Associations Between Human Exposure to Substituted p-Phenylenediamine-Derived Quinones and Colorectal Cancer Risk

Substituted p-phenylenediamine-derived quinones (PPD-Qs) have become ubiquitous contaminants in various environmental matrices. However, the understanding of the potential health risks posed by human exposure to these emerging compounds remains limited. In this case-control study, we investigated the association between urinary concentrations of six PPD-Q congeners and colorectal cancer (CRC) risk. Detection frequencies of all target PPD-Qs in human urine ranged from 73.7% to 88.2% in the control group and from 70.2% to 89.6% in the case group. 6PPD-Q (2-((4-methylpentan-2-yl)amino)-5-(phenylamino)cyclohexa-2,5-diene-1,4-dione; mean 1.37 μg/g creatinine), 77PD-Q (2,5-bis((5-methylhexan-2-yl)amino)cyclohexa-2,5-diene-1,4-dione; 0.68 μg/g creatinine), and IPPD-Q (2-(isopropylamino)-5-(phenylamino)cyclohexa-2,5-diene-1,4-dione; 0.70 μg/g creatinine) were the predominant PPD-Qs in urine from healthy controls. In CRC cases, 6PPD-Q had the highest mean urinary level (mean 1.75 μg/g creatinine), followed by DPPD-Q (2,5-bis(phenylamino)cyclohexa-2,5-diene-1,4-dione; 0.83 μg/g creatinine) and IPPD-Q (0.73 μg/g creatinine). After multivariable adjustment, higher urinary levels of 6PPD-Q (OR for Q4 vs. Q1 = 1.79, 95% CI: 1.26-2.32), CPPD-Q (2-(cyclohexylamino)-5-(phenylamino)cyclohexa-2,5-diene-1,4-dione; OR = 1.60, 95% CI: 1.26-1.94), and DPPD-Q (OR = 1.47, 95% CI: 1.25-1.68) were significantly associated with increased CRC odds, with nonlinear exposure-response patterns observed. Mixture analysis suggested a positive joint association between urinary PPD-Q concentrations and the odds of CRC, with 6PPD-Q and DPPD-Q contributing most strongly to the estimated statistical association. These findings highlight the need for further prospective studies and potential regulatory considerations to mitigate public health impacts from these contaminants.