Associations of human exposure to 6PPD and 6PPDQ with colorectal cancer: A mixture analysis

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its oxidation product, 6PPD-quinone (6PPDQ), are widely present in the environment. Toxicological studies have demonstrated that they can induce adverse health effects on the intestinal system. However, epidemiological studies examining the association between human 6PPD and 6PPDQ exposure and colorectal cancer (CRC) risk remain scarce. In this study, human urinary 6PPD and 6PPDQ concentrations were analyzed in 329 controls and 367 CRC cases from Quzhou, China. A combination of analyses, including unconditional logistic regression, Bayesian kernel machine regression (BKMR), and restricted cubic spline analysis, was employed to evaluate associations between urinary 6PPD and 6PPDQ levels and CRC risk, adjusting for demographic and lifestyle variables. The median concentration of 6PPDQ in CRC cases (0.94 vs 0.14 μg/g creatinine) was significantly higher than that in controls (Mann-Whitney U test, p = 0.001), while the median concentration of 6PPD showed no significant (p = 0.061) difference between the two groups (0.31 vs 0.38 μg/g creatinine). Higher urinary 6PPDQ concentrations were significantly associated with increased CRC risk, especially among participants with third (adjusted OR = 2.79, 95 % CI: 1.76-4.47; p for trend <0.001) and fourth (adjusted OR = 7.13, 95 % CI: 4.31-12.0; p for trend <0.001) quartiles of exposure. Additionally, the joint effects of 6PPD and 6PPDQ exposure, assessed using the BKMR model, indicated a positive association with CRC risk, suggesting a cumulative risk from co-exposure. This study provides the first epidemiological evidence linking human 6PPDQ exposure to CRC risk, highlighting its potential role in colorectal carcinogenesis.