ToxSci Advance Access originally published online on October 17, 2008
Toxicological Sciences 2009 107(1):247-257; 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, North Carolina 27514
Department of Genetic Toxicology, ILS, Inc., Research Triangle Park, North Carolina 27709
Drug Metabolism and Pharmacokinetics, RTI International, Research Triangle Park, North Carolina 27709
J. K. Haseman Consulting, Raleigh, North Carolina 27614
¶ University of Louisville School of Medicine, Louisville, Kentucky 40492
1 To whom correspondence should be addressed at Errol Zeiger Consulting, 800 Indian Springs Road, Chapel Hill, NC 27514. Fax: +1-919-932-3778. E-mail: zeiger{at}nc.rr.com.
Received July 15, 2008; accepted August 29, 2008
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Abstract |
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Acrylamide is an industrial chemical used in polymer manufacture. It is also formed in foods processed at high temperatures. It induces chromosome aberrations and micronuclei (MN) in somatic cells of mice, but not rats, and mutations in transgenic mice. This study evaluated the low-dose MN 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 to 24 mg/kg/day, and MN were assessed in peripheral blood reticulocytes (RETs) 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 MN response, with statistical significance at 6.0 mg/kg/day, or greater, in MN-RETs and at 4.0 mg/kg/day or greater in MN normochromatic erythrocytes (NCEs). 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 nonlinear, 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 MN test.
Key Words: acrylamide; glycidamide; mouse; micronucleus test; bone marrow; hemoglobin adducts; DNA adducts; threshold.