Limiting to directly measured exposures, incorporating the full NHANES design in the primary regression, and triangulating across complementary mixture frameworks provide a more rigorous platform than prior single-pollutant or design-naive approaches.
Abstract
Human per- and polyfluoroalkyl substances (PFAS) and metal exposures occur as mixtures, but most studies evaluate them independently. Using data from adults in the 2017–2018 National Health and Nutrition Examination Survey (NHANES) with directly measured PFAS and blood metals (N = 1648), we assessed joint associations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), lead, cadmium, and mercury with prevalent diabetes via survey-weighted logistic regression, Weighted Quantile Sum (WQS) regression, quantile g-computation, and design-aware and naïve Bayesian Kernel Machine Regression (BKMR). Survey-weighted diabetes prevalence was 11.4%. Lead and PFOS emerged as the dominant contributors to the exposure mixture in the BKMR model, with posterior inclusion probabilities of 1.00 and 0.997, respectively. In the WQS model, PFOS and PFOA were the primary drivers of the positive mixture index, consistent with their proposed roles in endocrine disruption and insulin resistance. BKMR exposure-response functions were non-monotonic, indicating that lead and cadmium associations with diabetes are nonlinear rather than uniformly directional across the exposure range, a structure that conventional logistic regression cannot capture. Overall, restricting to directly measured exposures, incorporating the full NHANES design in the primary regression, and triangulating across complementary mixture frameworks provide a more rigorous platform than prior single-pollutant or design-naive approaches.
Environmental pollutants have been implicated in colorectal cancer risk, but the association between plasma per- and polyfluoroalkyl substance (PFAS) concentrations and TNM stage remains unclear. We recruited 110 patients with colorectal cancer in Beijing, China, between March and June 2024. Plasma concentrations of 32 PFAS were measured, and 23 PFAS with detection rates greater than 70% were included in the analysis. Random forest analysis was used to identify the highest-ranking PFAS for TNM-stage classification, followed by multivariable ordinal logistic regression and restricted cubic spline models to evaluate single-PFAS associations and concentration–response patterns. Bayesian kernel machine regression was further applied to assess the joint associations of the selected PFAS mixture, and stratified analyses were conducted by sex and age. PFOA and n-PFOS showed the highest median concentrations, at 2.899 ng/mL and 2.444 ng/mL, respectively. Random forest analysis identified PFPeS, PFTrDA, PFTeDA, HFPO-DA and 8:2 Cl-PFESA as five highest-ranking PFAS for TNM-stage classification. In single-pollutant models, HFPO-DA was positively associated with more advanced TNM stage (odds ratio 2.76, 95% confidence interval 1.39–5.46; P = 0.004), with a linear concentration–response association suggested by restricted cubic spline analysis (overall P = 0.012). Mixture analysis further indicated that higher combined PFAS concentrations were associated with more advanced TNM stage, with a more pronounced positive mixture–response pattern among female patients. These findings suggest that higher plasma PFAS concentrations, particularly HFPO-DA, may be associated with more advanced TNM stage in colorectal cancer and warrant confirmation in larger prospective studies.
Ning Kang, Yang Zhao, Zhi Huang et al.· Frontiers in Toxicology· 1 citation
The impact of per- and polyfluoroalkyl substances (PFAS) on hyperlipidemia and the potential modifying role of overall lifestyle remain underexplored. We examined six serum PFAS and a composite lifestyle score among 192 propensity score-matched case-control pairs. Individual and joint associations were evaluated using conditional logistic regression, quantile g-computation, and Bayesian kernel machine regression. A composite healthy lifestyle score was constructed based on smoking, alcohol drinking, physical activity, body shape, and diet. Per interquartile range (IQR) increase in ln-transformed concentrations, perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), and perfluoroundecanoic acid (PFUnDA) were associated with 89%, 110%, 67%, 49%, and 42% higher odds of hyperlipidemia, respectively. Mixture analyses revealed a joint positive association (OR = 1.57; 95% CI: 1.22, 2.02), driven predominantly by PFNA, the emerging alternative 6:2 Cl-PFESA, and PFHxS. Among participants with an unhealthy lifestyle (defined as a composite score ≤2 based on the population median), higher levels of PFOA, PFHxS, and PFNA were associated with significantly elevated odds of hyperlipidemia. However, for 6:2 Cl-PFESA, perfluorodecanoic acid (PFDA), and PFUnDA, these associations were generally weaker in participants adhering to a relatively healthy lifestyle, as supported by significant multiplicative interactions. Negative additive interactions were also observed for 6:2 Cl-PFESA and PFNA. Our findings demonstrate that adherence to a healthy lifestyle was associated with substantially weaker associations between 6:2 Cl-PFESA and PFDA exposures and hyperlipidemia, highlighting lifestyle modification may serve as a potential public health strategy to reduce environmental metabolic hazards.
Peiwen Li, Lianlong Yu, Xiao Zhang et al.· International Journal of Hyg...· 0 citations
Relatively few epidemiologic studies in the US have measured the short-chain replacement per- or polyfluoroalkyl substance (PFAS) perfluorobutanesulfonic acid (PFBS), and little is known about its health impacts. We measured prenatal serum concentrations of 13 PFAS, including PFBS, among 500 participants in the New York University Children’s Health and Environment Study (NYU CHES) between 2016 and 2019. We investigated associations of PFAS exposures with demographic characteristics, including location of residence, and conducted an exploratory factor analysis to investigate common sources of exposure. PFBS concentrations were quantified in 95.6% of samples (median 0.40 ng/mL), which was unexpectedly higher than serum PFBS concentrations reported in other US-based cohorts. PFBS concentrations were not correlated with other PFAS, though they were positively correlated with each other. Unlike other PFAS, PFBS concentrations were not associated with participant characteristics, and there was no evidence for spatial autocorrelation. The changing PFAS exposure landscape warrants further investigation into the health effects of short-chain replacements, particularly in vulnerable populations.
