California has recently made legislative changes that required Coke and Pepsi to affix cancer warning labels to their soda products. From the news story:

A representative for Coca-Cola, Diana Garza-Ciarlante, said the company directed its caramel suppliers to modify their manufacturing processes to reduce the levels of the chemical 4-methylimidazole, which can be formed during the cooking process and, as a result, may be found in trace amounts in many foods.

“While we believe that there is no public health risk that justifies any such change, we did ask our caramel suppliers to take this step so that our products would not be subject to the requirement of a scientifically unfounded warning,” Garza-Ciarlante said in an email.

No other states or countries such as Canada or the UK have mandated a similar warning. What, if any evidence led to California considering 4-methylimidazole used in the manufacture of sodas to have a risk of causing cancer?

The AP news story mentions studies done on rats, although I can't find anything on Google Scholar.

1 Answer 1


The toxicity and cancerogenicity of 4-methylimidazole (4MI) has been indeed studied in mice and rats.

There were species difference in the carcinogenicity of 4MI (not carcinogenic in rats, but carcinogenic in mice). However several other types of toxicity have been reported.

In January 2008, California's Office of Environment Health Hazard Assessment sent out a request for information about 4-MI. They included a report called "Package 32" which detailed one study.

In May 2009, they announced their intention to list 4-MI and included a newer report called "Package 32b"

Both versions of the report reference:

The NTP study reports that:

Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of 4-methylimidazole in male F344/N rats exposed to 625, 1,250, or 2,500 ppm.

There was equivocal evidence of carcinogenic activity of 4-methylimidazole in female F344/N rats based on increased incidences of mononuclear cell leukemia.

There was clear evidence of carcinogenic activity of 4-methylimidazole in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms.

Exposure to 4-methylimidazole resulted in nonneoplastic lesions in the liver of male and female rats and the lung of female mice and in clinical findings of neurotoxicity in female rats.

A study (from the same dataset?) by the same people is also published in Arch Toxicol.

Chan PC, Hill GD, Kissling GE, Nyska A., Toxicity and carcinogenicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice. - Arch Toxicol. 2008 Jan;82(1):45-53.

From the abstract (bold is mine):

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. 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.

They conclude that:

Under the condition of the present studies 4MI induced alveolar/bronchiolar adenoma and carcinoma in male and female mice. 4MI also induced clonic seizures and mononuclear cell leukemia in female rats, and hepatic histiocytosis, hepatocellular eosinophilic and mixed cell foci in male and female rats. The related compound methimazole was reported to induce toxic changes in the olfactory epithelium of rats and mice (Bergman and Brittebo 1999; Genter et al. 1995; Jeffry et al. 2006). The nasal cavities of mice and rats exposed to 4MI were checked histologically, but no changes were noted. No other treatment-related changes were noted in any of the organs examined.

Now, does that mean that Coke/Pepsi is toxic/carcinogenic? Unfortunately I could not find the concentration of 4MI in Coke/Pepsi, which prevents me to give an answer to the question. (Remember: Sola dosis facit venenum.) Furthermore no evidence of carcinogenesis/toxicity has been reported so far in humans. The NTP report clearly states that:

Extrapolation of these results to other species, including characterization of hazards and risks to humans, requires analyses beyond the intent of these reports. Selection per se is not an indicator of a substance’s carcinogenic potential.

PS: usually Pubmed gives better results than Google Scholar when looking for scientific studies.

  • Good answer. But the key issue is whether it is reasonable to extrapolate patchy animal studies to people when legislating about food labels.
    – matt_black
    Mar 15, 2012 at 11:34
  • @Oddthinking: thanks for the edit, I just changed the last link you added, because that page did not really explain the concept in a way I liked
    – nico
    Mar 15, 2012 at 18:02
  • 1
    @matt_black: since when "reasonable" is important when talking politics (just kidding)? Anyhow, I guess any answer to your question would be debatable. Many people would appeal to the precautionary principle for instance.
    – nico
    Mar 15, 2012 at 18:07
  • 1
    An FDA spokesman said a person would have to drink "well over a thousand cans of soda a day to reach the doses administered in the studies that have shown links to cancer in rodents".Reuters
    – Chad
    Mar 15, 2012 at 19:41
  • @nico The trouble with the precautionary principle is it would never allow anything new. It would have us abandon mobile phones because we can't prove beyond doubt they don't cause cancers. In reality everything is a balance between some cost and some benefit: the precautionary principle wants us to forget half the equation.
    – matt_black
    Mar 15, 2012 at 20:42

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