Toxicity and carcinogenicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice

Toxicology Operation Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Archive für Toxikologie (Impact Factor: 5.98). 02/2008; 82(1):45-53. DOI: 10.1007/s00204-007-0222-5
Source: PubMed


4-Methylimidazole (4MI) is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation in foods and has been detected in mainstream and side stream tobacco smoke. 4MI was studied because of its high potential for human exposure. Groups of 50 male and 50 female F344/N rats were fed diets containing 0-, 625-, 1,250-, or 2,500 ppm 4MI (males) or 0-, 1,250-, 2,500-, or 5,000 ppm 4MI (females) for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 30, 55, or 115 mg 4MI/kg body weight to males and 60, 120, or 250 mg 4MI/kg to females. Survival of all exposed groups of males and females was similar to that of the control groups. The mean body weights of males in the 1,250- and 2,500 ppm groups and females in the 2,500- and 5,000 ppm groups were less than those of the control groups throughout the study. Feed consumption by 5,000 ppm females was less than that by the controls. Clonic seizures, excitability, hyperactivity, and impaired gait were observed primarily in 2,500- and 5,000 ppm females. The incidence of mononuclear cell leukemia in the 5,000 ppm females was significantly greater than that in the controls. The incidences of hepatic histiocytosis, chronic inflammation, and focal fatty change were significantly increased in all exposed groups of male and female rats. The incidences of hepatocellular eosinophilic and mixed cell foci were significantly increased in 2,500 ppm males and 5,000 ppm females. Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 0-, 312-, 625-, or 1,250 ppm 4MI for 106 weeks. Based on the food consumption the calculated average daily doses were approximately 40, 80, or 170 mg 4MI/kg body weight to males and females. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of males and females in the 1,250 ppm groups and that in the 312- and 625 ppm females were less than those of the control groups. Feed consumption by exposed groups of male and female mice was similar to that by the controls. The incidences of alveolar/bronchiolar adenoma in all exposed groups of females, alveolar/bronchiolar carcinoma in 1,250 ppm males, and alveolar/bronchiolar adenoma or carcinoma (combined) in 1,250 ppm males and 625- and 1,250 ppm females were significantly greater than those in the control groups. The incidence of alveolar epithelial hyperplasia was significantly increased in the 1,250 ppm females. 4MI is carcinogenic inducing alveolar/bronchiolar adenoma and carcinoma in male and female mice. 4MI may also induce mononuclear cell leukemia in female rats.