Eleanor A. Medley, Duong Q. Nguyen, A. Nigra et al.· Environmental Research· 0 citations
Exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to renal impairment, but evidence on mixed PFAS exposure in the general Chinese population and the underlying mechanisms remains limited. This study therefore investigated the associations between PFAS exposure and renal function and evaluated the potential mediating role of blood lipids. Serum levels of legacy and emerging PFAS, renal function parameters, and blood lipid profiles were measured in 1,370 adult residents from Zhejiang Province, China; additionally, 452 lipid metabolites were quantified in a subset of 316 participants. Using multiple linear regression, restricted cubic splines (RCS), and mixture exposure models, we found that PFAS mixture exposure was associated with reduced renal function, with eGFR decreases ranging from 2.2% to 2.9% per quartile increase across models, and PFOA as a predominant contributor. Mediation analyses further revealed that elevated total cholesterol, low-density lipoprotein cholesterol, and disturbances in fatty acids and phospholipids mediated 6.3% to 65.9% of the association between PFAS exposure and renal function decline. Collectively, these findings suggest that mixed PFAS exposure, particularly to PFOA and PFHpA, may induce impaired renal function, with increased blood lipids playing an important mediating role.
Dandan Xu, Z. Mo, Jie Xiang et al.· Environmental Pollution· 0 citations
BACKGROUND
The association between organochlorine pesticides (OCPs)/synthetic pyrethroids (SPs) and thyroid cancer (TC) remains poorly understood, with metabolic mechanisms unexplored.
METHODS
We conducted a 1:1 age- and sex-matched case-control study (n = 668). Serum levels of 27 target analytes (19 OCPs and 8 SPs) were quantified; subsequent analyses were restricted to 13 compounds (10 OCPs and 3 SPs) with detection frequencies ≥85%. Eight machine learning (ML) algorithms with Shapley Additive Explanations (SHAP) were used to identify key pollutants in the 334 case-control pairs. Untargeted metabolomics was performed in a subset of 50 age- and sex-matched case-control pairs. Mixture effects were assessed by Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regression. Furthermore, the Latent Unknown Clustering Integrating Multi-Omics Data (LUCID) model was employed to integrate exposure and metabolic data, enabling the identification of TC patient subgroups and the exploration of underlying metabolic mechanisms.
RESULTS
Participants (mean age 45.2 years, 82.3% female) had serum OCPs at 0.007-0.333 ng/mL and SPs at 0.046-0.095 ng/mL. ML algorithms identified fenpropathrin, β-BHC, cyhalothrin, α-BHC, and p,p'-DDD as the top five contributors to TC. Elevated OCPs/SPs exposure was significantly associated with increased TC risk (WQS: adjusted OR = 1.45, 95%CI = 1.34-2.24, P = 0.019; LUCID: OR = 9.33). Fenpropathrin was the primary contributor (BKMR posterior inclusion probability = 1.00; WQS weight = 67.6%). A total of 45 significant differential metabolites (DMs) were identified (VIP ≥1, P < 0.05, and qualitative level 1). LUCID revealed a distinct TC cluster characterized by upregulated S-sulfo-L-cysteine/adenosine and downregulated 2-hydroxycaprylic acid.
CONCLUSION
OCPs/SPs mixtures, driven by fenpropathrin, disrupt amino acid/nucleotide metabolism while suppressing organic acid metabolism, representing a potential TC-associated metabolic signature.
Fei Wang, Chunxiang Li, Linfang Zou et al.· Environment International· 0 citations
OBJECTIVE
This study aimed to examine the associations between heavy metal exposures and the prevalence of chronic obstructive pulmonary disease (COPD), identify the principal toxicant, and elucidate the molecular mechanisms underlying its pathogenic effects.
METHODS
We analyzed 3380 adults from three National Health and Nutrition Examination Survey (NHANES) cycles. Logistic regression, Bayesian Kernel Machine Regression (BKMR), and Quantile-based G-computation (qgcomp) were applied to evaluate individual and joint associations between urinary concentrations of ten heavy metals (arsenic [As], cadmium [Cd], lead [Pb], cobalt [Co], barium [Ba], cesium [Cs], molybdenum [Mo], antimony [Sb], thallium [Tl], and tungsten [W]) and COPD risk. Network pharmacology and molecular docking were used to identify Cd-related molecular targets and pathways, which were validated by immunofluorescence, and western blotting in a Cd-exposed mouse model.
RESULTS
Among 3380 participants (mean age: 46.0 years), 456 (13.5%) had COPD. Cd exposure was significantly associated with increased COPD risk (OR=1.79, 95% CI: 1.51-2.13) and was identified as the predominant contributor. The hub proteins exhibited strong binding affinities to Nuclear Factor κ-Light-Chain Enhancer of Activated B Cells 1 (NFKB1; NF-κB p50) and Hypoxia-Inducible Factor 1 alpha (HIF1A), implicating oxidative stress, inflammation, and cell survival pathways. In vivo, Cd inhalation induced emphysematous and fibrotic changes, elevated matrix metalloproteinase (MMP) expression, and NF-κB activation in mice, consistent with silico predictions.
CONCLUSION
Cd exposure was identified as the predominant heavy metal associated with increased odds of COPD. Integrative epidemiological, mechanistic, and experimental evidence implicates Cd-induced oxidative stress, inflammation, and tissue remodeling as key pathogenic processes.
Yincong Xue, Gen Chen, Wanying Chen et al.· Ecotoxicology and Environmen...· 0 citations