title: Toxicokinetics of acrylamide in rats and humans following single oral administration of low doses.
abstract: The rodent carcinogen acrylamide (AA) is formed during preparation of starch-containing foods. AA is partly metabolized to the genotoxic epoxide glycidamide (GA). After metabolic processing, the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), rac-N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) and rac-N-acetyl-S-(1-carbamoyl-moyl-2-hydroxyethyl)-L-cysteine (iso-GAMA) are excreted with urine. In humans, AAMA can be sulfoxidized to AAMA-sulfoxide. The aim of this study was to assess potential species-differences in AA-toxicokinetics in rats and humans after single oral administration of doses similar to the daily human dietary exposure. Male Fischer 344 rats (n=5/dose group) were administered 20 and 100 microg/kg b.w. (13)C(3)-AA in deionized water via oral gavage. Human subjects (n=3/gender) were orally administered 0.5 and 20 microg/kg b.w. (13)C(3)-AA with drinking water. Urine samples were collected in intervals for 96 and 94 h, respectively. Urinary concentrations of (13)C(3)-AAMA, (13)C(3)-GAMA and (13)C(3)-AAMA-sulfoxide were monitored by liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 66.3% and 70.5% of the 20 and 100 microg/kg b.w. doses in rats and for 71.3% and 70.0% of the 0.5 and 20 microg/kg b.w. doses in humans. In rats, (13)C(3)-AAMA accounted for 33.6% and 38.8% of dose and 32.7% and 31.7% of dose was recovered as (13)C(3)-GAMA; (13)C(3)-AAMA-sulfoxide was not detected in rat urine. In humans, (13)C(3)-AAMA, (13)C(3)-GAMA and (13)C(3)-AAMA-sulfoxide accounted for 51.7% and 49.2%, 6.3% and 6.4% and 13.2% and 14.5% of the applied dose, respectively. The obtained results suggest that the extent of AA bioactivation to GA in humans is lower than in rodents.
authors.affiliation: Department of Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
authors.forename: Eva Katharina
authors.initials: EK
authors.lastname: Kopp
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dekant
mesh_terms: D020106:Acrylamide / Q000493:pharmacokinetics* / Q000633:toxicity*; D000284:Administration, Oral; D000328:Adult; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D004032:Diet; D005260:Female; D006801:Humans; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D021241:Spectrometry, Mass, Electrospray Ionization; D055815:Young Adult
chemical_list: D020106:Acrylamide