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The food contaminant acetamide is not an in vivo clastogen, aneugen, or mutagen in rodent hematopoietic tissue.

ABSTRACT: Acetamide (CAS 60-35-5) is classified by IARC as a Group 2B, possible human carcinogen, based on the induction of hepatocellular carcinomas in rats following chronic exposure to high doses. Recently, acetamide was found to be present in a variety of human foods, warranting further investigation. The regulatory body JECFA has previously noted conflicting reports on acetamide's ability to induce micronuclei (MN) in mice in vivo. To better understand the potential in vivo genotoxicity of acetamide, we performed acute MN studies in rats and mice, and a subchronic study in rats, the target species for liver cancer. In the acute exposure, animals were gavaged with water vehicle control, 250, 1000, or 2000 mg/kg acetamide, or the positive control (1 mg/kg mitomycin C). In the subchronic assay, bone marrow of rats gavaged at 1000 mg/kg/day (limit dose) for 28 days was evaluated. Both acute and subchronic exposures showed no change in the ratio of polychromatic to total erythrocytes (P/E) at any dose, nor was there any increase in the incidence of micronucleated polychromatic erythrocytes (MN-PCE). Potential mutagenicity of acetamide was evaluated in male rats gavaged with vehicle control or 1500 mg/kg/day acetamide using the in vivoPig-a gene mutation assay. There was no increase in mutant red blood cells or reticulocytes in acetamide-treated animals. In both acute and sub-chronic studies, elevated blood plasma acetamide in treated animals provided evidence of systemic exposure. We conclude based on this study that acetamide is not clastogenic, aneugenic, or mutagenic in vivo in rodent hematopoietic tissue warranting a formal regulatory re-evaluation.

SUBMITTER: Moore MM

PROVIDER: S-EPMC6876283 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acetamide (CAS 60-35-5) is detected in common foods including milk, eggs, beef, and roasted coffee beans. Chronic rodent bioassays using high doses (≥1000 mg/kg/day) suggest acetamide is a group 2B possible human carcinogen due to the induction of liver tumors. Weight-of-evidence indicates acetamide is not genotoxic, and therefore a threshold response is expected. We used a toxicogenomics approach in Wistar rats gavaged daily for 7 and 28 days to determine the benchmark dose (BMD), and investigate its mode of action from differential gene expression. Two exposure experiements were carried out in succsession. An initial dose range finding experiment used male Wistar rats gavaged daily for 7 days at 0, 30, 100, 300 and 1000 mg/kd/day. A second experiment used both male and female Wistar rats exposed for 7 and 28 days to 0, 300,500,750,1000 and 1500 mg/kg/day. No treatment related changes in terminal body weight, clinical chemistry, or histopathology were observed at doses of 30, 100, or 300 mkd. At 1000 mkd, the dose reported to elicit carcinogenesis, liver weights decreased 1.3-fold with the presence of single cell necrosis, hepatocyte vacuolization, and increased mitotic activity consistent with a 4.2 fold increase in the cell proliferation index. Accordingly, plasma ALT and AST were increased 2.0- and 2.2-fold, respectively. RNA-Seq analysis identified 1 differentially expressed gene at 300 mkd, and 2,685 at 1000 mkd (|fold-change| ≥ 1.5 and FDR ≤ 0.05). Down-regulated genes were associated with lipid metabolism while up-regulated genes included cell signaling, immune response, and cell cycle functions. Collectively, these results revealed a no-observable adverse effect level (NOAEL) and no-observed-transcriptional effect level (NOTEL) at 300 mkd, warranting further investigation at doses between 300 and 1000 mkd to identify the benchmark dose (BMD). Functional enrichment indicates perturbation of cell cycle and lipid metabolism, though a more refined dose-response evaluation will be needed to demonstrate dose-dependent effects related to the MOA of acetamide. Funding by the Bill and Melinda Gates Foundation (OPP1142801).

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The food contaminant acetamide is not an in vivo clastogen, aneugen, or mutagen in rodent hematopoietic tissue.

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