Toxicokinetics of acrylamide in humans after ingestion of a defined dose in a test meal to improve risk assessment for acrylamide carcinogenicity.
High amounts of acrylamide in some foods result in an estimated daily mean intake of 50 microg for a western style diet. Animal studies have shown the carcinogenicity of acrylamide upon oral exposure. However, only sparse human toxicokinetic data is available for acrylamide, which is needed for the extrapolation of human cancer risk from animal data. We evaluated the toxicokinetics of acrylamide in six young healthy volunteers after the consumption of a meal containing 0.94 mg of acrylamide. Urine was collected up to 72 hours thereafter. Unchanged acrylamide, its mercapturic acid metabolite N-acetyl-S-(2-carbamoylethyl)cysteine (AAMA), its epoxy derivative glycidamide, and the respective metabolite of glycidamide, N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA), were quantified in the urine by liquid chromatography-mass spectrometry. Toxicokinetic variables were obtained by noncompartmental methods. Overall, 60.3 +/- 11.2% of the dose was recovered in the urine. Although no glycidamide was found, unchanged acrylamide, AAMA, and GAMA accounted for urinary excretion of (mean +/- SD) 4.4 +/- 1.5%, 50.0 +/- 9.4%, and 5.9 +/- 1.2% of the dose, respectively. Apparent terminal elimination half-lives for the substances were 2.4 +/- 0.4, 17.4 +/- 3.9, and 25.1 +/- 6.4 hours. The ratio of GAMA/AAMA amounts excreted was 0.12 +/- 0.02. In conclusion, most of the acrylamide ingested with food is absorbed in humans. Conjugation with glutathione exceeds the formation of the reactive metabolite glycidamide. The data suggests an at least 2-fold and 4-fold lower relative internal exposure for glycidamide from dietary acrylamide in humans compared with rats or mice, respectively. This should be considered for quantitative cancer risk assessment.
Department of Pharmacology, University Hospital, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany. uwe.fuhr@uk-koeln.de
Uwe
U
Fuhr
Melanie I
MI
Boettcher
Martina
M
Kinzig-Schippers
Alexandra
A
Weyer
Alexander
A
Jetter
Andreas
A
Lazar
Dirk
D
Taubert
Dorota
D
Tomalik-Scharte
Panagiota
P
Pournara
Verena
V
Jakob
Stefanie
S
Harlfinger
Tobias
T
Klaassen
Albrecht
A
Berkessel
Jürgen
J
Angerer
Fritz
F
Sörgel
Edgar
E
Schömig
D000042:Absorption; D020106:Acrylamide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D000328:Adult; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics; D003296:Cooking / Q000379:methods; D004041:Dietary Fats; D004852:Epoxy Compounds / Q000652:urine; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D018570:Risk Assessment; D011198:Solanum tuberosum / Q000737:chemistry; D013045:Species Specificity; D013997:Time Factors
D002273:Carcinogens; D004041:Dietary Fats; D004852:Epoxy Compounds; D020106:Acrylamide; C071834:glycidamide