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ToxSci Advance Access originally published online on July 25, 2003
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Toxicological Sciences 75, 260-270 (2003)
Copyright © 2003 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Acrylamide: A Comparison of Metabolism and Hemoglobin Adducts in Rodents following Dermal, Intraperitoneal, Oral, or Inhalation Exposure

Susan C. J. Sumner1, Carla C. Williams, Rodney W. Snyder2, Wojciech L. Krol3, Bahman Asgharian and Timothy R. Fennell4

CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, North Carolina 27709-2137

Acrylamide (AM), which is used to manufacture polymers, is carcinogenic and a reproductive and neurological toxicant. The objective of this study was to compare the metabolism of AM administered orally (po), dermally, intraperitoneally (ip), or by inhalation, and to measure the hemoglobin adducts produced. Rats and mice were exposed to 2.9 ppm [1,2,3-13C] and [2,3-14C]AM for 6 h. [2,3-14C]AM (162 mg/kg) or [1,2,3-13C]AM (13 8 mg/kg) in water was administered dermally to rats for 24 h, and [1,2,3-13C]AM was administered ip (47 mg/kg). Urine and feces were collected for 24 h. Urine was the major elimination route in rats (ip, 62% and po, 53% of the dose; dermal, 44% of the absorbed dose; inhalation, 31% of the recovered radioactivity) and mice (inhalation, 27% of the recovered radioactivity). Signals in the 13C-NMR spectra of urine were assigned to previously identified metabolites derived from AM glutathione conjugation (AM-GSH) and conversion to glycidamide (GA). AM-GSH was a major metabolic route in rats accounting for 69% (ip), 71% (po), 52% (dermal), and 64% (inhalation). In mice, AM-GSH accounted for only 27% (inhalation) of the total urinary metabolites. The remaining urinary metabolites were derived from GA. Valine hemoglobin adducts of AM and GA were characterized using liquid chromatography-mass spectrometry. The ratio of AM to GA adducts paralleled the flux through pathways based on urinary metabolites. This study demonstrates marked species differences in the metabolism and internal dose (Hb-adducts) of AM following inhalation exposure and marked differences in uptake comparing dermal with po and ip administration.

Key Words: acrylamide; glycidamide; metabolism; dermal; intraperitoneal; inhalation; hemoglobin adducts.


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