Population toxicokinetics of benzene.

Bois, Frédéric; Jackson, Elise T.; Pekari, Kaija; Smith, Martyn T.

doi:10.1289/ehp.961041405

Cited by 59 publications

(15 citation statements)

References 25 publications

(35 reference statements)

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“…The estimated values of X 50,1 and X 50,2 were 301 ppm and 0.594 ppm, respectively, indicating a 507-fold difference in enzyme affinities. Because the high-affinity metabolic pathway 2 would be essentially saturated at a benzene level of 1 ppm, it is perhaps not surprising that previous toxicokinetic studies, which relied primarily upon data from humans exposed to concentrations ≥1 ppm, would have failed to detect it ( Bois et al 1996 ; Travis et al 1990 ).…”

Section: Discussionmentioning

confidence: 99%

Evidence That Humans Metabolize Benzene via Two Pathways

Rappaport

Kim

Lan

et al. 2009

Environ Health Perspect

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BackgroundRecent evidence has shown that humans metabolize benzene more efficiently at environmental air concentrations than at concentrations > 1 ppm. This led us to speculate that an unidentified metabolic pathway was mainly responsible for benzene metabolism at ambient levels.ObjectiveWe statistically tested whether human metabolism of benzene is better fitted by a kinetic model having two pathways rather than one.MethodsWe fit Michaelis-Menten-like models to levels of urinary benzene metabolites and the corresponding air concentrations for 263 nonsmoking Chinese females. Estimated benzene concentrations ranged from less than 0.001 ppm to 299 ppm, with 10th and 90th percentile values of 0.002 ppm and 8.97 ppm, respectively.ResultsUsing values of Akaike’s information criterion obtained under the two models, we found strong statistical evidence favoring two metabolic pathways, with respective affinities (benzene air concentrations analogous to Km values) of 301 ppm for the low-affinity pathway (probably dominated by cytochrome P450 enzyme 2E1) and 0.594 ppm for the high-affinity pathway (unknown). The exposure-specific metabolite level predicted by our two-pathway model at nonsaturating concentrations was 184 μM/ppm of benzene, a value close to an independent estimate of 194 μM/ppm for a typical nonsmoking Chinese female. Our results indicate that a nonsmoking woman would metabolize about three times more benzene from the ambient environment under the two-pathway model (184 μM/ppm) than under the one-pathway model (68.6 μM/ppm). In fact, 73% of the ambient benzene dose would be metabolized via the unidentified high-affinity pathway.ConclusionBecause regulatory risk assessments have assumed nonsaturating metabolism of benzene in persons exposed to air concentrations well above 10 ppm, our findings suggest that the true leukemia risks could be substantially greater than currently thought at ambient levels of exposure—about 3-fold higher among nonsmoking females in the general population.

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Section: Discussionmentioning

confidence: 99%

Evidence That Humans Metabolize Benzene via Two Pathways

Rappaport

Kim

Lan

et al. 2009

Environ Health Perspect

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“…In total, 97 model parameters were fixed with values obtained from published literature or measured for this study (Table 1 ). The remaining 26 model parameters were calibrated using Markov Chain Monte Carlo simulation [ 44 - 47 ], which requires the definition of prior distributions for each parameter being calibrated.…”

Section: Methodsmentioning

confidence: 99%

A computational model of the hypothalamic - pituitary - gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol and 17β-trenbolone

