New publication investigating mode of action for high-dose effects of 4-methylimidazole

September 14, 2021

by Patrick McMullen

We are pleased to announce our most recent manuscript, A systematic approach to evaluate plausible modes of actions for mouse lung tumors in mice exposed to 4-methylimidazole, published in Regulatory Toxicology and Pharmacology. 4-methylimidazole is a ubiquitous compound present in foods that undergo thermal browning (i.e., Maillard reaction) processes. The work described here—a combined effort of investigators from ScitoVation and ToxStrategies supported by the American Beverage Association—aimed to develop a better understanding of how effects observed in rodents exposed to 4-methylimidozole might translate to people. 

Toxicology studies performed in rodents often feature compound exposures that are substantially higher than would be experienced by a human. There are several reasons for this approach to experimental design. Most significantly, constraints on the size of treatment groups (due to practical and animal welfare considerations) mean that a large effect size is required to acheive statistically meaningful results. However, this high-dose design raises several challenges for the interpretation of the results. In some cases, it is unclear how to extrapolate risk—from a quantitative perspective—from extremely high doses to a dose that would be relevant to human exposure. Additionally, the cause of toxicity in high dose animal studies may not be relevant at lower concentrations that humans might experience. For example, high concentrations in tissues in animal studies often saturate metabolism, leading to secondary effects on the processing of food and normal chemicals within the body that are not relevant for estimating human risk because they are unlikely to occur.  

A study performed by the National Toxicology Program found tumors in the lungs of mice exposed to a 4-methylimidazole concentration 170,000 times higher than the No Significant Risk Level set by California EPA. Our paper investigates what chemical-biological mechanisms might be driving the tumor formation in rodents. Understanding the mechanism behind the tumors is critical for interpreting potential impacts on humans. Central to the work is a review integrating existing studies into a framework known as the Key Characteristics of Carcinogens. By exploring what published evidence says about each characteristic, we were able to determine that genotoxic and cytotoxic mechanisms are unlikely to play a role. 

One of ScitoVation’s key contributions to the work was an investigation of the gene expression changes caused by 4-methylimidazole. Toxicogenomics—measurement of transcriptional changes in response to chemical exposure—is an invaluable tool for determining compound mode of action. Here, we compared the effects of 4-methylimidazole in mice to the effects of other compounds that cause liver tumors. The results indicated that the liver tumors were unlikely to form by a genotoxic mechanism. Toxicogenomics can be used in this way as a basis of identifying or narrowing possible modes of action.