Two-Year Toxicity and Carcinogenicity Study of Methyleugenol in F344/N Rats and B6C3F1 Mice

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• 作者：Jerry D. Johnson ; Michael J. Ryan ; John D. Toft II ; Steven W. Graves ; Milton R. Hejtmancik ; Michael L. Cunningham ; Ron Herbert ; and Kamal M. Abdo
• 刊名：Journal of Agricultural and Food Chemistry
• 出版年：2000
• 出版时间：August 2000
• 年：2000
• 卷：48
• 期：8
• 页码：3620 - 3632
• 全文大小：156K
• 年卷期：v.48,no.8(August 2000)
• ISSN：1520-5118

文摘

Methyleugenol (MEG) was tested for toxicity/carcinogenicity in a 2-yr carcinogenesis bioassay becauseof its widespread use in a variety of foods, beverages, and cosmetics as well as its structuralresemblance to the known carcinogen safrole. F344/N rats and B6C3F₁ mice (50 animals/sex/dosegroup) were given MEG suspended in 0.5% methylcellulose by gavage at doses of 37, 75, or 150mg/kg/day for 2 yr. Control groups (60 rats/sex and 50 mice/sex) received only the vehicle. A stop-exposure group of 60 rats/sex received 300 mg/kg/day by gavage for 53 weeks followed by the vehicleonly for the remaining 52 weeks of the study. A special study group (10 animals/sex/species/dosegroup) were used for toxicokinetic studies. All male rats given 150 and 300 mg/kg/day died beforethe end of the study; survival of female rats given 150 mg/kg/day and all treated female mice wasdecreased. Mean body weights of treated male and female rats and mice were decreased whencompared to control. Area under the curve results indicated that greater than dose proportionalincreases in plasma MEG occurred for male 150 and 300 mg/kg/day group rats (6 and 12 month)and male 150 mg/kg/day mice (12 month). Target organs included the liver, glandular stomach,forestomach (female rats) and kidney, mammary gland, and subcutaneous tissue (male rats). Liverneoplasms occurred in all dose groups of rats and mice and included hepatoadenoma, hepatocarcinoma, hepatocholangioma (rats only), hepatocholangiocarcinoma, and hepatoblastoma (mice only).Nonneoplastic liver lesions included eosinophilic and mixed cell foci (rats only), hypertrophy, ovalcell hyperplasia, cystic degeneration (rats only), and bile duct hyperplasia. Mice also exhibitednecrosis, hematopoietic cell proliferation, and hemosiderin pigmentation. Glandular stomach lesionsin rats and mice included benign and malignant neuroendocrine tumors, neuroendocrine cellhyperplasia, and atrophy and in mice included glandular ectasia/chronic active inflammation. Infemale rats, the forestomach showed a positive trend in the incidences of squamous cell papillomaor carcinoma (combined). Male rats also exhibited kidney (renal tubule hyperplasia, nephropathy,and adenomacarcinoma), mammary gland (fibroadenoma), and subcutaneous tissue (fibroma,fibrosarcoma) lesions. Male rats also exhibited malignant mesotheliomas and splenic fibrosis. Thesedata demonstrate that MEG is a multisite, multispecies carcinogen.Keywords: Methyleugenol; toxicity; carcinogenicity; toxicokinetics; rats; mice