Organ-specific carcinogenic risk heterogeneity of perfluorooctanoic acid exposure: Global evidence from bibliometric mapping, meta-analysis, and nonlinear dose-response modeling

To address the long-standing inconsistency in Perfluorooctanoic Acid (PFOA)-related carcinogenic evidence, a stepwise analytical framework was developed that integrated CiteSpace-based global hotspot mapping, organ-specific meta-analysis, and nonlinear restricted cubic spline (RCS) dose-response modeling to move from research landscape identification to quantitative heterogeneity synthesis and internal dose-based risk estimation. Bibliometric results revealed a recent frontier shift from organ-specific cancer risks toward serum PFOA biomonitoring, mixed exposure assessment, and endocrine-disruptive mechanisms, providing the conceptual basis for organ-oriented evaluation. Meta-analysis of 34 datasets across the four organ-specific cancers most associated with PFOA exposure demonstrated a heterogeneous and divergent risk profile, with modest yet measurable cumulative elevations in cancer risk of kidney (odds ratio (OR) = 1.27; 95% confidence interval (CI), 1.01-1.59; P = 0.04), borderline statistical significance in breast cancer risk (OR = 1.13; 95% CI: 1.00-1.27; p = 0.04), while liver cancers (OR = 1.02; 95% CI: 0.95-1.09; p = 0.64) and thyroid cancers (OR = 0.90; 95% CI: 0.76-1.05; p = 0.19) were statistically non-significant. The dose-response risk estimation with the RCS model further uncovered distinct nonlinear carcinogenic architectures, as characterized by Odds Ratios varying with serum/plasma PFOA concentration, including cumulative amplification in kidney, borderline statistical accumulation in breast cancers, and adaptive, non-monotonic modulation in liver and thyroid cancers. These findings highlighted organ-specific susceptibility rather than uniform carcinogenicity and advance a biomarker-driven, nonlinear, and prediction-oriented paradigm for global environmental carcinogenic risk assessment, providing mechanistically informed evidence to refine PFAS regulatory prioritization and precision public health decision-making.