Quantification of epoxide metabolite specific n-terminal globin adducts: a biomarker of internal dosimetry of 1,3-butadiene exposure and metabolism Public Deposited

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  • March 21, 2019
Creator
  • Bordeerat, Narisa K.
    • Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering
Abstract
  • Butadiene (BD) carcinogenicity in rodents shows gender, species and concentration dependency, making the extrapolation of animal results to humans complex. BD is a multispecies multisite carcinogen, with mice being a much more sensitive species than rats. This is considered to be related to the metabolism of BD to its epoxy metabolites, 1,2-epoxy-3-butene (EB), 1,2;3,4-diepoxybutane (DEB) and 1,2-epoxy-butanediol (EB-diol). The mutagenic potency of individual epoxides varies up to 200-fold, with DEB being the most mutagenic metabolite. For accurate risk assessment it is important to elucidate species differences in the internal formation of the individual epoxides in order to assign the relative risks associated with their different mutagenic potencies. N-terminal globin adducts have been widely used for measurements of the formation of BD derived epoxides. In this study, the formation of each epoxide was evaluated in globin samples from both genders of mice and rats exposed to BD by inhalation for 10 days. The numbers of globin adducts were then converted into EB dose equivalents. These were calculated on the basis of the combined internal dose (globin adducts) and the relative genotoxic potency of the respective epoxides inferred from the efficiency of inducing mutations at the Hprt locus. Then, the multiplicative cancer risk model was applied to quantitatively estimate tumor incidence by using the EB dose equivalent and long-term cancer bioassay data. Based on the EB equivalent, higher exposures formed lower amounts per ppm BD. This indicates that metabolism of BD to epoxides is most effective at low exposures. The EB equivalent for mice was about 40-fold higher than that of rats at similar exposures. No gender differences were noted in globin adducts of mice or rats at all exposures. As such, EB dose equivalents provide quantitative data on biomarkers of exposure that can be extended to a scientific basis for BD risk assessment.
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  • " ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Environmental Science and Engineering."
Advisor
  • Swenberg, James A.
Degree granting institution
  • University of North Carolina at Chapel Hill
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Place of publication
  • Chapel Hill, NC
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  • Open access
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