ToxSci Advance Access published online on October 17, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn214
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Investigation of the Low-Dose Response in the In Vivo Induction of Micronuclei and Adducts by Acrylamide
* Errol Zeiger Consulting, Chapel Hill, NC 27514
ILS, Inc., Research Triangle Park, NC 27709
RTI International, Research Triangle Park, NC 27709
J.K. Haseman Consulting, Raleigh, NC 27614
¶ University of Louisville School of Medicine, Louisville, KY 40492
Corresponding author: Errol Zeiger Ph.D., J.D., Errol Zeiger Consulting, 800 Indian Springs Road, Chapel Hill, NC 27514, 1-919-932-3778, zeiger{at}nc.rr.com.
Received July 15, 2008; revision received August 25, 2008; accepted August 29, 2008
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Abstract |
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Acrylamide is an industrial chemical used in polymer manufacture. It also is formed in foods processed at high temperatures. It induces chromosome aberrations and micronuclei in somatic cells of mice but not rats, and mutations in transgenic mice. This study evaluated the low-dose micronucleus response in mouse bone marrow, and the shape of the dose-response curve. Mice were treated orally with acrylamide for 28 days using logarithmically spaced doses from 0.125 - 24 mg/kg/day, and micronuclei were assessed in peripheral blood reticulocytes and erythrocytes by flow cytometry. Liver glycidamide DNA adducts, and acrylamide and glycidamide N-terminal valine hemoglobin adducts were also determined. Acrylamide produced a weak micronucleus response, with statistical significance at 6.0 mg/kg/day, or greater, in micronucleated reticulocytes (MN-RET) and at 4.0 mg/kg/day or greater in normochromatic erythrocytes (MN-NCE). The MN responses at the lower doses were indistinguishable from the concurrent and historical controls. The adducts increased at a much different rate than the MN. When the MN-NCE values were compared to administered dose, the response was consistent with a linear model. However, when hemoglobin or DNA adducts were used as the dose metric, the response was significantly non-linear, and models that assumed a threshold dose of 1 or 2 mg/kg/day provided a better fit than a linear model. The MN-RET dose-response had greater variability than the MN-NCE response, and was consistent with linearity and with a threshold at 1 or 2 mg/kg/day, regardless of the dose metric. These data suggest a threshold for acrylamide in the micronucleus test.
Key Words: acrylamide; glycidamide; mouse; micronucleus test; bone marrow; hemoglobin adducts; DNA adducts; threshold.
Portions of this work were presented orally at the Environmental Mutagen Society annual meeting, October 20-24, 2007, in Atlanta GA, and as a poster at the Society for Risk Assessment annual meeting, December 9-12, 2007, in San Antonio TX.