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Background: Per- and polyfluoroalkyl substances (PFASs) are emerging environmental contaminants with multiple hazardous properties including immunomodulation potency. Human exposure to PFASs has been associated with various immune-mediated diseases and outcomes. This study aimed to investigate the association between PFAS exposure and immune-mediated diseases such as allergies, eczemas, and autoimmune diseases in a population of adults in the Czech Republic., Methods: This study included 309 adults from the Central European Longitudinal Study of Parents and Children: Young Adults (CELSPAC: YA). 12 PFASs were measured in participants' serum by HPLC-MS/MS, 3 PFASs were removed from the subsequent analyses due to low detection frequency. The associations of 9 PFASs with 9 immune-mediated diseases were assessed by logistic regression. Furthermore, Bayesian kernel machine regression (BKMR) was used to estimate the effect of the PFAS mixture on immune-mediated diseases. All analyses were adjusted for sex, age, BMI, smoking, education, and family history of immune-mediated diseases. In cases of a statistically significant interaction of PFASs and sex, stratified analyses were performed for men and women., Results: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) were negatively associated with both atopic eczema (OR per IQR increase 0.58 (95% CI 0.37-0.90) for PFOA and 0.56 (0.32-0.95) for PFOS) and contact dermatitis (0.37 (0.16-0.85) for PFOA and 0.33 (0.11-0.94) for PFOS). Perfluoroundecanoate (PFUnDA) was negatively associated with pollen, dust, and mite allergy (0.62 (0.43-0.89)). BKMR modelling showed a negative tendency in the overall effect of PFAS mixture on immune-health outcomes. Based on the stratified analysis, sex was suggested to be an effect modifier in the association of PFOS and atopic eczema., Conclusion: Our results contribute to the body of literature that observes the immunosuppressive effect of PFAS exposure during eczemas and allergies, both for PFASs individually and as a mixture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)