Introduction
Cumene is a natural component of petroleum and is found in gasoline and petroleum-based solvents and is used in gasoline blending, diesel fuel, and high-octane motor fuels, particularly as an aviation fuel. It is a high-production chemical with 98% of it used in the production of acetone and phenol. People are primarily exposed to cumene from the environment by breathing in cumene in industrial and urban areas. They can also be exposed to cumene in workplaces that use or produce cumene, from gasoline transport-related jobs, and via cigarette smoke.
Methods
The National Toxicology Program (NTP) evaluated evidence for human exposure, cancer studies in experimental animals, mechanisms of carcinogenesis, and other relevant information; no epidemiological studies or case reports were identified that evaluated the relationship between human cancer and exposure specifically to cumene. Evidence was evaluated for study quality, integrated across studies, and assessed across each data stream (mechanistic and animal data). Using established criteria, NTP reached conclusions on the strength of evidence for the carcinogenicity of cumene from cancer studies in experimental animals and the final listing recommendation was reached by applying the Report on Carcinogens (RoC) listing criteria to the body of evidence.
Results and discussion
Cancer studies in experimental animals
NTP concluded that there was sufficient evidence of carcinogenicity in animals based on its review of carcinogenicity studies in rodents. Inhalation exposure of mice of both sexes caused lung tumors (alveolar/bronchiolar adenoma, carcinoma, and adenoma and carcinoma combined). In female mice, cumene also caused dose-related increases in the incidence of liver tumors (hepatocellular adenoma or combined with carcinoma). In rats of both sexes, there was an increase in benign nasal tumors (adenoma of the respiratory epithelium); however, this type of tumor does not usually progress to malignancy. In male rats, cumene also increased the incidence of kidney tumors (renal tubule adenoma and carcinoma). Human relevance of male rat kidney tumors is uncertain, as α2u-globulin nephropathy is a mechanism considered not relevant to humans; however, additional mechanisms have not been ruled out.
Mechanistic data
Although the specific mechanism by which cumene causes cancer is not known, several potential modes of action have been identified suggesting the relevance of the findings in experimental animals to humans. Both humans and animals metabolize cumene through similar pathways. Cumene exposure has caused DNA damage in the livers of male rats and lungs of female mice. In addition, molecular alterations in mouse lung tumors resemble molecular alterations found in human lung cancers. A metabolite of cumene, α-methylstyrene, caused mutations in bacteria and caused liver tumors in mice and rats. Other evidence has shown that cumene can cause cell proliferation and epigenetic effects.
Human cancer studies
No epidemiological studies or case reports were identified that evaluated the relationship between human cancer and exposure specifically to cumene.
NTP cancer hazard conclusion
The conclusion of the cancer hazard evaluation was that cumene should be listed as reasonably anticipated to be a human carcinogen in the RoC. The Secretary of Health and Human Services approved the listing of cumene in the 14th RoC. The rationale for the listing was sufficient evidence from studies in experimental animals.
National Toxicology Program (NTP). 2013. Report on Carcinogens monograph on cumene. Research Triangle Park, NC: National Toxicology Program. RoC Monograph 02. https://doi.org/10.22427/ROC-MGRAPH-02