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ToxSci Advance Access originally published online on December 29, 2004
Toxicological Sciences 2005 85(1):447-459; doi:10.1093/toxsci/kfi069
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Toxicological Sciences vol. 85 no. 1 © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Metabolism and Hemoglobin Adduct Formation of Acrylamide in Humans

Timothy R. Fennell*,1, Susan C.J. Sumner*, Rodney W. Snyder*, Jason Burgess*, Rebecca Spicer{dagger}, William E. Bridson{dagger} and Marvin A. Friedman{ddagger}

* Research Triangle Institute, Research Triangle Park, North Carolina 27709; {dagger} Covance Clinical Research Unit, Inc., Madison, Wisconsin 53703; and {ddagger} University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

Received July 16, 2004; accepted December 22, 2004

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.

Key Words: acrylamide; glycidamide; hemoglobin; adducts.


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