Benzene Metabolism in Humans: Dose-dependent Metabolism and Interindividual Variability

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  • March 20, 2019
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  • Kim, Sungkyoon
    • Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering
Abstract
  • In order to gain a better understanding of dose-dependant metabolism of benzene and interindividual variation, we analyzed air benzene, urinary metabolites and personal information, including single nucleotide polymorphisms of key metabolic enzymes, from 389 subjects exposed to benzene occupationally/environmentally. The apparent levels of benzene metabolites increased with exposure, and levels of benzene metabolites were unambiguously different from background levels at: ~ 0.2 ppm for E,E-muconic acid (MA) and Sphenylmercapturic acid (SPMA), ~ 0.5 ppm for phenol (PH) and hydroquinone (HQ), and ~2 ppm for catechol (CA). After adjustment for the background levels, MA, PH, CA and HQ showed significant (p<0.001) downward trends of dose-related production between 0.027 and 15.4 ppm. The transitions were particularly accentuated at lower exposure (0.027 and 0.274 ppm) for all metabolites. These were confirmed with generalized linear models with natural splines (GLM+NS). Based on analysis using the molar fraction, CYP-mediated metabolic pathways favored MA and HQ below 20 ppm and favored PH and CA above 20 ppm. Noticeably, ~90% of the reductions in dose-specific levels occurred below ~3 ppm for each major metabolite. Metabolite levels were about 20% higher in females and decreased between one and 2% per year of life. Also, levels of HQ and CA were greater in smokers. After adjustment for age, gender, BMI and smoking status, the following SNPs showed significant effect on various metabolites, either as main effects or as interactions with benzene exposure and/or smoking: NQO1*2 for all metabolites, CYP2E1 for all metabolites except CA, GSTT1 and GSTM1 for SPMA, EPHX1 (Ex4+52A>G) for SPMA and CA, and EPHX1 (Ex3-28T>C) for CA. Interestingly, variant alleles of all genes [except EPHX1 (Ex4+52A>G)] appeared to be associated with lower levels of benzene metabolites relative to homozygous wild alleles. In conclusion, our results indicate that benzene metabolism is highly nonlinear with increasing benzene exposure above 0.03 ppm, and that metabolism shifts away from CA and PH at low doses in favor of MA and HQ. Also, metabolism of benzene is modulated by exposure, gender, age, smoking, and genetic polymorphisms.
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  • Rappaport, Stephen Morris
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