Inverse association of legacy PFAS mixture exposure with neutrophil-to-lymphocyte ratio in United States adults: A survey-weighted analysis of the national health and nutrition examination survey (NHANES) 2005-2018

Abstract

Abstract Background & Objective Per- and polyfluoroalkyl substances (PFAS) may alter immune function. We tested whether serum levels of a legacy PFAS mixture are associated with the neutrophil-to-lymphocyte ratio (NLR)—a widely used inflammation and prognostic marker in hematology—in a nationally representative U.S. sample. Methods Seven NHANES waves (2005–2018) were combined, yielding 8,209 adults (≥20 years) with complete PFAS data. Molar concentrations of PFOA, PFOS, PFHxS, and PFNA were summed and log-transformed (ln ΣPFAS). Survey-weighted linear regression adjusted for age, sex, race/ethnicity, BMI, serum cotinine, eGFR, CRP, and survey wave. Missing covariates were multiply imputed (m=5), and estimates pooled with Rubin's rules. Results Each 1-unit increase in ln ΣPFAS was associated with a 0.078-unit decrease in ln NLR (β=−0.078, SE=0.010; 95% CI −0.098 to −0.057; p<0.001). ln NLR increased with age, BMI, and cotinine, and was lower in women and at higher eGFR; race/ethnicity contrasts were inconsistent, and survey-wave coefficients were near null. Imputation diagnostics showed <2% fractions of missing information. Clinically, a doubling of ΣPFAS corresponded to ~5.3% lower NLR (≈3.8–6.6% lower). Conclusions Higher serum legacy PFAS levels are associated with lower NLR. Because NLR informs risk stratification and outcome studies in hematologic disorders, environmental PFAS exposure may systematically depress NLR, with implications for study design, confounding control, and clinical interpretation. Prospective and mechanistic work should assess causality and pathways.