1 Follower
29 Reads
  • Source
    • "4MI is produced by the interaction of ammonia with reducing sugars and, commercially formed by the cyclocondensation of aldehyde and ammonia with methylglyoxal (Perdok and Leng 1987). This compound may be utilized as chemical intermediate, starting material, or component in the manufacture of pharmaceuticals, photographic and photothermographic chemicals, dyes and pigments, agricultural chemicals, and finally in the manufacture of rubber (Chan et al. 2008). 4MI has also been used as a starting material in the synthesis of epoxy resins, anticholesteremics , disinfectants, antiprotozoal antiseptic agents, caramel coloring, soy sauce, wine, ammoniated molasses, and caramel-colored syrups (Wong and Bernhard 1988). "
    [Show abstract] [Hide abstract]
    ABSTRACT: 4-methylimidazole (4MI) is a compound widely used in various industrial and consumer applications. The most important sources of exposure include chemical caramel coloring, ammoniated molasses, dyes and pigments, rube, cleaning and agricultural chemicals. Toxicity attributed to 4MI in foods has recently become a focus of research. Recent studies showed that 4MI induced adverse changes in various target tissues. Brain is known to be a target organ for 4MI-induced toxicity but its cytotoxic mechanisms have not yet been elucidated. In this study, experiments were divided into two parts: (1) using in vivo methodology, doses of 4MI at 100, 200, or 300 mg/kg were administered orally to mice daily for 14 to obtain brain mitochondria; and (2) utilizing in vitro methodology, brain mitochondria were incubated with 4MI at 400, 800, or 1600 μM concentrations. Subsequently, the neurotoxicity of 4MI was assessed using mitochondrial dysfunction tests, including reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and cytochrome c release. Our results from both in vivo and in vitro experiments on isolated brain mitochondria showed a significant decrease in complex II activity and also marked elevation in the ROS formation, MMP collapse, mitochondrial swelling, and enhanced release of cytochrome c. Data indicated that 4MI induced neurotoxicity through the impairment of electron transfer chain especially at complex II and elevated ROS formation leading to subsequent oxidative stress events including mitochondrial membrane depolarization, mitochondrial swelling, and release of cytochrome c, which is the starting point of mitochondrial-mediated apoptosis signaling and neurodegeneration.
    Toxicological and Environmental Chemistry 05/2015; 97(5). DOI:10.1080/02772248.2015.1058054 · 0.83 Impact Factor
  • Source
    • "4(5)-methylimidazole (4-MI) and 2-acethyl-4(5)-tetrahydroxybuthylimidazole (THI), unwanted byproducts, were reported to be toxic with adverse effects on the immune system. 4-MI was considered a carcinogenic substance in animal experiments (2) and classified with the group 2B substances that are possible carcinogens to human (3). California’s Office of Environmental Health hazard Assessment (OEHHA) in USA registered 4-MI as a carcinogen with no significant risk level (NSRL) when ingesting 16 μg/day (4). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, the quick HPLC-MS/MS method for the simultaneous separation of 2-acetyl-4(5)-tetrahydrox-ybuthylimidazole (THI) and 4-(5)-methylimidazole (4-MI) in alkaline medium was used for caramel color and processed foods in Korea. After a simple sample pretreatment, 51 4-MI-labeled samples were positive for 4-MI and 2 also contained THI. The concentration of 4-MI was 260.5 ~ 24,499.3 μg/kg in caramel color, less than LOD ~ 1,712.5 μg/kg in sauce, 1,242.3, 5,972.2 μg/kg in balsamic vinegar, 2,118.3 ~ 5,802.4 μg/kg in complex seasoning, 82.7 ~ 5,110.6 μg/kg in curry, and 29.9 ~ 464.4 μg/kg in soft drinks. The recovery rate of 4-MI was 97.1 ~ 111.0% in sauce and 81.9 ~ 110.0% in powder and that of THI was 83.6 ~ 106.4% in sauce and 61.2 ~ 99.4% in powder. Our results concluded a safe amount of 4-MI and THI compared to the limit of Korea additive code but the processed foods do not have a limit of caramel color and 4-MI in Korea. Therefore, research and monitoring of 4-MI and THI is needed for processed foods in Korea.
    Preventive Nutrition and Food Science 12/2013; 18(4):263-8. DOI:10.3746/pnf.2013.18.4.263
  • Source
    • "The consumption of foods high in sugars and other harmful substances that cause serious adverse effects when consumed inappropriately is of great concern (LUDWIG; PETERSON; GORTMAKER, 2001). Studies have linked the consumption of sugar and sweetened soft drinks with the occurrence of nontransmissible chronic diseases such as obesity, diabetes, cancer, arthritis, dyslipidemia, and atherosclerosis (BERKEY et al., 2004; JAMES; KERR, 2005; CHOI; CURHAN, 2008). Soft drinks are industrialized, non-alcoholic, carbonated beverages, with added flavors and high refreshing power. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Due to the large consumption of soft drinks in Brazil and worldwide in recent years and considering that some of the components present in their composition pose potential risks to human health, the aim of this study was to evaluate the cytotoxic and mutagenic potential of specific cola and grape-flavored soft drink brands. Bone marrow cells of Wistar rats were initially treated by gavage with one single dose of Cola or Grape soft drink, which was next offered ad libitum (instead of water) for 24 hours. A negative control treatment was performed by administering one single dose of water and a positive control administering cyclophosphamide intraperitoneally. Statistical analysis showed that the Cola and Grape soft drinks studied were not cytotoxic. However, the Cola soft drink proved mutagenic in this experiment treatment time. Therefore, this study serves as a warning about the consumption of Cola-flavored soft drink and for the need for further subchronic and chronic studies on soft drinks in order to evaluate the long term mutagenic and cytotoxic effects of these substances.
    Ciência e Tecnologia de Alimentos 03/2013; 33(1):122-126. DOI:10.1590/S0101-20612013005000011 · 0.41 Impact Factor
Show more

Similar Publications

Preview (2 Sources)

29 Reads
Available from