a single exposure to BD (31). A predominant difference between the mouse and the rat was observed with regard to the AUC of DEB, which at 3 ppm already was high in the mouse, and f16 times lower in the rat.…”

Section: Doses In Blood Of Epoxide Metabolites Of Bdmentioning

confidence: 53%

“…For the monoepoxy metabolites, EB and EBdiol, adducts with Ntermini in Hb were measured as N-(2-monohydroxybutenyl)valine (EBVal) and N-(2,3,4-trihydroxybutenyl)valine (EBdiol-Val), respectively. These Hb adducts were measured after detachment as fluorinated derivatives according to the modified Edman method by gas chromatographytandem mass spectrometry (19,20). DEB forms a ring-closed adduct, a pyrrolidine, in the reaction with NH 2 -terminal valine in Hb [N,N-(2,3-dihydroxy-1,4-butadiyl)valine, called DEB-Val; refs.…”

Section: Methodsmentioning

confidence: 99%

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Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

2008

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In cancer tests with 1,3-butadiene (BD), the mouse is much more sensitive than the rat. This is considered to be related to the metabolism of BD to the epoxide metabolites, 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane, and 1,2-epoxy-3,4-butanediol. This study evaluates whether the large difference in outcome in cancer tests with BD could be predicted quantitatively on the basis of the concentration over time in blood (AUC) of the epoxide metabolites, their mutagenic potency, and a multiplicative cancer risk model, which has earlier been used for ionizing radiation. Published data on hemoglobin adduct levels from inhalation experiments with BD were used for the estimation of the AUC of the epoxide metabolites in the cancer tests. The estimated AUC of the epoxides were then weighed together to a total genotoxic dose, by using the relative genotoxic potency of the respective epoxide inferred from in vitro hprt mutation assays using EB as standard. The tumor incidences predicted with the risk model on the basis of the total genotoxic dose correlated well with the earlier observed tumor incidences in the cancer tests. The total genotoxic dose that leads to a doubling of the tumor incidences was estimated to be the same in both species, 9 to 10 mmol/LÂh EB-equivalents. The study validates the applicability of the multiplicative cancer risk model to genotoxic chemicals. Furthermore, according to this evaluation, different epoxide metabolites are predominating cancer-initiating agents in the cancer tests with BD, the diepoxide in the mouse, and the monoepoxides in the rat.

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Section: Doses In Blood Of Epoxide Metabolites Of Bdsupporting

confidence: 88%

Section: Doses In Blood Of Epoxide Metabolites Of Bdmentioning

confidence: 53%

Section: Methodsmentioning

confidence: 99%

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Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

2008

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“…Surprisingly, the 1,2,3-trihydroxybutyl-valine values were similar in mice and rats at 3 and at 62.5 ppm 1,3-butadiene, and no consistent relationship between 1,2,3-trihydroxybutyl-valine and 2-hydroxy-3-butenyl-valine or N,N-(2,3-dihydroxy-1,4-butadiyl)-valine was observed at the different exposures studied. These phenomena are most likely due to the fact that 1,2,3-trihydroxybutyl-valine, as suggested previously, is mainly derived from the 3-butene-1,2-diol pathway (15)(16)(17). 3-Butene-1,2-diol, the precursor to 3,4-epoxy-1,2-butanediol, may also be converted to hydroxymethylvinyl ketone (18), that itself can form DNA (19) and N-terminal valine adducts (Dr. Mark Powley, personal communication).…”

Section: Resultsmentioning

confidence: 53%

“…It was previously proposed that 1,2,3-trihydroxybutyl-valine adducts are mainly formed from 3,4-epoxy-1,2-butanediol and not from 1,2;3,4-diepoxybutane (15)(16)(17). allows the first accurate estimation of the ratio between 3,4-epoxy-1,2-butanediol and 1,2;3,4-diepoxybutane formation.…”

Section: Resultsmentioning

confidence: 99%

Analysis of Diepoxide-Specific Cyclic N -Terminal Globin Adducts in Mice and Rats after Inhalation Exposure to 1,3-Butadiene

et al. 2004

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Abstract1,3-Butadiene is an important industrial chemical used in the production of synthetic rubber and is also found in gasoline and combustion products. It is a multispecies, multisite carcinogen in rodents, with mice being the most sensitive species. 1,3-Butadiene is metabolized to several epoxides that form DNA and protein adducts. Previous analysis of 1,2,3-trihydroxybutyl-valine globin adducts suggested that most adducts resulted from 3-butene-1,2-diol metabolism to 3,4-epoxy-1,2-butanediol, rather than from 1,2;3,4-diepoxybutane. To specifically examine metabolism of 1,3-butadiene to 1,2;3,4-diepoxybutane, the formation of the 1,2;3,4-diepoxybutane-specific adduct N,N-(2,3-dihydroxy-1,4-butadiyl)-valine was evaluated in mice treated with 3, 62.5, or 1250 ppm 1,3-butadiene for 10 days and rats exposed to 3 or 62.5 ppm 1,3-butadiene for 10 days, or to 1000 ppm 1,3-butadiene for 90 days, using a newly developed immunoaffinity liquid chromatography tandem mass spectrometry assay. In addition, 2-hydroxy-3-butenyl-valine and 1,2,3-trihydroxybutylvaline adducts were determined. The analyses of several adducts derived from 1,3-butadiene metabolites provided new insight into species and exposure differences in 1,3-butadiene metabolism. Mice formed much higher amounts of N,N-(2,3-dihydroxy-1,4-butadiyl)-valine than rats. The formation of 2-hydroxy-3-butenyl-valine and N,N-(2,3-dihydroxy-1,4-butadiyl)-valine was similar in mice exposed to 3 or 62.5 ppm 1,3-butadiene, whereas 2-hydroxy-3-butenyl-valine was 3-fold higher at 1250 ppm. In both species, 1,2,3-trihydroxybutyl-valine adducts were much higher than 2-hydroxy-3-butenyl-valine and N,N-(2,3-dihydroxy-1,4-butadiyl)-valine. Together, these data show that 1,3-butadiene is primarily metabolized via the 3-butene-1,2-diol pathway, but that mice are much more efficient at forming 1,2;3,4-diepoxybutane than rats, particularly at low exposures. This assay should also be readily adaptable to molecular epidemiology studies on 1,3-butadiene-exposed workers

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1,3‐Butadien [BAT Value Documentation in German language, 2006]

Csanády¹

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Biologische Arbeitsstoff‐Toleranz‐Werte (BAT‐Werte), Expositionsäquivalente für krebserzeugende Arbeitsstoffe (EKA) und Biologische Leitwerte (BLW) , 13. Lieferung, Ausgabe 2006 Der Artikel enthält folgende Kapitel: Metabolismus und Toxikokinetik Kritische Toxizität Belastung und Beanspruchung Auswahl der Indikatoren Butadien in der Alveolarluft Merkaptursäuren im Urin 3‐Buten‐1 ,2‐diol im Urin Hämoglobinaddukte DNA‐Addukte Mutationen Cytogenetische Effekte Schlussfolgerung Untersuchungsmethoden Hintergrundbelastung Evaluierung der biologischen Expositionsäquivalente Interpretation von Untersuchungsdaten

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Haemoglobin adducts of epoxybutanediol from exposure to 1,3-butadiene or butadiene epoxides

Cited by 63 publications

References 24 publications

Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

Analysis of Diepoxide-Specific Cyclic N -Terminal Globin Adducts in Mice and Rats after Inhalation Exposure to 1,3-Butadiene

1,3‐Butadien [BAT Value Documentation in German language, 2006]

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