Metabolism and Hemoglobin Adduct Formation of Acrylamide in Humans

• Published in: Toxicological sciences Vol. 85; no. 1; pp. 447 - 459
• Main Authors: Fennell, Timothy R., Sumner, Susan C.J., Snyder, Rodney W., Burgess, Jason, Spicer, Rebecca, Bridson, William E., Friedman, Marvin A.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.05.2005
• Subjects: acrylamide; Acrylamide - metabolism; Acrylamide - pharmacokinetics; Acrylamide - toxicity; adducts; Administration, Cutaneous; Administration, Oral; Adult; Aged; Animals; Carbon Isotopes; Dose-Response Relationship, Drug; Epoxy Compounds - metabolism; glycidamide; hemoglobin; Hemoglobins - drug effects; Hemoglobins - metabolism; Hemoglobins - physiology; Humans; Inactivation, Metabolic; Linear Models; Magnetic Resonance Spectroscopy; Male; Middle Aged; Rats; Rats, Inbred F344
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfi069

Acrylamide (AM), used in the manufacture of polyacrylamide and grouting agents, is produced during the cooking of foods. Workplace exposure to AM can occur through the dermal and inhalation routes. The objectives of this study were to evaluate the metabolism of AM in humans following oral administration, to compare hemoglobin adduct formation on oral and dermal administration, and to measure hormone levels. The health of the people exposed under controlled conditions was continually monitored. Prior to conducting exposures in humans, a low-dose study was conducted in rats administered 3 mg/kg (1,2,3-13C3) AM by gavage. The study protocol was reviewed and approved by Institute Review Boards both at RTI, which performed the sample analysis, and the clinical research center conducting the study. (1,2,3-13C3) AM was administered in an aqueous solution orally (single dose of 0.5, 1.0, or 3.0 mg/kg) or dermally (three daily doses of 3.0 mg/kg) to sterile male volunteers. Urine samples (3 mg/kg oral dose) were analyzed for AM metabolites using 13C NMR spectroscopy. Approximately 86% of the urinary metabolites were derived from GSH conjugation and excreted as N-acetyl-S-(3-amino-3-oxopropyl)cysteine and its S-oxide. Glycidamide, glyceramide, and low levels of N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine were detected in urine. On oral administration, a linear dose response was observed for N-(2-carbamoylethyl)valine (AAVal) and N-(2-carbamoyl-2-hydroxyethyl)valine (GAVal) in hemoglobin. Dermal administration resulted in lower levels of AAVal and GAVal. This study indicated that humans metabolize AM via glycidamide to a lesser extent than rodents, and dermal uptake was approximately 6.6% of that observed with oral uptake.