Human Exposure to Tire-Derived p-Phenylenediamines and 6PPD-Quinone: Associations with Thyroid Nodules and Mechanistic Insights.

N-Substituted p-phenylenediamines (PPDs), widely used as antioxidants in rubber products, and their transformation product 6PPD-quinone (6PPD-Q) have recently emerged as contaminants of increasing environmental and health concern. However, human biomonitoring data and associated health implications remain limited. In this study, urinary concentrations of six PPDs and 6PPD-Q were quantified in 368 individuals from South China, including patients with thyroid nodules (TNs, n = 120) and controls (n = 248). PPDs were widely detected, with detection frequencies ranging from 40% to 89%, indicating ubiquitous exposure. Epidemiological analyses revealed that 6PPD-Q was significantly associated with TN prevalence, exhibiting a monotonic exposure-response relationship with adjusted odds ratios exceeding 2 across exposure quartiles. In contrast, 6PPD showed a non-monotonic association. Mixture models did not identify a significant overall effect but consistently highlighted 6PPD-Q and 6PPD as primary contributors. To provide mechanistic context, network toxicology and molecular docking analyses were conducted. The results indicated that 6PPD and 6PPD-Q may interact with key pathways related to cell proliferation, inflammation, endocrine regulation, and oxidative stress. Notably, 6PPD-Q showed stronger enrichment in endocrine and oxidative stress pathways, consistent with its epidemiological association. Overall, these findings suggest that exposure to tire-derived antioxidants, particularly 6PPD-Q, may be associated with thyroid-related outcomes and highlight the importance of considering transformation products in risk assessment.