Species differences in toxicokinetic parameters of glycidol after a single dose of glycidol or glycidol linoleate in rats and monkeys

Wakabayashi, Keiji; Kurata, Yoshimasa; Harada, Tomoo; Tamaki, Yasushi; Nishiyama, Naohiro; Kasamatsu, Toshio

doi:10.2131/jts.37.691

Cited by 23 publications

(14 citation statements)

References 15 publications

(17 reference statements)

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“…Wakabayashi et al. () evaluated the plasma pharmacokinetics of glycidol using GC‐MS after oral and i.v. administration to Sprague‐Dawley rats (n = 189) and cynomolgus monkeys (n = 3).…”

Section: Assessmentmentioning

confidence: 99%

“…There was retention of radioactivity in tissues (9-12% at 24 h and 7-8% at 72 h) with the skeletal muscle, skin, blood cells and liver containing the highest amounts (1-4% of dose each at 24 h), which could result from either covalent binding of glycidol or incorporation of radiolabel into macromolecules through entry into normal intermediary metabolism. Wakabayashi et al (2012) evaluated the plasma pharmacokinetics of glycidol using GC-MS after oral and i.v. administration to Sprague-Dawley rats (n = 189) and cynomolgus monkeys (n = 3).…”

Section: Glycidol and Glycidyl Fatty Acid Estersmentioning

confidence: 99%

“…Some pharmacokinetic data (C max and AUC) were also reported for oral dosing at 1.64 and 4.92 mg/kg bw in rats and for monkeys at 4.92 mg/kg bw. Wakabayashi et al (2012) also evaluated the plasma toxicokinetics for a single dose of glycidyl di-linoleate (341 mg/kg bw, which was equimolar to the dose of glycidol, using gavage administration) to Sprague-Dawley rats and cynomolgus monkeys. While the parent ester was observed in plasma from dosed rats, it was undetectable in monkeys; however, the pharmacokinetics of the glycidol derived from ester hydrolysis was measured in plasma in both species.…”

Section: Glycidol and Glycidyl Fatty Acid Estersmentioning

confidence: 99%

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Risks for human health related to the presence of 3‐ and 2‐monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food

Wallace¹,

Alexander²,

Barregård³

et al. 2016

EFS2

126

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EFSA was asked to deliver a scientific opinion on free and esterified 3-and 2-monochloropropane-1, 2-diol (MCPD) and glycidyl esters in food. Esters of 3-and 2-MCPD and glycidol are contaminants of processed vegetable oils; free MCPDs are formed in some processed foods. The Panel on Contaminants in the Food Chain (CONTAM Panel) evaluated 7,175 occurrence data. Esters of 3-and 2-MCPD and glycidyl esters were found at the highest levels in palm oil/fat, but most vegetable oil/fats contain substantial quantities. Mean middle bound (MB) dietary exposure values to total 3-MCPD, 2-MCPD and glycidol, respectively, across surveys and age groups in µg/kg body weight (bw) per day were 0.2-1.5, 0.1-0.7 and 0.1-0.9; high exposure (P95) values were 0.3-2.6, 0.2-1.2 and 0.2-2.1. Animal studies show extensive hydrolysis of esterified 3-MCPD and glycidol following oral administration; esterified and free forms were assumed to contribute equally to internal exposures. Nephrotoxicity was consistently observed in rats treated with 3-MCPD. Data on 2-MCPD toxicity were insufficient for dose-response assessments. Chronic treatment with glycidol increased the incidence of tumours in several tissues of rats and mice, likely via a genotoxic mode of action. The Panel selected a BMDL 10 value for 3-MCPD of 0.077 mg/kg bw per day for induction of renal tubular hyperplasia in rats and derived a tolerable daily intake (TDI) of 0.8 µg/kg bw per day. The mean exposure to 3-MCPD was above the TDI for 'Infants', 'Toddlers' and 'Other children'. For glycidol, the Panel selected a T25 value of 10.2 mg/kg bw per day for neoplastic effects in rats. The margins of exposure (MoEs) were 11,300-102,000 and 4,900-51,000 across surveys and age groups at mean and P95 exposures, respectively. An exposure scenario for infants receiving formula only resulted in MoEs of 5,500 (mean) and 2,100 (P95). MoEs of 25,000 or higher were considered of low health concern. Amendment: A few editorial amendments were carried out that do not materially affect the contents of the outcome of this scientific output: on pages 5 and 91 'chorine' has been replaced with 'chlorine'; on page 52 the word 'it' has been replaced by 'its' in the first paragraph after Figure 7; on page 54 in the Repeated dose section the reference to MCPD has been replaced with 3-MCPD; on page 54 the 429.5 mg/kg bw day dose has been replaced with 29.5 mg/kg bw day; on page 55 in the first paragraph of the Hematology section the reference 'mg/kg per day' has been replaced with 'mg/kg bw per day; on page 55 the year for the reference Marchesini et al. has been changed from 1989 to 1986; on page 59, in the first paragraph of the Developmental toxicity section the word 'days' has been cancelled; on page 65 the reference 'Onami et al., 2014a,b' has been replaced with 'Onami et al., 2014b'; on page 85 first paragraph, reference to the lowest T25 of 10 has been replaced to 10.2. To avoid confusion, the older version has been removed from the EFSA Journal, but is available on request, as is a version sho...