Kroll

Jensen

et al. 2011

BMC Syst Biol

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BackgroundEndocrine disrupting chemicals (e.g., estrogens, androgens and their mimics) are known to affect reproduction in fish. 17α-ethynylestradiol is a synthetic estrogen used in birth control pills. 17β-trenbolone is a relatively stable metabolite of trenbolone acetate, a synthetic androgen used as a growth promoter in livestock. Both 17α-ethynylestradiol and 17β-trenbolone have been found in the aquatic environment and affect fish reproduction. In this study, we developed a physiologically-based computational model for female fathead minnows (FHM, Pimephales promelas), a small fish species used in ecotoxicology, to simulate how estrogens (i.e., 17α-ethynylestradiol) or androgens (i.e., 17β-trenbolone) affect reproductive endpoints such as plasma concentrations of steroid hormones (e.g., 17β-estradiol and testosterone) and vitellogenin (a precursor to egg yolk proteins).ResultsUsing Markov Chain Monte Carlo simulations, the model was calibrated with data from unexposed, 17α-ethynylestradiol-exposed, and 17β-trenbolone-exposed FHMs. Four Markov chains were simulated, and the chains for each calibrated model parameter (26 in total) converged within 20,000 iterations. With the converged parameter values, we evaluated the model's predictive ability by simulating a variety of independent experimental data. The model predictions agreed with the experimental data well.ConclusionsThe physiologically-based computational model represents the hypothalamic-pituitary-gonadal axis in adult female FHM robustly. The model is useful to estimate how estrogens (e.g., 17α-ethynylestradiol) or androgens (e.g., 17β-trenbolone) affect plasma concentrations of 17β-estradiol, testosterone and vitellogenin, which are important determinants of fecundity in fish.

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“…metabolic rates) to quantitatively describe the absorption, metabolism, distribution and elimination of a chemical. A number of PBPK models have been developed for benzene in animals and humans (Bois et al., 1996; Brown et al., 1998; Sinclair et al., 1999; Travis et al., 1990; Yokley et al., 2006; and reviewed in ATSDR, 2007 and VCEEP, 2006). In general, these models provide good simulations of benzene disposition in several species following an acute inhaled or ingested acute dose and lactational transfer of benzene in humans.…”

Section: Toxicology/toxicokineticsmentioning

confidence: 99%

“…Recently, Hays et al. (2012) evaluated the existing human PBPK models for benzene (Bois et al., 1996; Brown et al., 1998; Sinclair et al., 1999; Travis et al., 1990; Yokley et al., 2006) in derivation of a blood and urinary-based benzene biomonitoring guidance value termed the biomonitoring equivalent. The authors selected the model of Brown et al.…”

Section: Toxicology/toxicokineticsmentioning

confidence: 99%

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The use of biomonitoring data in exposure and human health risk assessment: benzene case study

Arnold

Angerer

Boogaard

et al. 2013

Critical Reviews in Toxicology

121

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A framework of “Common Criteria” (i.e. a series of questions) has been developed to inform the use and evaluation of biomonitoring data in the context of human exposure and risk assessment. The data-rich chemical benzene was selected for use in a case study to assess whether refinement of the Common Criteria framework was necessary, and to gain additional perspective on approaches for integrating biomonitoring data into a risk-based context. The available data for benzene satisfied most of the Common Criteria and allowed for a risk-based evaluation of the benzene biomonitoring data. In general, biomarker (blood benzene, urinary benzene and urinary S-phenylmercapturic acid) central tendency (i.e. mean, median and geometric mean) concentrations for non-smokers are at or below the predicted blood or urine concentrations that would correspond to exposure at the US Environmental Protection Agency reference concentration (30 µg/m3), but greater than blood or urine concentrations relating to the air concentration at the 1 × 10−5 excess cancer risk (2.9 µg/m3). Smokers clearly have higher levels of benzene exposure, and biomarker levels of benzene for non-smokers are generally consistent with ambient air monitoring results. While some biomarkers of benzene are specific indicators of exposure, the interpretation of benzene biomonitoring levels in a health-risk context are complicated by issues associated with short half-lives and gaps in knowledge regarding the relationship between the biomarkers and subsequent toxic effects.

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Population toxicokinetics of benzene.

Cited by 59 publications

References 25 publications

Evidence That Humans Metabolize Benzene via Two Pathways

Evidence That Humans Metabolize Benzene via Two Pathways

A computational model of the hypothalamic - pituitary - gonadal axis in female fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol and 17β-trenbolone

The use of biomonitoring data in exposure and human health risk assessment: benzene case study

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