Higher serum PFDA is associated with increased non-melanoma skin cancer odds in NHANES 2003-2018

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals commonly employed in heat- and water-resistant applications. Experimental evidence indicates a biological plausibility for PFAS-related carcinogenic effects through mechanisms such as oxidative stress and immunomodulation; however, epidemiological evidence regarding skin cancers remains limited. This study aimed to investigate the association between serum concentrations of three understudied PFAS-perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), and 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (2-(N-methyl-PFOSA) acetate)-and the incidence of non-melanoma skin cancer (NMSC) and melanoma among U.S. adults. We conducted a cross-sectional analysis utilizing data from eight NHANES cycles (2003-2018), which included 5,934 adults aged 20 years and older with complete data. Skin cancer outcomes were determined based on self-reported physician diagnoses, while PFAS concentrations were assessed in serum samples. We employed multivariable logistic regression, adjusting for age, sex, race/ethnicity, body mass index, smoking status, and NHANES cycle. PFAS exposure was evaluated using tertiles, detectable/undetectable status, and log-transformed continuous measures. Additionally, exploratory age- and sex-stratified analyses were conducted using Firth penalized logistic regression, and multiple imputation was applied to address potential selection bias due to missing covariates. Compared to the lowest tertile, PFDA in the second tertile was associated with an increased likelihood of NMSC (adjusted odds ratio [aOR] 1.73, 95% uncertainty interval [UI] 1.01-2.89; p=0.048), although no clear dose-response trend was observed across tertiles. Among adults aged 60 years and older, PFDA in the second tertile was linked to higher odds of NMSC (aOR 2.29, 95% UI 1.29-4.05; p=0.004). Associations for PFUnDA and 2-(N-methyl-PFOSA) acetate were generally inconsistent across exposure metrics, and analyses for melanoma did not reveal a definitive association. These findings suggest a potential link between higher PFDA exposure and NMSC, particularly in older adults, underscoring the necessity for ongoing PFAS monitoring and well-designed prospective studies to elucidate the temporal relationship and causality.