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“…Wakabayashi et al. () evaluated the plasma pharmacokinetics of glycidol using GC‐MS after oral and i.v. administration to Sprague‐Dawley rats (n = 189) and cynomolgus monkeys (n = 3).…”

Section: Assessmentmentioning

confidence: 99%

Section: Glycidol and Glycidyl Fatty Acid Estersmentioning

confidence: 99%

Section: Glycidol and Glycidyl Fatty Acid Estersmentioning

confidence: 99%

See 1 more Smart Citation

Risks for human health related to the presence of 3‐ and 2‐monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food

Wallace¹,

Alexander²,

Barregård³

et al. 2016

EFS2

126

View full text Add to dashboard Cite

show abstract

“…The cornerstone of this approach is the measurement of in vitro enzyme kinetic parameters in different species and the availability of data on the Hb adduct levels of at least one of the different animal species. However, species-difference in the relation between AUC and exposure dose might also be due to other factors such as absorption process due to difference in gastrointestinal environment, which are not reflected by the metabolism in liver S9 (Wakabayashi et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: An inter-species extrapolation approach

Motwani

Törnqvist

2014

Toxicology and Applied Pharmacology

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“…Since then, research has been initiated on industrial mitigation strategies on the one hand, and on toxicological properties of these heat-induced food contaminants on the other hand. As demonstrated in rats, glycidyl esters are nearly completely digested in the gastrointestinal tract, leading to a systemic exposure to the reactive epoxide glycidol (Appel et al 2013;Wakabayashi et al 2012). The substance is a genotoxic multisite carcinogen (National Toxicology Program 1990) as well as a teratogen (Slott and Hales 1985) in rodents, and rated as probably carcinogenic to humans [IARC group 2A (International Agency for Research on Cancer 2000)].…”

Section: Introductionmentioning

confidence: 99%

The hemoglobin adduct N-(2,3-dihydroxypropyl)-valine as biomarker of dietary exposure to glycidyl esters: a controlled exposure study in humans

et al. 2018

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Fatty acid esters of glycidol (glycidyl esters) are heat-induced food contaminants predominantly formed during industrial deodorization of vegetable oils and fats. After consumption, the esters are digested in the gastrointestinal tract, leading to a systemic exposure to the reactive epoxide glycidol. The compound is carcinogenic, genotoxic and teratogenic in rodents, and rated as probably carcinogenic to humans (IARC group 2A). Assessment of exposure from occurrence and consumption data is difficult, as lots of different foods containing refined oils and fats may contribute to human exposure. Therefore, assessment of the internal exposure using the hemoglobin adduct of glycidol, N-(2,3-dihydroxypropyl)-valine (2,3-diHOPr-Val), may be promising, but a proof-of-principle study is needed to interpret adduct levels with respect to the underlying external exposure. A controlled exposure study was conducted with 11 healthy participants consuming a daily portion of about 36 g commercially available palm fat with a relatively high content of ester-bound glycidol (8.7 mg glycidol/kg) over 4 weeks (total amount 1 kg fat, individual doses between 2.7 and 5.2 µg/kg body weight per day). Frequent blood sampling was performed to monitor the 2,3-diHOPr-Val adduct levels during formation and the following removal over 15 weeks, using a modified Edman degradation and ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/ MS). Results demonstrated for the first time that the relatively high exposure during the intervention period was reflected in corresponding distinct increases of 2,3-diHOPr-Val levels in all participants, following the expected slope for hemoglobin adduct formation and removal over time. The mean adduct level increased from 4.0 to 12.2 pmol 2,3-diHOPr-Val/g hemoglobin. By using a nonlinear mixed model, values for the adduct level/dose ratio (k, mean 0.082 pmol 2,3-diHOPr-Val/g hemoglobin per µg glycidol/kg body weight) and the adduct lifetime (τ, mean 104 days, likely the lifetime of the erythrocytes) were determined. Interindividual variability was generally low. 2,3-DiHOPr-Val was therefore proven to be a biomarker of the external dietary exposure to fatty acid esters of glycidol. From the background adduct levels observed in our study, a mean external glycidol exposure of 0.94 µg/kg body weight was estimated. This value is considerably higher than current estimates for adults using occurrence and consumption data of food. Possible reasons for this discrepancy are discussed (other oral or inhalational glycidol sources, endogenous formation, exposure to other chemicals also forming the adduct 2,3-diHOPr-Val). Further research is necessary to clarify the issue. KeywordsGlycidol · Edman degradation · Protein adduct · Biomarker · Exposure study Abbreviations DHP-Val-FTH N-(2,3-Dihydroxypropyl)-valine fluorescein thiohydantoin 2,3-diHOPr-Val N-(2,3-Dihydroxypropyl)-valine FITC Fluorescein-5-isothiocyanate FTH Fluorescein thiohydantoin Hb Hemoglogin MRM Multiple reaction monitoring T 25Dose...

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Species differences in toxicokinetic parameters of glycidol after a single dose of glycidol or glycidol linoleate in rats and monkeys

Cited by 23 publications

References 15 publications

Risks for human health related to the presence of 3‐ and 2‐monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food

Risks for human health related to the presence of 3‐ and 2‐monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food

In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: An inter-species extrapolation approach

The hemoglobin adduct N-(2,3-dihydroxypropyl)-valine as biomarker of dietary exposure to glycidyl esters: a controlled exposure study in humans

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